Neuropsychoanalysis, 2009, 11 (1)
7
Depression: An Evolutionarily Conserved Mechanism to Terminate
Separation Distress? A Review of Aminergic, Peptidergic, and Neural
Network Perspectives
Douglas F. Watt (Cambridge, MA) & Jaak Panksepp (Pullman, WA)
Our basic thesis is that depression is an evolutionarily conserved mechanism in mammalian brains, selected as a shutdown mechanism to terminate protracted separation distress (a prototype mammalian emotional state), which, if sustained, would be dangerous
for infant mammals. However, this fundamental shutdown mechanism remains available to more mature mammalian and hominid
brains, particularly those with certain polymorphisms in genetic endowment, early loss/separation trauma, or other predisposing
factors, which can promote reactivation in relationship to almost any chronic stressor. Such evolutionarily selected shutdown mechanisms could become hypertrophied, and released from normal adaptive control mechanisms in vulnerable individuals, to potentially
yield the full spectrum of depressive illness. Depression remains a challenging puzzle of neurobiological correlates, involving changes
in many biogenic amine and neuropeptide systems and alterations in neuroendocrine and immune function. We suggest that core
factors form an interactive and even synergistic “depressive matrix,” which argues against any “single-factor” theory. We examine
core contributions from stress cascades, immune function, and multiple neuropeptide and monoamine systems. Contrary to many
single-factor or primary factors, our review suggests active synergisms between factors, as well as a complex recursive (looping) control architecture regulating both entry and exit from depression. Such an interactive matrix of factors may help explain why such an
enormous multiplicity of potential treatments are antidepressant, ranging from psychotherapy and exercise to multiple drugs, vagal
and deep brain stimulation, and ECT. This review bridges domains generally disconnected in current literature. Traditional biological
psychiatric perspectives are almost totally “bottom-up” (neglecting relationships between depression and social stress) and typically
cannot explain why depression is such a pervasive problem, or why evolution could have ever selected for such a mechanism. Linking
depression to protracted separation distress provides a heuristic potential integration of findings, particularly between long-standing
psychotherapy and psychodynamic perspectives and emerging neuroscience insights. This hypothesis yields various testable predictions at both clinical and neuroscience levels.
Keywords: depression; neuropeptides; dynorphin; attachment; separation distress; stress; corticotropin-releasing factor ; opioids
The heart asks pleasure first,
And then, excuse from pain;
And then, those little anodynes
That deaden suffering;
“Let us make no bones about it: We do not really know what
causes depression. We do not really know what constitutes
depression. We do not really know why certain treatments may
be effective for depression. We do not know how depression
made it through the evolutionary process. We do not know
why one person gets a depression from circumstances that do
not trouble another.”
And then, to go to sleep;
And then, if it should be
The will of its Inquisitor,
The liberty to die.
Andrew Solomon (2001), p. 29
Emily Dickinson
Douglas F. Watt: Clinic for Cognitive Disorders, Quincy Medical Center, Boston University School of Medicine, Boston, MA, U.S.A.; Jaak Panksepp:
Department of VCAPP, College of Veterinary Medicine, Washington State University, Pullman, WA, U.S.A.
Correspondence to: Douglas F. Watt: Clinic for Cognitive Disorders, Quincy Medical Center, Boston University School of Medicine, Boston, MA 01760,
U.S.A (email: [email protected]).
Acknowledgments: The construction of this manuscript was partly supported by a Hope for Depression Research Foundation grant to JP. The first author,
DFW, wishes to express his deep appreciation for the contributions by many hundreds of depressed patients, who through the years of clinical practice have
keenly expressed in words and behavior their suffering, expressions that provided ample motivation for this review, with the hope that the review does do
justice to those who are suffering, or have suffered from, depression.
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
8
Introduction: the problem space
Depression is truly an ancient issue for human beings, with references to depression appearing in many
classical sources, onward from the earliest recorded
human history. A classic account of depression from
the late Renaissance was Burton’s 1621 Anatomy of
Melancholy. Depression is probably the most common
neuropsychiatric and emotional disturbance to which
human beings potentially fall prey. The true epidemiologic incidence of depression remains poorly charted,
but official estimates suggest that 20% of the population across the globe may be affected at one time or
another by variants of major depression (WPA Bulletin
on Depression, 2002). If one were to include its milder
forms or briefer depressive episodes, the lifetime incidence of some form of depressive-spectrum disorder
is probably much higher, perhaps as high as 75–80%.
Not only is it the most common mental health or emotional issue bringing patients to physicians and mental
health professionals, it is also probably substantially
underdiagnosed (Lecrubier, 2007). For unknown reasons, there is perhaps a twofold higher prevalence in
females, potentially indicating that their social–emotional systems are more sensitive or more affected by
the abundant stressors that can promote depression.
According to DSM-IV (APA, 1994), lifetime risk for
major depression is roughly 10% to 25% for women
and 5% to 12% for men. Given the many who never
seek treatment, these numbers are probably significant
underestimates. The true incidence of depression in
the general population is probably higher than official
epidemiological estimates.
Although twin studies suggest significant heritability or vulnerability to major depression, ranging from
31% to 42% (Sullivan, Neale, & Kendler, 2000), this
implies that roughly two thirds of the variance may be
environmental. From a societal perspective, depression constitutes staggering human and economic costs,
including recent estimates that major depression is a
leading cause of disability worldwide and hence the
single most expensive disorder confronting Western
societies (WPA Bulletin on Depression, 2002). Since
depression may worsen many other medical conditions
(Kessler et al., 2003), including being a significant
risk factor for cardiac disease, immune dysregulation,
obesity, addiction, just to name a few, the total human
and economic costs associated with depression may be
larger than has yet been estimated.
The challenges in integrating both data and theory
in relationship to depression are formidable, involving major conceptual and empirical problems, spanning a huge, sprawling, and heterogeneous literature.
Douglas F. Watt & Jaak Panksepp
Although the popular media typically conceptualizes
depression as an “illness caused by a chemical imbalance,” with major pharmaceutical firms highly motivated to advance similar perspectives,1 most scientific
literature suggests that depression should be treated
as a syndrome and not a distinct illness. Additionally,
popular depictions of depression as “a chemical imbalance” are trivial without a concurrent functional–psychological analysis; all problems in living, including
death, are accompanied by “chemical imbalances.”
Furthermore, the presence of untreated depressive affect in significant numbers of the general population
argues that depression is not a traditional “illness.”
The “illness” categorization also begs the question of
why evolution might have permitted, even selected
for, such a common dysphoric mood state in the first
place. Although study into the genetics of depression
is mushrooming (Levinson, 2006), only a few investigators (e.g., Allen & Badcock, 2006; Nesse, 2000)
have asked, “what is the adaptive basis for depression?” This is especially perplexing since depressive
disorders promote profoundly maladaptive behavior,
leading to many social and occupational failures. The
equation of depression with maladaptive behaviors is
partly related to the ability of depression to promote
suicide, a most dramatic violation of evolutionary and
adaptive survival mandates, which imposes tragic burdens on surviving loved ones.
Equating clinical depression with maladaptation
is understandable but is scientifically unsatisfying if
allowed to obscure two core questions: (1) Why is
depression so commonplace? (2) What are the evolutionarily conserved brain mechanisms that promote
depression? The neglect of such issues reflects, in part,
psychiatry’s attempt to map psychiatric syndromes
directly onto brain mechanisms while ignoring the
intervening psychobehavioral systems that generate
prototype emotional states in mammalian brains (for
1“
Big Pharma,” as big business, seeks antidepressants that may become
billion-dollar blockbuster drugs. Accordingly, it may neglect drugs that are
off-patent (e.g., buprenorphine) as well as those that only serve a small
subset of the population. Many authors (ever since Valenstein, 1998) have
argued that the pharmaceutical industry may be exercising an increasingly
distorting influence on prescription and treatment landscapes for the whole
of medicine in the United States. This may be particularly true in relationship to depression, where many depressed patients are never referred to
psychotherapy and instead are only put on first-line antidepressant drug
regimens under the simplistic aegis that depression is “just a chemical
imbalance.” These trends take place despite evidence that pharmacology
is often only partially effective in depression (see recent STAR*D reports:
Rush, 2007; Rush, Trivedi, & Fava, 2003) and despite evidence that patients
suffering from trauma-related depressions do quite poorly treated alone
with psychopharmacology without psychotherapy.
Depression: An Evolutionarily Conserved Mechanism?
9
detailed reviews, see Panksepp, 1998, 2005). Curiously, this long-standing neglect of potential relationships
between depression and mammalian-brain emotional
systems exists side-by-side with vigorous ongoing efforts to develop animal models for antidepressant drug
discovery.
Our lack of integrated understanding of depression is
evident in the dozens of neurobiological correlates for
depression, yet without any clearly defined etiological
integration that might allow clinicians and researchers
to link disparate facts to central generative mechanisms.
So far, candidate “driving” mechanisms in depression
are envisioned largely in neuromodulatory and biochemical terms. They include classic notions emphasizing some form of monoamine deficiency (Shieldkraut,
1965), cholinergic overactivity (Janowsky, El-Yousef,
Davis, & Sekerke, 1972), hypothalamic–pituitary–adrenal (HPA) stress axis alterations (de Kloet, Joëls, &
Holsboer, 2005; Holsboer, 2000) that may promote cell
death or at least atrophic change in the hippocampus
(Dranovskya & Hen, 2006), potential deficits in neuronal growth factors (Duman & Monteggia, 2006), and
associated alterations in corticotropin-releasing factor
(CRF), brain-derived neurotrophic factor (BDNF), and
glucocorticoid receptors. A recent reappraisal of the
role played by stress cascades has emphasized fundamental changes in the hippocampus associated with
cortisol versus BDNF (Holsboer, 2000), coincident
with the finding that antidepressants promote or restore
neuronal proliferation and neuroplasticity in this brain
region (see sections on neuroendocrine and neuroplasticity issues). Additionally there are more recent ideas
emphasizing multiple alterations in other neuropeptide
systems besides CRF, especially substance P, opioids,
and oxytocin (Holsboer, 2003), as well as potential
upregulation of dynorphin (the “dysphoric opioid”)
reducing “reward” activity in the nucleus accumbens
(Todtenkopf, Marcus, Portoghese, & Carlezon, 2004).
There is also evidence for significant functional alterations in both glutamate and γ-aminobutyric acid
(GABA). In short there exists a complex panoply of
neuromodulatory changes in depression. In addition
to these traditional bottom-up neurochemical perspectives, which often seem informed by a strong sense
of neural reductionism (where psychological concepts
about depression have taken a back seat), there has
been increasing interest in the possibility that depression arises from fundamental changes in large-scale
corticolimbic emotional networks (e.g., hyperactivity
in Brodmann’s area 25—subcallosal cingulate—in severe refractory depressions; Mayberg et al., 2005).
However any putative functional integration of all
of these disparate candidate mechanisms is rarely if
ever evident in the currently available literature. Here
we focus on how the evolution and functions of basic
emotional systems within the brain may help coordinate many disparate lines of thinking. We suspect
that such integrative approaches may eventually help
improve biological treatments of depression and better
clarify and refine psychotherapeutic practices. It may
also help coordinate the growing numbers of putative
neurochemical correlates and causes into a more coherent theoretical framework than presently exists.
A multifaceted separation-distress hypothesis
of depression
The many brain changes in depression may be differential manifestations—different “faces,” as it were—of a
fundamental shutdown process, reflecting ancient and
evolutionarily conserved mammalian brain mechanisms aimed at the termination of separation-distress
responses triggered by social loss. In Bowlby’s (1980)
terms, the shift from a “protest” to a “despair” phase
following social losses suggests a conserved psychobehavioral shutdown mechanism that may initiate and
promote depression. The evolutionary adaptation (i.e.,
“purpose”) of such a shutdown mechanism may have
been the benefits of terminating protracted separation
distress particularly in younger and infant mammals.
Sustained separation distress (crying) might prove fatal, either by alerting predators to prey availability or
by metabolically exhausting infants if they remained
in a protracted panic phase. Analogously, the protest
that follows the loss of other rewards, as well as other
homeostatic losses (e.g., illness and chronic pain), may
engender comparable types of depressive shutdown.
Thus, there may be several variants of depression, although empirically validated subtypes of unipolar depression remain unavailable in the literature. Although
depression as a syndrome may eventually be unpacked
into several distinct subtypes, all subtypes presumably
operate through a fundamental inhibition of the major
social emotional systems of the brain—namely, within
the PANIC/Separation distress, maternal CARE/Nurturance, LUST/Sexuality, PLAY/Social Joy (Panksepp,
1998, 2005), and SEEKING/appetitive systems (for
recent reviews see Alcaro, Huber, & Panksepp, 2007;
Panksepp & Moskal, 2008).
From an evolutionary perspective, this shutdown
mechanism may be self-terminating and time-limited
(see section on separation distress), consistent with
evidence that depressive episodes can be self-limiting even without treatment. Of course, self-limiting
mechanisms to arrest the shutdown may fail in many
10
depressive disorders. But instead of a simple “chemical
imbalance” being responsible for depression, evidence
argues for changes in perhaps a dozen neurotransmitter systems, along with many associated intracellular
events, to create a depressive cascade (Stone, Lin,
Rosengarten, Kramer, & Quartermain, 2008). However,
like any adaptive mechanism, this putative “shutdown”
process can become disinhibited, hypertrophied, released from its normal control mechanisms, and subsequently recruited pathologically in the context of fairly
minimal stresses or precipitants, yielding the diverse
symptoms and variants of depressive illness.
This hypothesis is advanced as a provisional synthesis, open to both further affirmation and falsification. In
the closing section we will offer several critical predictions to test our hypothesis. Even though the seeds of
this idea can be found in various places from Bowlby
(1980) onward, a critical neuroscience evaluation of
such a hypothesis is not available in the literature at
this date. In this sense, we will argue that depression is
fundamentally connected to social attachment, social
status, and comfort, and its many vicissitudes. This is
not a new idea, but the possibility that the fundamental
neuroscience of depression could be better integrated
under this affective neuroscience umbrella remains
relatively novel in biological psychiatry, and we wish
to give it an open hearing. Indeed, one of the oldest and
recurrent correlations in the psychiatric literature is the
association between depression and social attachment
losses, first discussed in classic psychoanalytic literature by Sigmund Freud in “Mourning and Melancholia” (1917e [1915])
In sum, the position we advance in this article is
that to understand depression, as well as many other
psychiatric symptomatologies, we need to properly
conceptualize the functional emotional networks of the
brain and their imbalances (Panksepp, 1998, 2006). A
mere brute-force cataloguing of dozens of neurochemical changes will probably not suffice. Although the
neural network perspective of depression is gaining
ground (Castrén, 2005; Harro & Oreland, 2001), few
have tried to consistently conceptualize depression in
more coherent psychological–evolutionary terms. The
prevailing radical reductionism in mainstream psychiatry still envisions that one can go from molecules
and brain details to psychiatric diagnostic categories,
with no psychologically meaningful neuroscience of
emotions in between, almost as if the psychological
properties of the brain and its adaptive mandates are
somehow irrelevant to the analysis. We believe that
this is fundamentally incomplete, if not totally wrong,
and here offer an alternative view. Unless we conceptualize basic brain emotional networks more clearly,
Douglas F. Watt & Jaak Panksepp
we will have a fundamentally fragmented image of the
substrates of depression, how they interact with higher
cognitive regulatory processes, and how various forms
of treatment might provide optimal help. Thus, here
we will offer an evolutionary view of depression that
remains to be fully developed in the literature, but one
fully testable empirically. In our closing section we
will offer several testable predictions deriving directly
from our core hypothesis.
Evolutionary views of depression
Evolutionary perspectives on depression have not been
prominently featured in mainline psychiatric journals,
with the first major volley occurring just at the beginning of this new century. Neese (2000) argued
that depression might serve several adaptive purposes
including communicating a need for help, as well
as signaling submission in social hierarchy conflicts
where one has little chance of winning and considerable chance of losing or being injured (Malatynska &
Knapp, 2005). Thus, depression may provide a mechanism for disengagement from unreachable goals and for
regulating patterns of maladaptive emotional investment. The idea that social loss leads to depression was
articulated in the 1970s–1980s (Bowlby, 1980; Reite,
Short, Seiler, & Pauley, 1981) but remained without
neuroscientific foundations until recently. Since then,
several other contributions, following themes advanced
by Nesse, have emphasized that brain mechanisms promoting depressive states must have evolutionary bases,
otherwise they would not exist. More recently, Keller
and Nesse (2006) have argued that not only was there
selection for depressive mood, but also that depression may come in subtypes according to the particular
types of adaptive challenges for which an organism
has no ready solution. They argue, along with others
(e.g., Panksepp, Burgdorf, Beinfeld, Kroes, & Moskal,
2004; Panksepp, Yates, Ikemoto, & Nelson, 1991) that
various types of social losses are unique, with perhaps
different forms of depression forming around each
type of challenge. Nesse and colleagues argue that
low mood may actually increase an organism’s ability to cope with adaptive challenges, especially when
sustained efforts to pursue difficult goals may result
in danger, loss, injury, or wasted effort. In such situations, depressive pessimism and lack of motivation
may provide a fitness advantage by virtue of inhibiting
actions when one has inadequate resources or plans,
particularly when challenges to dominant figures may
be hazardous. Depression could thus help terminate
risky or damaging dominance conflicts.
Depression: An Evolutionarily Conserved Mechanism?
11
These arguments are complementary to our main
hypothesis, which focuses on the adaptive value of
terminating protracted separation distress, especially
for young and vulnerable infants. Although the idea
that early-life vicissitudes predispose organisms to depression is now a well-established theme (e.g., Heim
& Nemeroff, 1999; Pryce et al., 2005), much of that
literature is only linked to putative changes in the HPA
stress axis, often with little consideration for a primary
role by brain systems promoting attachment and separation distress. Separation distress is indeed intimately
coordinated with the generalized HPA stress response
that has been a mainstay of depression research, in humans as well as in animal models (Henn & Vollmayr,
2005; Keck, Ohl, Holsboer, & Muller, 2005; Maier &
Watkins, 2005). Shutdown mechanisms activated in
early-life separation-distress episodes could be recruited later in life in relation to social losses experienced in
dominance hierarchy conflicts. Indeed, it seems likely
that evolution would select a mechanism if it could
“kill several birds with one stone,” so to speak.
various noradrenergic and serotonergic antidepressant
drugs, resulting in significantly more synaptic availability of biogenic amines in forebrain areas within
hours of ingestion (Delgado, 2000, 2004). Antidepressant efficacy for these classic amine facilitators occurs
weeks later, and although one classical viewpoint has
been that the therapeutic effects are associated with an
active downregulation of receptors and/or their active
pruning in the forebrain, more recent hypotheses have
focused on a variety of neuronal growth factors (Stone,
Lin, & Quartermain, 2008; Stone, Lin, Rosengarten,
Kramer, & Quartermain, 2003).
In addition to older hypotheses emphasizing the role
of norepinephrine and serotonin, more recently monoamine perspectives have increasingly focused on dopamine as well, particularly given its superordinate role
in motivated behavior (Alacaro, Huber, & Panksepp,
2007; Berridge, 2007; Ikemoto & Panksepp, 1999;
Panksepp, 1998; Panksepp & Moskal, 2008). Also,
there is now mounting evidence that multiple other
neurotransmitter systems, including GABA, glutamate,
and multiple neuropeptides (CRF, substance P, cholecystokinin, dynorphin and other opioids, and oxytocin),
may also be centrally involved in depression. Many
of these aminergic and peptidergic neurotransmitters
systems intimately coregulate each other in ways still
incompletely understood (see section on neuromodulatory interactions), adding layers of complexity to any
purely neuroscientific understanding and treatment of
depression (Norman & Burrows, 2007; Stone, Lin, &
Quartermain, 2008; Wong & Licinio, 2001). Additionally, much thinking about depression is restrictively
guided by how depression is related to important alterations of the HPA axis (e.g., hypercortisolemia, which
promotes hippocampal atrophy); it is rarely made clear
how such changes may be related to the affective
changes of depression (Drew & Hen, 2007; McEwen,
2004; Warner-Schmidt & Duman, 2006).
In addition to these more traditional bottom-up neuromodulatory perspectives, the neuroscientific and
clinical literature on depression has also increasingly
focused on the possibility that depression may reflect
some kind of fundamental alteration in corticolimbic
networks, and such network perspectives are crucial
given the evidence that changes in conscious state and
mood must reflect relatively global neurodynamic phenomena (Watt & Pincus, 2004). However, since we do
not have a clearly validated theory of conscious state,
we do not yet have an accepted understanding for how
mood and baseline emotional states (as fundamental
parameters of consciousness) are instantiated in the
brain. Recent work suggests that mood and self-related
emotional information processing probably reflects
A neuroscientific overview of depression
Aside from the general acceptance that life stress is
a prominent factor in the genesis of depression (e.g.,
among many others, see Holsboer, 2000; Vollmayr &
Henn, 2003), the largest “bin” in the neurobiology of
depression “box” would clearly be neurotransmitter
perspectives, and, classically, the earliest hypotheses
about depression centered on the first three monoamines characterized in the brain—norepinephrine,
serotonin, and dopamine—along with the first transmitter discovered in the brain back in the 1920s, acetylcholine. The monoamine deficiency hypothesis,
with a focus on norepinephrine deficits, is the oldest
neurochemical hypothesis about depression (Schildkraut, 1965; for an updating, see Harro & Oreland,
2001). However, simple aminergic deficiency as an
explanatory hypothesis has fallen by the wayside, in
the context of enormous evidence that depression is
significantly more complicated than a simple deficiency state in any monoaminergic system, singly or
even collectively (for summary of history, see Healey,
1997). The strongest data pointing against a simple
noradrenergic (NE)/5-HT deficiency hypothesis are:
(1) the failure of norepinephrine or serotonin synthesis inhibition to simulate classic depressive symptoms
in normal individuals, even though it can diminish
mood in recently depressed individuals (Delgado et al.,
1990); and (2) the lack of rapid amelioration of depression following the rapid onset of reuptake inhibition of
12
changes and dynamics within highly distributed medial
subcortical–cortical networks (Northoff & Panksepp,
2008; Panksepp & Northoff, 2009). Regions of interest
in such distributed network formulations would centrally include the prefrontal systems, the hippocampus,
the ventral or limbic stratum, particularly the shell
of the nucleus accumbens/olfactory tubercle, along
with several other subcortical limbic and paleocortical paralimbic structures, including periaqueductal
gray (PAG) (Liotti & Panksepp, 2004; Northoff et
al., 2006). Such a network effect is seen when stress
reduces reward-SEEKING urges through a global reduction of mesolimbic dopamine transmission, partly
by the capacity of dynorphin to make this whole hedonic network less responsive (Nestler & Carlezon,
2006). Considered jointly, these distributed network
and neuromodulatory perspectives suggest that depression may reflect global changes in large-scale reticular–limbic–cortical networks critical to SEEKING and
exploratory behavior and critical also to attachment behaviors. These multifactorial neurobiological perspectives, in our judgment, have to be integrated with the
long-standing (indeed, centuries-old) intuitive insight
that depression is fundamentally related to the brain’s
reaction to emotional/social loss, particularly losses
where the subject feels a keen helplessness to mitigate
the loss, or where the loss is particularly penetrating
and hurtful (see section on psychodynamic issues and
depression).
We will review these diverse literatures not with the
goal of maximum depth of coverage of the neurobiological details, which is enormous, but instead with an
eye toward a heuristic (“big picture”) summation and
in order to highlight potential lines of evidence supporting our core hypothesis that depression reflects an
ancient mammalian mechanism to protect a vulnerable
social brain from the potentially fatal consequences of
protracted separation distress.
A critical review of DSM-IV criteria for major
depressive episode
Like every syndrome in DSM-IV (APA, 1994), there
are no objective or laboratory diagnostic tests for the
presence of depression, even though abundant brain
abnormalities at both the structural and the biochemical level have been demonstrated, some of which
can be corrected by shifting network dynamics with
deep-brain stimulation (Mayberg et al., 2005). Indeed,
given the lack of bona fide objective tests for depression beyond this compilation of symptoms approach,
there is probably no absolutely clear line distinguish-
Douglas F. Watt & Jaak Panksepp
ing someone with a mild form of clinical depression
from those of us who are simply having a difficult time
in the course of our day-to-day existence and are simply moderately dysphoric. This may further underline,
however, the ubiquitous nature of depressive-spectrum
phenomena. The DSM-IV criteria for Major Depressive
Episode are the following:
A. Five (or more) of the following symptoms have
been present during the same 2-week period and
represent a change; at least one of the symptoms
is either (1) depressed mood or (2) loss of interest
or pleasure. (Note: Do not include symptoms that
are clearly due to a general medical condition, or
mood-incongruent delusions or hallucinations.)
1. Depressed mood most of the day, nearly every
day, as indicated by either subjective report
(e.g., feels sad or empty) or observation made
by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.
2. Markedly diminished interest or pleasure in
all, or almost all, activities most of the day,
nearly every day (as indicated by subjective
account or observation).
3. Significant weight loss when not dieting or
weight gain (e.g., a change of more than 5%
of body weight in a month), or decrease or
increase in appetite nearly every day. Note:
In children, consider failure to make expected
weight gains.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly
every day (NED) (observable).
6. Fatigue or loss of energy NED (nearlyevery
day).
7. Feelings of worthlessness or excessive or inappropriate guilt (may be delusional) (not merely
self-reproach or guilt about being sick) NED.
8. Diminished ability to think or concentrate, or
indecisiveness, NED (either by subjective account or as observed by others).
9. Recurrent thoughts of death (not just fear of
dying), recurrent suicidal ideation without a
plan, or a suicide attempt or a specific plan for
committing suicide.
B. The symptoms do not meet criteria for a Mixed
Episode.
C. The symptoms cause clinically significant distress
or impairment in social, occupational, or other
important areas of functioning.
D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition (e.g.,
hypothyroidism).
E. The symptoms are not better accounted for by bereavement. [APA, 1994, p. 56]
Depression: An Evolutionarily Conserved Mechanism?
13
There are several issues worth noting in regards to
these criteria. First of all, the criteria cut across the
entire hierarchy of functional domains in the brain
(cognition, emotion, homeostasis) and involve cognitive disruption (especially criteria #8 and, to a lesser
extent, #9), obvious changes in emotion/mood (criteria
#1, #2, # 7, #9), and altered homeostasis (criteria #3
through #6, with sleep and appetite typically disrupted,
but also sexual functioning, endocrine status, and, even
more recently appreciated, immune status, all altered
in depression). This suggests that the fundamental
mood-altering mechanisms in depression have a wide
reach or, alternatively, that the fundamental depressive
alterations in emotion and mood are fully capable of
generating downstream changes in both “superordinate” cognitive functions as well as “subordinate” homeostatic processing. That primary-process affective
changes within the organism can profoundly gate or
alter cognitive activities is predicted by recent neural
models for emotion (Panksepp, 1998).
Core criteria emphasize either (1) depressed mood
or (2) loss of interest or pleasure as required for the
diagnosis of Major Depression. Unfortunately, the
notion of a “depressed mood” as a central diagnostic
criterion for depression remains somewhat circular.
Also unfortunately, the criteria fail to make a careful distinction between sadness and depression, using
them as rough synonyms, a recurrent problem in the
psychiatric literature. We would argue instead that
these states have to be viewed as distinct, albeit potentially related. They are commonly conflated in part
because they are found together in many instances.
In other words, patients are simultaneously both sad
as well as depressed, a coincidence of states underlining that depressions are often reactions to losses,
although many depressions, especially retarded or
severe ones, show no sadness whatsoever, suggesting that sadness is actually terminated by deepening
depression, supporting our core hypothesis. However,
this question of both a critical differentiation of and
relationship between sadness and depression is one
that we will explore in greater detail later in our discussion of separation-distress systems. Additionally,
we would argue that the core criteria of depressed
mood necessarily indexes a fundamental loss of
hopefulness—in other words, that “depressed mood”
means an intrinsically less hopeful mood. Indeed, in
our judgment, it is a curious omission that hopelessness is not specified at all in the DSM-IV criteria,
even though despair and loss of hope probably have
a quite fundamental connection to suicidal ideation
and wishes to die. Earlier DSM II–III criteria did reference hopelessness, but, for uncertain reasons, this
notion has been pulled out of the more recent versions of DSM diagnostic criteria.
Although “hopefulness” is not easily defined and
operationalized (perhaps leading recent revisers of the
DSM to drop hopelessness as a criterion), hopefulness
is traditionally contrasted with its antonyms, hopelessness and despair. Although depression is, in a sense,
more complex than simple despair, these considerations suggest intrinsically close linkages between loss
of hope and depression. Perhaps one of the clearest
operational indices of hopefulness may be an organism’s willingness to struggle with adversity. Indeed,
this ability to struggle with adversity without giving
up pursuit of rewarding activities may directly index
a fundamental emotional resilience and resistance to
depression. This connection between hopefulness and
a willingness to struggle is implicit in one of the most
important behavioral tests of antidepressants and resistance to depression in the animal literature: the
“forced swim test.” In this very important sense, depressed individuals lose their fundamental willingness
and ability to struggle with challenging circumstances
and basically “give up.” This “giving up” of core
organism goals is a fundamental dimension to depression that any candidate theory must at least attempt
to explain, and it certainly suggests that depression
must have fundamental inhibitory effects on basic motivational systems in the brain, especially the complex
brain network “engergized” by the ventral tegmental mesolimbic dopamine system (conceptualized in
Panksepp, 1998, as a generalized motivational arousal,
or SEEKING, system). Indeed, if our core hypothesis
about depression is correct—namely, that it emerges
from an evolutionarily selected mechanism to terminate protracted separation distress—such a putative
shutdown mechanism would have to feedback on central motivational arousal mechanisms in the brain and
attenuate significantly the ability of those mechanisms
to energize behavior.
The second core criterion in DSM-IV for major
depression (after “depressed mood”) is anhedonia and
loss of interest. Interest in a wide variety of stimuli and
pursuits in the world, and the anticipation of reward,
may both be intrinsically related to the operation of
the ventral tegmental mesolimbic-mesocortical SEEKING system (Panksepp, 1998) as well as to the social
rewards obtained by low activity in separation-distress
PANIC systems and high activity in social CARE
and PLAY systems. Taken together, this suggests that
depression may fundamentally disrupt both the anticipation and the pursuit of rewards (“interest”), along
with a diminished ability to experience pleasure, even
when rewards are available and obtained. We would
14
Douglas F. Watt & Jaak Panksepp
argue that this loss of interest and anhedonia are also
fundamental phenomena that any heuristic theory must
attempt to explain. Although loss of interest and loss of
pleasure are treated as one entity in this important criterion, evidence suggests that these are probably somewhat separate issues, with perhaps one that is more
dopamine-mediated, and the other more opioidergic
(for a thorough review, see Berridge, 2004).
None of the subsequent seven criteria after these
first two are necessarily required for the diagnosis of
depression, but one must have at least four of the other
“subordinate” criteria and either depressed mood or
loss of interest/pleasure to meet diagnostic criteria.
This approach (“at least one from column A” and “at
least four from column B”), with two core criteria and
seven secondary criteria, allows the DSM-IV diagnostic criteria to at least partially cover the challenging heterogeneity of depression, without prematurely
committing to a subtyping paradigm (when subtypes
are still not completely understood or extensively validated in the literature).
terations in aminergic projection systems, alterations
in forebrain receptors systems, and alterations in mood
and behavior remain both confusing and challenging,
with many questions remaining about precisely what
is causing what. Newer amine-centered conceptions
about depression attempt to integrate many of these
correlations under general concepts such as “spreading
adjustment disorder of monoaminergic neurons” (Harro & Oreland, 2001), or equally ambiguous notions
about depression reflecting a “cortical-limbic dysregulation.” Although these general notions avoid previous
oversimplifications (that depression emerged from a
simple “shortage” of monoamines), they are often so
general as to lack heuristic value. Indeed, one might
ask what nosological entity in psychiatry does not
present potentially as “corticolimbic dysregulation”
or show an “adjustment disorder” of monoaminergic
neurons? However, with all these qualifications, it is
clear that aminergic perspectives remain a critical, if
still confusing, piece of the puzzle in our attempts to
understand depressive states.
Neuromodulatory perspectives:
biogenic amines, acetylcholine, and amino acids
Noradrenergic issues
From the standpoint of the fundamental neurobiology
of depression, neuromodulatory perspectives clearly
constitute the largest and most substantive scientific
“bin” in the literature. Most antidepressant drugs modulate three major amine systems—serotonin, dopamine,
and norepinephrine—and this includes newer selective
serotonin reuptake inhibitors (SSRIs) as well as older
monoamine oxidase (MAO) inhibitors and tricyclic
antidepressants, although the vast majority of agents
used in modern psychiatry primarily affect serotonin
and/or norepinephrine. Although a comprehensive and
detailed review of literature covering all neuromodulatory perspectives in depression is beyond the scope of
this article, a brief summary of the literature will highlight several fundamental issues and questions.
Of these neuromodulatory perspectives, the monoamine efficiency hypothesis is the oldest hypothesis
of depression (Shildkraut, 1965). However, simple deficiency models (initially focused on norepinephrine
and serotonin) have fallen by the wayside, as evidence has accumulated that the changes in aminergic
systems associated with depressed mood cannot be
conceptualized in terms of simple chemical deficiency.
However, despite an enormous base of literature documenting abundant correlations between depression
and various changes in these three amine systems,
attempts to decipher precise relationships between al-
Of all the monoamine systems, correlation between
changes in noradrenergic circuitry and depression is
probably the oldest and largest thread in the literature,
and, in a recent encyclopedic review of hundreds of
studies, Harro & Oreland (2001) advanced the valuable (but debatable) argument that although depression might reflect a “spreading adjustment disorder”
in multiple monoamine systems, dysfunction in the
locus coeruleus (LC) was the primary and generative
“fault line.” We have known for some time that the
LC/lateral tegmental areas (the two main NE projection nuclei) show a tonic pacemaker activity with phasic bursts, with increased firing rates during arousal or
stress, decreasing activity during slow-wave sleep, and
largely deactivation during REM sleep (Hobson, PaceSchott, & Stickgold, 2000). There is evidence that in
depression either the projection system or forebrain
responsiveness to the projection system—or probably
both—show fundamental alterations.
The original insight about the importance of the
norepinephrine system in depression was prompted
by serendipitous observations about the now-classic
induction of depression from reserpine (which blocks
monoamine storage). However, only a modest percentage of patients taking reserpine became depressed,
suggesting that the drug elicits some kind of systemic
vulnerability in a fraction of individuals rather than NE
depletion being any version of a simple and invariable
Depression: An Evolutionarily Conserved Mechanism?
15
cause. Rapid depletion of NE in patients on NE-facilitating antidepressants can provoke relapse, particularly
in those who have recently suffered depression, but not
in normal individuals (for a review of difficulties with
early biogenic amine deficit theories of depression,
see Nestler, 1998). Depressed patients often show increased tyrosine hydroxylase (the rate-limiting enzyme
in synthesis of NE suggesting increased demand), decreased NE transporter binding, and increased binding to α2/β receptors. Reserpine also increases TH
(tyrosine hydroxylase) expression, suggesting that
it provokes increased NE demand and/or decreased
availability and also leads to increased α2 binding/
proliferation (Flügge, van Kampen, Meyer, & Fuchs,
2003; Ordway, Schenk, Stockmeier, May, & Klimek,
2003). On the other hand, SSRIs and serotonin/norepinephrine reuptake inhibitors (SNRIs) downregulate
tyrosine hydroxylase and α2/β adrenoceptors (both
apparently upregulated in patients with depression),
and these drugs appear to generate a decrease in overall
demand for norepinephrine and a quieting of LC activity (Weiss, Blier, & de Montigny, 2007).
Perhaps the strongest data point for the classical
argument linking the noradrenergic system and depression was the discovery that antidepressants caused
downregulation of noradrenergic receptor density and
sensitivity coincident with their therapeutic onset, particularly downregulation of beta NE receptors (Baker,
Coutts, & Greenshaw, 2000). Additional supportive
findings are increased β-adrenoceptors and 5-HT2
receptors, along with fewer neurons in rostral LC,
in suicide victims relative to controls (Mann, 2003).
However it is unclear whether these findings in suicide
relate to severity of depression primarily or to depression further compromised by poor impulse control.
Additionally, “learned-helplessness” animal models
(such as uncontrollable foot shock) show increased
NE release, suggesting that chronic stresses that an
individual cannot mitigate may lead to the noradrenergic system being chronically overdriven, and this may
recruit a number of compensatory mechanisms leading
to depression.
A very different point of view on norepinephrine
function in depression has been suggested by newer
work that has implicated a subgroup of brain α1B-adrenoceptors as a key factor in positively motivated behavioral activity (Stone et al., 2003). These “motoric”
α1-receptors are located in or close to monoaminecontaining neuron cell bodies or their major targets
(such as nucleus accumbens for the dopamine system)
and actually utilize epinephrine (EPI) as their primary
neurotransmitter. Stone and colleagues hypothesized
that this “EPI-innervated-α1-system” activates behav-
ior by generating a coordinated and relatively simultaneous excitation of the major monoaminergic systems
of the brain. They found evidence that this epinephrine
activation system may be impaired or pathologically
inhibited in depressive illness (findings of altered responsiveness of brain α1-receptors in depressed patients and low levels of EPI in the cerebrospinal fluid,
CSF). They also speculated that this impairment may
help to foster central nervous system (CNS) brain atrophic effects documented in depression, due to linkages
to mitogen-activated protein kinase (MAPK) activation and growth-factor induction. This would also suggest some interesting functional parallels between this
component of the noradrenergic system and dynorphin,
which inhibits mesolimbic dopamine activation (see
section on kappa opioids).
However, even this conceptual updating of the classic monoamine-deficiency hypothesis faces stiff challenges from key findings. First, a major weakness in
adrenergic-centered viewpoints on depression is that
most studies have not found any reduction in the brain
concentrations of norepinephrine or its metabolites
that could be unequivocally correlated with depressed
mood (although bipolar patients typically show lower
noradrenergic metabolites during depressed phases).
Additionally, monoamine-depletion studies in healthy
volunteers have not supported the idea that low levels
of norepinephrine invariably lead to depression, except
perhaps in a subset of vulnerable subjects (the abundant
data in this area are well summarized in various mood
disorder chapters in Charney, Nestler, & Bunney, 1999;
for thorough historical perspectives, see Healy, 1996).
One of the most critical and potentially paradigm-shifting studies with respect to the monoamine hypothesis
of depression was by Delgado and colleagues in the
early 1990s. They found that dietary depletion of neither serotonin nor norepinephrine creates depressive
symptoms in most individuals. However, in patients
that previously responded to selective norepinephrine
reuptake inhibitors, dietary norepinephrine depletions
could readily cause the appearance of clinical symptoms (Delgado, Price, Heninger, & Charney, 1992).
Paralleling these studies on human subjects, classic
work on animals suggests that many mammals can show
grossly normal behavior and no obvious alterations in
affective behaviors in spite of very low norepinephrine (and other amine) levels (Haggendal & Lindqvist,
1964). In terms of the primary impact of noradrenergic
drugs on depression, why downregulation of receptor
sensitivity or pruning of noradrenergic receptors would
correlate clearly with an elevation of mood remains
poorly specified. An additional challenge to noradrenergic-centered points of view on depression has been
16
the recent discovery in one important animal model
(Monteggia et al., 2004) that blocking the effect that
noradrenergic and serotonergic antidepressants have
on the upregulation of BDNF prevents antidepressant
efficacy in these drugs. Last but not least, noradrenergic antidepressants have little to no effect on elevating
or indeed altering at all the baseline mood in subjects
without depression, suggesting that they do not really
impact mood neurochemistry directly and that noradrenergic dysfunctions must operate in concert with a
host of other brain changes. Likewise, it is generally
believed that serotonergic antidepressants also do not
affect the mood of euthymic individuals, but careful
studies indicate that facilitation of serotonin makes
normal people more “laid back,” less aggressive, and
more socially affiliative (Knutson, Wolkowitz, Cole,
Chan, & Moore, 1998). It is possible that comparable
careful studies with noradrenergic agents may reveal
comparable mood effects.
An overall model suggested by these findings may
be that depression is potentially associated with a long
period of increased NE demand and overdrive, possible
NE depletion including an epinephrine component emphasized by Stone et al. (2003), and subsequent compensatory changes in both the projection system and
in forebrain receptor populations. Most theorists and
reviewers now agree that depression can be conceptualized not simply in terms of simple NE deficiency but,
rather, in terms of a still poorly understood global shift
within NE systems possibly characterized by increased
receptor sensitivity and/or proliferation. In any event,
although changes in the NE system are no doubt important in depression, NE “tone” and the functional state
of both the LC projection system and various forebrain
receptors continue to have rather murky and uncertain
direct correlations with affective and behavioral state,
suggesting that theories of depression attempting to
explain characteristic depressive changes in mood, affect, and behavior must consider and incorporate other
perspectives.
Serotonergic issues
Although the serotonin system is the neuromodulatory system most people associate with depression
(partly through relentless and effective drug company
advertising), evidence for a direct link between serotonin, affective state, and depression is only modestly
stronger than the data supporting a primary role for
norepinephrine. Interest in the serotonin system in
depression began almost as early as interest in the
noradrenergic system, coincident with the serendipi-
Douglas F. Watt & Jaak Panksepp
tous discovery that tricyclic drugs that affected both
serotonin and norepinephrine reuptake or blocked
their metabolism by inhibition of MAO were effective
antidepressants (see Healy, 1996). Due to a number of
side effects of the MAO inhibitors (especially dietary
restriction of foods containing tyramine) and cognitive
and cardiac side effects of the older tricyclic drugs,
these two classes of medicines have been largely superseded by SSRIs. Many classic studies have found
abnormal levels of serotonin metabolites (5-HIAA)
in blood, urine, and CSF in depressed patients, along
with decreased plasma tryptophan levels (Coppen, Eccleston, Craft, & Bye, 1973; Cowen, Parry-Billings,
& Newsholme, 1989), both suggesting decreased central serotonergic drive and metabolism. Additionally,
brain imaging studies (Drevets et al., 1999; Sargent et
al., 2000) have reported a reduction in 5-HT1a receptor binding—both pre- and postsynaptically, in the
raphe as well as in medial temporal areas—that may
be a marker of vulnerability to depression, as this apparently does not normalize after remission of depression. Although the precise basis for this serotonergic
deficiency in depression is still uncertain, evidence
suggests an immune-system connection, arguing that
a cytokine-induced IDO (indolamine dioxygenase)mediated decrease in tryptophan may lead to a serotonergic deficiency (Muller & Schwartz, 2007).
Additionally, both depressed as well as remitted subjects show blunted neuroendocrine responses (cortisol and prolactin) to drugs stimulating serotonergic
turnover such as fenfluramine (Flory, Mann, Manuck,
& Muldoon, 1998; Kapitany et al., 1999), suggesting
decreased serotonergic responsiveness, possibly pointing to state/trait relationship issues, with a trait of decreased serotonergic function likely putting patients at
risk for the state of depression (Bhagwagar, Whale, &
Cowen, 2002).
One of the most detailed reviews to date of the serotonergic system and depression (Jans, Riedell, Marcus, & Blokland, 2006) interpreted these and many
other similar kinds of findings as supportive of the
concept of “serotonergic vulnerability” in depression.
However, Jans and colleagues acknowledge that not
all depressed patients show significant abnormalities
in serotonin systems and that the earlier “categorical”
view that low serotonin was specific for depression
is now simply outdated. They advocate for a “dimensional approach” similar to ours, in which serotonergic
hypofunction places patients at risk for a broad spectrum of mood and affective regulation issues across
multiple DSM-IV categories, including depression,
anxiety disorders, impulse control disorders, etc. From
this perspective, low serotonergic neurotransmission,
Depression: An Evolutionarily Conserved Mechanism?
17
whether due to genetic or to environmental factors (or
both), operates as a significant biological risk factor for
depression, as well as for other disorders of affective
regulation. Jans and colleagues argue that serotonergic
vulnerability can be demonstrated by challenging the
system particularly with tryptophan depletion but also
with neuroendocrine probes. Further support for this
general point of view emerges from work by Flory,
Manuck, Matthews, and Muldoon (2004), who found
a positive correlation between baseline serotonergic
tone, indexed by prolactin release to serotonin facilitation with fenfluramine, and baseline mood, suggesting
that serotonergic deficiencies may put individuals at
risk for mood regulatory disorders. In general, this
idea is consistent with the well-established preclinical
findings that serotonin generally dampens every active
emotional and motivational process, while facilitating
sleep.
Also consistent with this set of assumptions have
been studies trying to identify genes that predispose
to depression. Studies have found some evidence for
an association between a polymorphism affecting the
serotonin transporter gene-linked promoter region
and depression, with subjects having the short form
of the allele being more vulnerable to depression,
and the brain changes that may account for this (increased sensitivity of limbic negative-affect circuits)
have been characterized by Pezawas et al. (2005).
Although a less efficient serotonin transporter might
be presumed similar in its effects to a pro-serotonin
drug, lower serotonergic uptake caused by the short
form of the allele may theoretically result in increased
serotonin binding to auto-receptors in the raphe that
would exert a negative feedback on global serotonergic transmission. Supporting this assumption, combined treatment with 5-HT1a (auto)receptor blockers
and SSRIs compensated for the typically worse antidepressant effect of SSRIs in genotypes showing at
least one short form of the serotonin transporter allele
(Smeraldi et al., 1998). This suggests that the short
form of the serotonin transporter allele decreases tonic
output of the projection system via auto-receptor effects.
The most compelling and robust clinical correlation between depression and serotonergic issues appears between low serotonergic tone and impulsivity
and risk for suicide (Mann, 2003), including evidence
that a polymorphism producing proliferation of 5-HT1a
auto-receptors (presumably leading to lower overall
tonic activation of the serotonin system) predisposes to
depression and suicide (Lemonde et al., 2003). Indeed,
serotonin may exercise a general affective regulatory
influence within the CNS, allowing the brain to bet-
ter modulate and inhibit emotion, while a subset of
serotonin receptors (5-HT2) appears critically involved
in a poorly defined aspect of negative emotions (Celada, Puig, Amargós-Bosch, Adell, & Artigas, 2004;
Panksepp, 1998). Consistent with this, there has been a
finding of downregulation of 5-HT2 in animal models
after long-term treatment with serotonergic reuptake
inhibitors, with this appearing within the 1- to 3-week
window for therapeutic efficacy of these drugs in human clinical populations, suggesting that this effect
may be correlated with onset of therapeutic efficacy.
Since sleep problems are common in depression and
often constitutive, it is intriguing that certain drugs can
concurrently promote melatonergic facilitation of sleep
and also block 5-HT2 receptors (Zupancic & Guilleminault, 2006).
Analogous to the findings with norepinephrine, dietary depletion of serotonin fails to produce depression
in the majority of subjects, with the exception of a
vulnerable subset of individuals. Directly analogous
to the findings with norepinephrine, patients that had
previously responded to a SSRI showed a significant
incidence of clinical regression when serotonin was
depleted through diet (Delgado et al., 1990). This suggests that, like norepinephrine, the serotonin system
may play a critical role in depressive cascades for
some individuals but not for others. However, as with
norepinephrine, compelling data linking the state of
the serotonin system and mood in a direct fashion are
equivocal.
Additional challenges for classic monoamine theories reside in recent work suggesting that both noradrenergic and serotonergic antidepressants may have
their primary therapeutic effects mediated through
upregulation of BDNF. Brain monoamines such as
5-HT and NE seem to be critical mediators of antidepressant-induced TrkB activation (the primary BDNF
receptor) promoting upregulation of BDNF (Calabrese
et al., 2007). A final and stunning challenge to aminecentered points of view comes from actions of a new
atypical antidepressant, tianeptine (marketed as Stablon in Europe), which appears to actually accelerate
or enhance rather than inhibit serotonin reuptake (although there is controversy about whether its therapeutic efficacy is from this property or may be attributable
to other yet-unknown effects). This all suggests that,
as with norepinephrine, alterations in serotonin systems—even the accepted notion of downregulation and
pruning of serotonergic and/or noradrenergic receptors—cannot be elevated to any version of a “linchpin
mechanism” in depression but are, perhaps, part of a
cascade, including genetic vulnerability factors (Pezawas et al., 2005). Although many if not virtually all
18
antidepressants affect norepinephrine and serotonin,
their primary therapeutic effects may indeed be via
modulation of classical stress cascades (for an excellent review, see de Kloet, Joëls, & Holsboer, 2005) as
well as their ability to modulate arousal in all known
primary-process emotional and motivational systems
of the brain.
From a more strictly neuroscience perspective, although the serendipitous finding of antidepressant efficacy in MAO inhibitors and tricyclics initially pointed
psychiatry in the direction of serotonin and norepinephrine modulatory effects, it may be that therapeutic
potency is effected through downstream changes in
key peptide and neurotrophin systems, not to mention
facilitated neurogenesis in brain regions such as the
hippocampus. This is consistent with conclusions by
Delgado (2000), who argued that while intact noradrenergic and serotonergic systems appear to be required
for antidepressant drug efficacy in SSRIs and SNRIs,
norepinephrine and serotonin realistically could not
be considered the final common pathway of action
for our current amine-based antidepressants. These
complexities suggest that broader and more integrative
theories of depression need to look beyond serotonin
and norepinephrine, without neglecting their likely
contribution to the overall brain-network dysfunctions
that characterize depression (Stone, Lin, & Quartermain, 2008).
Dopaminergic issues
In general, until recently, dopamine has taken a backseat in the depression literature to serotonin and norepinephrine, but it started to garner more attention when
it was found both that relatively selective dopamine
reuptake inhibitors, such as bupropion, were highly effective in some depressed individuals and that various
noradrenergic and serotonergic drugs also regulated
mesolimbic dopamine activity. Since then, dopamine
has attracted increasing interest as researchers and clinicians have realized the central role dopamine plays in
all motivated behavior and the former have struggled
to model anhedonia and loss of motivation as essential depressive phenomena (Barr, Markou, & Phillips,
2002; Nestler & Carlezon, 2006). Although the ventral
tegmental dopamine neurons and their associated mesolimbic and mesocortical projections are often mistakenly referred to as “the pleasure–reward system” in
the brain, much work has made it clear (see Berridge,
2007; Ikemoto & Panksepp, 1999; Panksepp, 1998)
that this system promotes a generalized motivational
Douglas F. Watt & Jaak Panksepp
arousal and the seeking of rewards and is not neurally
underpinning pleasures associated with their consummation. Indeed, the evidence is now compelling that
the pleasure of consummation has comparatively little
to do with central dopaminergic processes and, instead,
may have much more to do with the opioidergic tone
within a distributed network of systems involving the
accumbens shell, the ventral pallidum, parabrachial
areas, and perhaps other basal forebrain regions (Berridge, 2004, 2007).
In any case, recent work suggests that particularly in
retarded depressions or depressions with severe abulia,
the ventral tegmental system is not operating normally.
A variety of animal models of depression have emerged
from the increasing recognition that dopamine may be
critical for euthymia, including ones related to animal
responsivity to novelty (Bevins & Besheer, 2005),
changes in the threshold of self-stimulation reward
(Leith & Barrett, 1980), withdrawal from sustained
treatment with amphetamines (Barr & Markou, 2005),
as well as the recognition that depressogenic peptides
such as dynorphin robustly inhibit mesolimbic dopamine functions in the brain (Nestler & Carlezon, 2006).
Indeed, various forms of stress, ranging from forced
swimming to social defeat, produce a depressive phenotype by facilitating brain dynorphin activity especially in dopamine “reward” systems (McLaughlin,
Li, Valdez, Chavkin, & Chavkin , 2006; McLaughlin,
Marton-Popovici, & Chavkin, 2003) (see section on
kappa opioids). Thus, a reduction of dopamine activity
seems highly likely to be a prominent aspect of depression, and it may underpin the amotivational state that
typically accompanies most depressive disorders.
Cholinergic issues
Cholinergic systems have been identified with dysphoria by virtue of their promoting aversion and distress
vocalizations in animal models, especially in subcortical basal forebrain and anterior hypothalamic regions
of the brain (Brudzynski, 2007). Social stress can
increase cholinergic activity in brain regions such as
the PAG where many negative affective systems converge (Kroes, Burgdorf, Otto, Panksepp, & Moskal,
2007). An older hypothesis about depression is that
depression reflected changes in the relationship between amine and cholinergic systems (Janowsky et al.,
1972), with suggested genetic markers for depression
(Janowsky, Overstreet, & Nurnberger, 1994). A line of
rats genetically selected for high cholinergic activity,
the Flinders Sensitive Line (FSL), has proved to be a
Depression: An Evolutionarily Conserved Mechanism?
19
useful animal model of depression (Overstreet, Friedman, Mathé, & Yadid, 2005). The FSL rat partially
resembles depressed individuals in terms of showing reduced appetite and psychomotor function, along
with sleep and immune abnormalities similar to those
observed in depressed individuals. However, this is not
a completely convincing animal model due to showing
no signs of anhedonia or cognitive deficits. FSL rats
exhibit changes consistent with dopaminergic, serotonergic, cholinergic, NPY (neuropeptide Y), and circadian rhythm models of depression but not HPA-axis,
noradrenergic, or GABAergic models of depression
(Overstreet et al., 2005). However despite this quite
partial fit with human clinical data, the FSL rat model
has been used to screen for antidepressants and has
been effective in detecting several novel antidepressants, suggesting at least decent face validity.
An interesting recent probe of a cholinergic hypothesis of depression was completed by Furey and Drevets (2006), who found that infusions of scopolamine
to block muscarinic acetylcholine receptors yielded
rapid and robust antidepressant effects without significant autonomic or cognitive side-effects, although
such studies have not yet controlled for REM sleep
deprivation coming from cholinergic blockade. It has
been known for quite some time that REM sleep deprivation is a very effective antidepressant, and recent
work even suggests a single night of REM deprivation can promote hippocampal neurogenesis (Zucconi,
Cipriani, Balgkouranidou, & Scattoni, 2006), one of
the candidate mechanisms that may contribute to pharmacological antidepressant effects (Dranovsky & Hen,
2006; Jacobs, Praag, & Gage, 2000), and REM disruption indeed may account for the efficacy of anticholinergic drugs and some SSRIs in depression. In any
event, since there are at least five muscarinic receptors,
it is unclear which might best account for the these
antidepressant effects, but the rapid antidepressant effects seen with scopolamine (Furey & Drevets, 2006)
are promising, as most antidepressants take several
weeks or more to achieve full efficacy, a period where
continued despondency, along with the psychomotor
activation that is produced by some traditional antidepressants, can jointly promote suicidal intent.
GABAergic systems. These rapidly acting excitatory
and inhibitory transmitters, respectively, are currently
implicated in virtually all psychiatric disorders and,
indeed, in practically all brain functions. Both GABA
and glutamate appear to be affected in depression, with
the general picture being one of failing inhibitory controls and downregulation of GABA and overpromotion
of excitatory cascades and some kind of functional
overactivity in glutamatergic systems. However, the
basis for these changes in both GABA and glutamate
is unclear. Glutamatergic changes may be driven in
part by possible upregulation of quinolinic acid, which
acts as an N-methyl-D-aspartate (NMDA) agonist, due
to alterations in pathways associated with upregulated
pro-inflammatory cytokines (for review, see Muller &
Schwartz, 2007). Because of the prolific roles in all
brain functions of GABA and glutamate, so far with
limited therapeutic implication for depression (e.g.,
Matsumoto, Puia, Dong, & Pinna, 2007) except for the
mood-stabilizing ability of certain antiepileptic agents
that inhibit excitatory drive/processes (such as affecting sodium channels), we would only note the most
promising new lines of evidence in this enormous field
of research.
Because of some preclinical reports suggesting that
blockade of glutamate might have antidepressant effects, a recent provocative clinical report indicated that
intravenous administration of ketamine, which blocks
one of the glutamatergic receptors (the NMDA receptor)
yielded robust and rapid (within 2 hours, after a short
dissociative effect) antidepressant effects that could
last for several days to a week (Zarate et al., 2006).
This study is part of a larger body of work suggesting
that in a variety of preclinical models metabotropic
glutamate receptor (mGluR1 and mGluR5) antagonists, as well as agonists at alpha-amino-3-hydroxy-5methylisoxazole-4-propionic acid (AMPA) receptors,
have antidepressant-like activity. Of course, how this
effect is traduced in the brain remains uncertain, but it
must be noted that glutamatergic stimulation of many
subcortical brain sites can produce strong negative
emotional arousals (Panksepp, 1998). Furthermore,
these results appear to validate a long-held taxonomic
separation between depression and psychosis, as fundamentally counterposed processes in the mind/brain,
since ketamine administration appears to be currently
the best single-drug model for schizophrenia and dissociative disorders. Perhaps psychosis reflects some
form of fundamental dampening failures in affective
regulatory and “channelizing” systems, while clinical
depression reflects a complementary and largely opposite problem—namely, release or disinhibition of a
GABA and glutamate
A discussion of the traditional neurotransmitters would
not be complete without some consideration of the
dysregulations that may exist in the most prolific amino-acid transmitters of the brain, both glutamate and
20
fundamental affective shutdown mechanism.2 An intuitive speculation would be that NMDA antagonism
or AMPA agonism disrupts instantiation of major inhibitory networks normally dampening and modulating affective arousal systems, and that this disruption
effectively and rapidly terminates the shutdown associated with depressive responses while also potentially
promoting psychosis, particularly in nondepressed
subjects. Whether the antidepressant effect of NMDA
antagonists can be achieved with slower administration
via the oral route remains unclear, but in any event,
this strategy offers a robust way to alleviate depressive
symptoms rapidly, during which more traditional antidepressants might be titrated up to therapeutic levels.
In lieu of further discussion of the traditional neurochemical systems that have been targets for most
psychiatric drug development, we will now turn to a
discussion of what we deem to be the most exciting
general arena of depression-relevant work—namely,
the role of neuropeptides in regulating specific types
of emotional arousal and bodily homeostasis. These
lines of research offer many new therapeutic possibilities along with functional insights into how distinct
emotional processes may participate in the genesis
of depression. We will first cover the largest traditional area of research related to depression—namely,
the physiological consequences of stress, which is
commonly discussed independently of the kinds of
emotions people and animals experience during stress
(Panksepp, 1998, 2005). We will then address the social separation-distress system. This will be followed
by a discussion of those stress-responsive and social
neuropeptides that provide a new conceptual structure
for understanding and potentially treating depression
in more effective ways.
The neuroendocrine axis and depression:
the HPA axis, CRF, glucocorticoids, and BDNF
Neuroendocrine alterations constitute a complex and
often confusing set of findings in relationship to depression, with many neuroendocrine functions affected
in depression, including alterations in the classic HPA
stress axis, disruption of thyroid and growth hormone
function, decreased secretion of melatonin, decreased
prolactin production, decreased basal levels of follicle
2
A challenge to this may be the existence of psychotic depression, where
one may need to explain affective regulatory failure of putatively two different kinds. Alternatively, the psychotic aspect may reflect emergence of
maladaptive object relations or repetition compulsions during early preconscious cognitive development and may simply be a cognitive comorbidity
as opposed to a distinct set of affective imbalances.
Douglas F. Watt & Jaak Panksepp
stimulating hormone (FSH) and luteinizing hormone
(LH), and, as already noted, promotion of various cytokines that modulate immune responses. How these
neuroendocrine alterations all might fit together remains poorly understood. There have been broad correlations established between depression and disorders
of thyroid function (blunted release of thyroid-stimulating hormone, TSH, to infusion of thyrotropin-releasing hormone, TRH, although this may be nonspecific
to many psychiatric conditions) and growth hormone
(GH) function (generally blunted, particularly in terms
of GH response in slow-wave sleep, and blunted GH
response to clonidine). However, these other indices of
endocrine dysfunction (changes in melatonin, prolactin, GH, TSH, LH, FSH) are generally regarded to be
less important than alterations in stress cascades and
alterations in CRF/ACTH/cortisol signaling loops and
set points. Although earlier work on depression tended
to regard alterations in the HPA axis as epiphenomenal
or as an interesting sideline to the main action of aminergic dysregulation, accumulating evidence from many
quarters suggests that changes in CRF and glucocorticoids are not epiphenomenal to depression. Many
reviews (de Kloet, Joëls, & Holsboer, 2005; Holsboer,
2000; Young et al., 2004) have offered persuasive arguments that depression is intimately related to complex
alterations in corticosteroid signaling and HPA-axis
alterations associated with chronic severe stress. Almost 90 years ago, Bleuler (1919) presaged the current
interest in the HPA–endocrine–depression connection
by suggesting that endocrine modulators could serve
as potential antidepressants and by demonstrating that
hormones have effects on mood and emotional status.
For instance, the ability of testosterone to produce psychological and physiological energizing has long been
recognized. Given the primary role that the endocrine
system has in regulating metabolism and basic energy
production, our primary hypothesis would predict that
a shutdown mechanism, aimed at termination of separation distress and selected in part because of its ability
to preserve precious metabolic supplies, would of necessity have widespread endocrine effects.
Indeed, since there is a fundamental relationship
between depression and protracted stress cascades,
an intact stress system is an essential component of
an individual’s ability to respond adaptively to life
circumstances that can promote depression (McEwen,
2000, 2007). Pathological overactivity of the pituitary
adrenal axis, as in Cushing’s disease, has typically
been accompanied by depressive-melancholic symptoms, leading to recent attempts to bring melancholia
back into the diagnostic picture as a fundamental type
of depression (see Fink & Taylor, 2007; for full discus-
Depression: An Evolutionarily Conserved Mechanism?
21
sion of this, see the whole issue of Acta Psychiatrica
Scandinavica Supplement in which the Fink & Taylor
paper appeared). In this context, it is informative that
people with significant lesions of this system, as in Addison’s disease, causing virtually total failure of stress
cascades, also have twice the incidence of depressive
and related affective disorders than do those with other
medical disorders such as osteoarthritis (Thomsen,
Kvist, Andersen, & Kessing, 2006).
Depression and other forms of severe chronic stress
appear to alter or fundamentally dysregulate these basic
stress cascades in complex and only partly understood
ways. A general principle appears to be that anything
that tends to restore homeostatic regulation within the
HPA axis has potential to therapeutically reduce depressive disorders. Hence, both reductions of cortisol
in Cushing’s disease and increases of cortisol in Addison’s disease help restore affective homeostasis and
euthymia. This suggests that dysregulation of normal
stress responsivity, in either direction, is incompatible
with affective health and that both over- and underactivity of the pituitary–adrenal stress axis is incompatible with affective well-being. In short, stress-cascade
dysregulation appears to be a common characteristic
of depression, as reflected in the failure of the system
to autoregulate, possibly through altered set points
and disrupted feedback in chronic severe stress. It is
common (although not universal) for depression to be
characterized by elevated cortisol levels, especially
in the last third of the sleep cycle, when REM and
excessive cortisol secretion prevails, leading to early
restless sleep and early morning arousals that lead
to sleepless nights (Tsuno, Besset, & Ritchie, 2005).
Additionally, the full neurobiology of stress probably
involves (at a minimum) complex interactions between
stress cascades and their set points, cortisol production,
sympathetic activity, proinflammatory cytokines, and
declines in parasympathetic activity. The relationships
between these various players are nonlinear and
complex (McEwen, 2007), and even an apparently
“simple” stressor (such as sleep deprivation) is capable
of significantly altering all of these processes.
adrenal glands, and this in turn, in a normal neuroendocrine system, causes downregulation of CRF release.
Cortisol feedback appears to have several mechanisms,
including a fast-feedback mechanism more sensitive to
the rate of cortisol increase, operating partly through
cortisol receptors in the hippocampus, while a slower
feedback mechanism, sensitive to steady-state cortisol concentrations, probably operates more through
pituitary, adrenal, and PVN hypothalamic receptors
(PVN receptors are almost all glucocorticoid, GR,
with very few mineralocorticoid, MR, type) (McEwen,
2007). The “fast mode” involves more sympathetic
and behavioral “fight–flight” activation mediated by
CRF1 receptors, while the “slow mode” that promotes
adaptation and recovery is governed by more recently
discovered urocortins, which act through the CRF2
receptor system.
Vasopressin, synthesized in paraventricular and supraoptic hypothalamic nuclei, significantly potentiates
the effects of CRF on ACTH release, and stress upregulates vasopressin also. Thus, vasopressin antagonists
have attracted some theoretical interest as antidepressants (Scott & Dinan, 2002), although perhaps not as
much as CRF antagonists. Underlining the complexity
of the system, while classically inhibiting CRF production in regions like the hypothalamus, corticosteroid
feedback can be excitatory and promoting of CRF
in places such as the amygdala. Additionally, within
extremely stress-sensitive brain regions such as the
hippocampus and other limbic areas, corticosteroid receptors appear in two fundamental varieties—the MR
receptors and GR receptors—with different feedback
effects from these two receptor systems on CRF, on
gene transcription, and on hippocampal neurodynamics. MR (activated by smaller amounts of steroids) is
more implicated in the initial appraisal process and in
the onset of the stress response, while GR (activated
by larger amounts of steroid) helps to terminate stress
reactions and thus facilitates homeostatic recovery. In
the colorful metaphor of one classic reviewer (Tausk,
1952), metaphorically, “glucocorticoids contain the
water damage caused by the fire brigade.” Tellingly,
GR density is highest in the PVN of the HPA axis, in
neurons of ascending aminergic systems, and in other
limbic neurons that might modulate and inhibit PVN
function (Miklos & Kovacs, 2002). Another complexity is that there appear to be various co-modulators
of CRF receptors besides CRF (such as the peptide
urocortin, which activates CRF2 receptors), as mice
with deletions of the CRF gene exhibit apparently
normal stress-induced behavior (for elegant summaries of complex interactions within the HPA axis, see
de Kloet, Joëls, & Holsboer, 2005; Holsboer, 2000;
Basic stress neurophysiology
In terms of the classical stress cascades, CRF is released by the paraventricular nucleus (PVN) of the
hypothalamus (with the PVN presumably driven by a
host of forebrain limbic system structures, especially
the hippocampus), stimulating the release of corticotrophin (ACTH) from the anterior pituitary, which in turn
drives release of glucocorticoids from the cortex of the
22
McEwen, 2007). The utility of animal models in working out the details of what is actually happening within
the “stressed-out” brain is widely recognized (Keck
et al., 2005). For instance, it has recently been demonstrated that for excessive CRF to promote a depressogenic stress cascade, it has to operate with an intact
dynorphin system, and the CRF2 receptor is critically
involved in these interactions between dynorphin and
stress cascades (Land et al., 2008).
Altered stress cascades in depression, separation
distress, and depressive phenotypes
There are intrinsic and powerful linkages between
stress physiology and basic attachment machinery in
the mammalian brain. It is well known that separation
distress is a highly effective instigator of arousal in the
HPA system (Levine, 2001, 2005; Rosenfeld, Suchecki,
& Levine, 1992). Indeed, perhaps the most robust neuropeptide manipulation to generate separation-distress
vocalizations in infant mammals is to inject CRF or urocortin intraventricularly (Panksepp & Bekkedal, 1997).
This finding converges with much other evidence that
separation distress is indeed a prototype stress for the
social brain, with complex relationships between earlyattachment history, genetic endowment, and phenotypes of stress cascades. Early-attachment experience
in mammals appears to permanently mold individual
stress neurophysiology, for better or for worse (Levine,
2001, 2005), pushing the brain onto epigenetic pathways that determine either a reduced or an increased
potential for depressive responses. Underlining these
intimate relationships between stress cascades and attachment, animals subjected to severe separation distress early in life show permanent alterations in the
HPA axis and permanent upregulation of CRF (Heim
& Nemeroff, 1999). Similarly, increased handling and
particularly licking and grooming by maternal animals
appears to result in long-term downregulation of stress
cascades and increased neuroemotional resilience to
stress (Cameron et al., 2005; Meaney, 2001). These
effects of stress on vulnerable brains may be transgenerationally instantiated through multifactorial mechanisms, as recent work has found—for example, that
excessive exposure to glucocorticoids (mirroring high
stress levels) in maternal animals nursing infant pups
led to permanently altered cytoarchitecture in brain dopamine systems in those perinatal infants (McArthur,
McHale, & Gillies, 2007).
That long-term security in a social attachment matrix—in a sense, the antithesis of traumatic attach-
Douglas F. Watt & Jaak Panksepp
ment loss and unmitigated separation distress—might
significantly reduce the long-term risk for depression
is consistent with our primary hypothesis.3 Early evidence thus suggests that maternal attunement and
good maternal care may reflect a powerful neurodevelopmental influence virtually antithetical to stress
(Cameron et al., 2005; Meaney, 2001). Both opioids
and oxytocin significantly inhibit separation distress
(Panksepp, Siviy, & Normansell, 1985; Panksepp et
al., 1980, 1988) (even though oxytocin can also increase the pituitary adrenal stress response). A recent
human study by Heinrichs, Baumgartner, Kirschbaum,
and Ehlert (2003) showed that intranasal oxytocin
lowered free cortisol levels in response to a standardized social stress test, as did social support, and the
combination of both social support and intranasal
oxytocin produced the lowest cortisol concentrations.
Indeed, one interesting conclusion from all this is that
emotional grounding in a good attachment (social
comfort, in other words) and stress may well represent
opposite poles for the “state space” of a social brain.
This also is consistent with our primary hypothesis.
In other words, the basic failure of an attachment
(typically involving protracted separation distress or
related traumatic events) potentially activates chronic
stress cascades in a fashion that leads directly into
depression and, if occurring early in development,
may additionally promote a long-term vulnerability
to depression as well by permanently altering the underlying CNS physiology of stress cascades. Abuse
and neglect may reflect two differential pathways into
severe social stress, presumably with both partially
overlapping and also differential long-term consequences. Childhood mistreatment was shown empirically to permanently alter stress cascades and also to
reduce the size of the corpus callosum and alter structural development of the left neocortex, hippocampus,
and amygdala (Teicher, Andersen, Polcari, Anderson,
& Navalta, 2002; Teicher et al., 2003). Additionally,
low self-esteem (a risk factor for both major depression and dysthymic disorder) appears to impair control
over stress cascades, while high self-esteem individuals demonstrate more rapid attenuation of stress responses in a public-speaking stress paradigm (for a
3
How such emotional resilience and resistance to depression is somehow neurodevelopmentally “transduced” into the brain through maternal
care (and by such behaviors as anogenital licking!) has been substantially
clarified at the epigenetic level (Szyf, McGowan, & Meaney, 2008), but the
sensory inputs into such changing processes remain to be clarified, and they
may be elaborated through long-term changes in the complex brainstem/
limbic trajectories of C-fiber systems.
Depression: An Evolutionarily Conserved Mechanism?
23
fine summary review of stress neurophysiology, see
McEwen, 2007). Public speaking is a robust probe of
the vulnerability to shame, and shame in turn can be
thought of as a cognitive (secondary-process) extension of separation distress (see section on separation
distress). This suggests intimate relationships between
attachment history, self-esteem, adaptive control over
stress physiology, and vulnerability to depression.
Elevated cortisol is one of the best-established markers of adult depression (Burke, Davis, Otte, & Mohr,
2005), even though lower than normal levels are seen
in childhood depression (Kaufman, Martin, King, &
Charney, 2001). The potential therapeutic role of other
neuroactive steroids remains an active line of inquiry
(Dubrovsky, 2006). Excessive activity of the CRF/
ACTH/cortisol system, or, more broadly, perhaps some
form of fundamental dysregulation driven by excessive
emotional activity of various sorts (Maier & Watkins,
2005), has been consistently implicated in depression,
with the most classic early finding being the failure to
suppress endogenous cortisol production in reaction to
exogenous dexamethasone, the classic Dexamethasone
Suppression Test (DST) (Duval et al., 2005; Rush et al.,
1996) and the associated finding of hypercortisolemia.
This so-called nonsuppression response has generally
been thought to index more severe and often psychotic
depressions, although clinical presence of this nonsuppression can be nonspecific, and, conversely, a normal
suppression response does not necessarily mean that
someone is not depressed. However, some work (Zobel
et al., 2001) suggests that a nonsuppression response,
particularly if it does not normalize with treatment,
indexes a greater likelihood of relapse compared to
a DST response that does normalize, suggesting that
these neuroendocrine alterations may more accurately
index some kind of vulnerability to depression rather
than a depressive state per se. Additionally, Holsboer
(2000) suggests that there is blunted ACTH response
to exogenous CRF release while depressed, as well
as normalization of the elevated CRF in cerebrospinal
fluid seen in most depressed patients after clinical remission of depressive symptoms.
An even more sensitive test (although much less
widely appreciated) to detect fundamental HPA-axis
dysregulation in depression combines dexamethasone and CRF (referred to as the “dex-CRF test”;
von Bardeleben & Holsboer, 1988). In this test, patients are treated with a single low dose, typically 1.5
mg, of dexamethasone at 11 p.m. and receive intravenously 100 µg CRF at 3 p.m. the following day. The
amount of ACTH and cortisol subsequently released
is much higher in depressed patients than in euthymic
controls in response to this combined probe, with
the specificity for depression above 80%, depending
on gender and age (Heuser, Yassouridis, & Holsboer,
1994). Whereas CRF-elicited ACTH response is typically blunted in depressed patients, pretreatment with
dexamethasone produces the opposite effect and, paradoxically, enhances ACTH release following CRF
administration. CRF-induced cortisol release is much
higher in these patients who are pretreated with dexamethasone than following CRF alone. Although this
does sound like a convoluted set of interactions, Holsboer (2000) suggests that dexamethasone has little
direct access to the brain and acts primarily at the
pituitary to depress ACTH and that, subsequent to
this, the resulting decrease in cortisol and the failure
of dexamethasone to compensate for the decreased
cortisol levels in the nervous system create a situation
that is sensed by the CNS regulatory elements of the
HPA axis (primarily the hypothalamus) almost as a
transient loss of adrenals. In response to this, there is
a large secretion of central neuropeptides (CRF and
vasopressin) driving production of ACTH and then
cortisol. Again, all of this underlines regulatory failure
in the HPA axis.
Holsboer (2000) argues that when these various
neuroendocrine probes (CRF administration, dexamethasone administration, and the combined dexamethasone/CRF administration) are abnormal,
normalization of the HPA axis often appears necessary
for clinical remission in depressed patients. He also
finds evidence for a shift in the dose–response curve
to higher dexamethasone doses and interprets this as
evidence that negative-feedback mechanisms through
glucocorticoid receptors are impaired in depressed patients. Although the precise molecular mechanisms for
some kind of functional derailment of the HPA axis
remain to be clarified, there is an emerging consensus
that normalization of HPA function may be necessary
for remission of depressive symptoms, and that failure
to normalize HPA function indexes an increased risk
of depressive relapse (Heuser et al., 1996; Zobel, Yassouridis, Frieboes, & Holsboer, 1999).
Consequences for impaired regulation of cortisol
are many, but the most critical ones may be changes in
CNS tissues, especially the impact of excess cortisol
on the hippocampus. Sustained elevation of cortisol is
currently suspected to be the primary etiological factor
for the modest reductions in hippocampal volume seen
in patients with depression and posttraumatic stress
disorder (PTSD) (Dranovsky & Hen, 2006; Jacobs
et al., 2000), although this correlation still remains
controversial. There is evidence also that excessive
24
cortisol disrupts the hippocampus functionally, perhaps
through impairing long-term potentiation (Pavlides,
Nivón, & McEwen, 2002) potentially contributing to
the mild amnestic syndrome seen in many depressions.
Bremner (2000) found evidence that hippocampal volume loss is correlated with the duration of depressive
illness. In animal models, hypercortisolemia appears
to generate a form of excitotoxicity in hippocampal
neurons, particularly pyramidal cells, causing dendritic
spine loss and atrophy and possibly eventual cell death
(Lee, Ogle, & Sapolsky, 2002; Sapolsky, 2003), although reductions in hippocampal volume may only
partly reflect neuronal death. One intriguing hypothesis, by no means proven, is that the above hippocampal
disruptions are critical for the deficit of cortisol-induced negative feedback on the pituitary–adrenal axis
as typically monitored with the DST, particularly in the
ventral hippocampus.
In addition to its role in orchestrating classic stress
cascades, equally important is the fact that CRF is an
essential neuromodulator in a number of core limbic
regions, including the hypothalamus, the amygdala,
the septum, limbic and midline thalamic areas, the bed
nucleus of stria terminalis (BNST), and paralimbic
paleocortical areas such as the cingulate and insula
(Bale & Vale, 2004). A rapidly increasing literature
is directing interest in both CRF and glucocorticoid
receptors as targets for the development of novel nonaminergic antidepressants. Either overexpression of
CRF in transgenic mice, or chronic CRF administration into the brain, generates a phenotype strongly
suggestive of depressive-spectrum responses including hypercortisolemia, decreased appetite and weight
loss, hyposexuality, increased arousal, and anxiety-like
behaviors (Keck et al., 2005). Precisely where in the
limbic circuitry these responses are being generated is
still unclear, but presumably they come through alterations in many of the above-noted core subcortical/limbic systems, with certain hotspots like the bed-nucleus
of the stria terminalis, which contains an abundance
of separation-distress circuitry, likely to be preeminent. As noted earlier, one recent important finding is
that many CRF stress effects are secondarily mediated
through changes in downstream dynorphin dynamics,
which potentially promotes shutdown of the ventral
tegmental area (VTA) (Land et al., 2008).
Antidepressant drug targets implicated in stress
cascades
The above considerations suggest that both CRF as well
as corticosteroid receptors, and also dynorphin, may be
Douglas F. Watt & Jaak Panksepp
highly effective targets for pharmacological modulation of depression. Currently, two primary receptor
subtypes for corticotrophin-releasing factor, CRF1 and
CRF2, are generally acknowledged, and both appear
coupled to G proteins. CRF1 is probably the more
predominant and widely distributed receptor subtype,
with enriched expression in the pituitary and throughout limbic brain regions. Selective deletion of these
receptors tends to curtail classic behavioral responses
to stress (Bale & Vale, 2004; Charmandari, Tsigos,
& Chrousos, 2005; Keck et. al, 2005). Based on this,
there has been a major effort to develop CRF1 antagonists both as anti-anxiety and antidepressant medicines
(Zoebel et al., 2000), but this effort has been plagued
by ongoing major difficulties with side effects, particularly hepatotoxicity. CRF2, which has a more restricted
expression in the CNS, has been targeted more recently
as a receptor of interest in depression, given consistent side-effect difficulties with CRF1 modulation.
CRF2 antagonists do show anti-anxiety and perhaps
antidepressive effects in animal models and significant
efficacy and learned helplessness and chronic stress
depression paradigms in animals. There appears to
be some conceptual debate whether drugs modulating
CRF receptors are “really” antidepressants or are more
anti-anxiety/anti-stress agents (for an excellent review,
see Berton & Nestler, 2006). However, we would argue
that a strict distinction between these is only critical if
one does not presume any necessary etiologic relationship between chronic stress and depression. We would
argue that these may be intrinsically related domains,
especially in a social brain dealing with prototype social stressors such as loss and separation distress.
Glucocorticoid receptors (GR) have also attracted
increasing interest as a potential therapy target in depression. Glucocorticoids diffuse passively through
cellular membranes and bind to intracellular glucocorticoid receptors, precipitating ligand-activated transcription, with the activated genes apparently affecting
many aspects of neuronal function, particularly metabolism, and various aspects of neuroplasticity and
synaptic transmission. Glucocorticoid elevations, of
course, also normally promote termination of classic
stress cascades through at least two neural feedback
loops, as outlined above, with CNS negative feedback
mediated perhaps largely through the more ventral
hippocampus and periventricular hypothalamic areas,
ultimately causing repression of target genes promoting CRF production. Interestingly, a glucocorticoid
antagonist (Mifepristone) has demonstrated efficacy in
psychotic depressions. As noted above, and opposed
to this classic feedback inhibition, glucocorticoids can
exert a promoting effect on CRF expression in other
Depression: An Evolutionarily Conserved Mechanism?
circuits in the brain, particularly the amygdala and bed
nucleus of stria terminalis, which further underlines the
complexity of stress responses, stress modulators, and
CNS architectures involved in stress responses. Thus a
glucocorticoid drug (agonist or antagonist) might well
have differential effects on CRF expression in disparate brain regions, promoting it in some areas while
inhibiting it in others.
As mentioned above, there is fundamental disruption
of normal adaptive feedback suppression of the HPA
axis by glucocorticoids, suggesting that GR negative
feedback on the stress axis is somehow not working, an
effect found in many depressed individuals (although
not universally). Consistent with this is a recent mouse
model reproducing some of the fundamental neuroendocrine alterations in depression that was achieved by
selective deletion of the GR2 receptor in the forebrain
(Boyle et al., 2005). These mice showed a fairly strong
depression-like phenotype, and positive behavioral responses to tricyclic antidepressants, suggesting that this
is indeed an animal-analog to human clinical depression
(see Appendix for animal models) and that depression
may involve some baseline disruption of corticosteroid
signaling in the context of chronic severe stress. Supporting that these correlations are not coincidental,
transgenic mice overexpressing GR2 show increasing
emotional lability in response to stress, along with
enhanced sensitivity to the effects of antidepressants.
Most antidepressant treatments gradually restore negative-feedback inhibition of the HPA axis, an effect that
may arise from increased expression of GR receptors
in the forebrain, particularly in regions of interest such
as the hippocampus (Barden, 2004; de Kloet, Joëls, &
Holsboer, 2005). An interesting and still unanswered
set of questions, however, hinges around the potential
relationships between these complex HPA-axis issues
and BDNF signaling, a neuropeptide that appears to
have effects antithetical to cortisol and stress (see sections on BDNF and neuroplasticity).
Summary of evidence for link between stress
cascades and depression
We believe overall that a “stressed-out” neurophysiology is not just a “peripheral correlate” of depression
(the predominant early assumption in psychiatry), but
that protracted severe stress (with separation distress
as a prototype stressor) may constitute the essential
pathway into depression. In one of the most detailed
reviews of these issues to date in the neuroscience literature, de Kloet, Joëls, and Holsboer (2005) elegantly
summarize the basic data points for this view:
25
• The hyperdrive of hypothalamic corticotropin-releasing hormone (CRF)/vasopressin neurons and
hypothalamic–pituitary–adrenocortical (HPA) hyperreactivity seen in chronic stress occurs also in
major depression.
• Neuroendocrine signs of depression can be discriminated from other stress-induced psychiatric disorders, such as post-traumatic stress disorder (PTSD),
which is characterized by CRF/vasopressin hyperdrive and hypocortisolemia.
• Hypercortisolemia disturbs anxiety and aggression
regulation, producing cognitive impairments that are
associated with a depression-like phenotype.
• Hypercortisolemia disturbs monoaminergic systems
in a manner similar to that observed in depression.
• Hypercortisolemia causes volume reductions in limbic structures, similar to that observed in depression.
• Early-life stress can produce enhanced emotional
and neuroendocrine reactivity, creating a vulnerable
phenotype for depression.
• HPA normalization/dysregulation is an excellent
predictor for both remission/relapse of depressive
symptoms in patients with major depression.
• Intracerebroventricular CRF induces anxiety and a
depression-like phenotype.
• Glucocorticoid receptor (GR) and CRF1 receptor
mutagenesis in mice modulates stress reactivity, anxiety, aggression and cognitive performance.
• Antidepressants enhance limbic mineralocorticoid
receptor (MR) and GR expression in correspondence
with normalization of the HPA axis.
• CRF1 antagonists ameliorate the signs and symptoms
of depression.
• GR antagonists improve psychotic symptoms in depression.
• MR antagonists worsen antidepressant outcome in
depression. [p. 470]
De Kloet, Joëls, and Holsboer conclude that the body
of evidence suggests that sustained hyperactivity of
the HPA axis and MR/GR imbalances, perhaps precipitated epigenetically by early-life stresses and/or
vulnerable genotypes, generates a stress-vulnerable
phenotype that traverses multiple DSM-IV psychiatric
diagnostic categories. Additionally, there is evidence
that the disturbance in the MR/GR ratio may directly
contribute to serotonergic dysfunction in depression
(Young, Lopez, Murphy-Weinberg, Watson, & Akil,
2003), with these 5-HT deficits amplified by the effects
of increased proinflammatory cytokines in chronic
stress (Leonard, 2006). Further underlining intimate
loops between these systems, cytokines also play a role
in impairing HPA-axis feedback (Schiepers, Wichers,
& Maes, 2005).
26
The separation-distress system
Separation distress has been conceptualized as a prototype mammalian emotional system, one of a handful of primary emotional systems, intrinsically part
of bonding and social attachment and prototypically
triggered by separation events in infancy and early
childhood. Separation distress obviously drives reunion-seeking and thus helps to sustain social bonds
in a critical fashion. In simplest terms, separation distress underlines that one cannot love another deeply
and, at the same time, not miss the other at all if that
person is unavailable. Both separation distress and
other aspects of social bonding are heavily regulated
by central neuropeptides, specifically by endogenous
opioids, oxytocin, and prolactin. Localized electrical stimulation of the brain (ESB) in animals (Panksepp, 1998) suggests a distributed network of systems
underpinning this prototype emotional reaction, involving paleocortical regions, particularly anterior
cingulate, the ventral septum, the bed nucleus of stria
terminalis, the dorsal preoptic area, limbic thalamic
areas in dorsomedial regions, and portions of PAG.
Intriguingly, and underlining an intrinsic relationship
between stress and separation distress in mammalian brains, injection of CRF into the ventricles of
young birds will consistently produce a robust and
lasting separation-distress reaction including classic
separation-distress vocalizations, despite the presence
of conspecifics (Panksepp, 1988, 1990; Zhang et al.,
2004). This suggests that CRF facilitates the separation/loss state, which could be viewed as a prototype stressor for young and vulnerable social brains.
Unfortunately, the CRF response is modest and not
as clear in primates (Kalin, 1985) and actually is reversed in rats, where CRF inhibits separation-induced
vocalizations (Insel & Harbaugh, 1989). The reversal
of this response in rats may be due to the fact that
their ultrasonics are not a true social separation-distress vocalization (Panksepp, 2003a), and the milder
effect in primates may reflect the fact that CRF also
promotes fearful responses, and fear is inhibitory of
separation-distress vocalizations.
Correspondingly, injection of nonsedating doses of
opioids (essentially at very low, subanalgesic doses)
will suppress these separation cries with remarkable
effectiveness in dogs, guinea pigs, and domestic chicks
(Panksepp, 1981; Panksepp, Herman, Vilberg, Bishop,
& DeEskinazi, 1980; Panksepp, Normansell, Herman,
Bishop, & Crepeau, 1988; Panksepp, Siviy, & Normansell, 1985), now replicated in many species (Panksepp,
2003a), from rats (Kehoe & Blass, 1986) to primates
(Kalin, Shelton, & Barksdale, 1988). This work high-
Douglas F. Watt & Jaak Panksepp
lights the critical role that endogenous opioids have in
regulating attachment and separation-distress responses
across all species that have been studied. Recent functional imaging work in humans has confirmed findings
from animal models, suggesting that opioids play a
central role in human mood regulation, including the
transitions between more euthymic states and states of
significant sadness (Zubieta et al., 2003). Induction of
a sad emotional state (perhaps the clearest adult human
homologue to infant mammals to separation-distress
reactions) was accompanied by significant decrements
in brain opioidergic tone, particularly in rostral anterior cingulate, ventral pallidum, left amygdala, and
left inferior temporal cortex. Additional findings were
that reductions in opioid tone in rostral anterior cingulate, right ventral pallidum, left hypothalamus, and
left insular cortex predicted increases in negative affect, while reductions in endogenous mu opioids in the
ventral pallidum bilaterally and in the left amygdala
best predicted reductions in positive affect. Follow-up
work has confirmed that opioid circuitry appears “dysregulated” in depression (Kennedy, Koeppe, Young, &
Zubieta, 2006) (for more details, see section on endogenous opioids).
Critical for our discussion, separation distress in
classic work (Bowlby, 1980; Elliot & Scott, 1961;
Panksepp, 1981) suggests an initial protest phase (lasting varying amounts of time in different individuals
and species), followed by a so-called despair phase,
in which animals demonstrate an analog to human
depression, characterized by apathy, lethargy, pining,
social withdrawal, and reductions in crying (Harris,
1989). Critical for the purposes of our discussion is the
transition between the protest phase and the despair
phase, as this transition may best index mechanisms
critically generative of depression. This “cusp” or transition has recently been linked to increased cytokine
production (Hennessy, Deak, & Schiml-Webb, 2001),
along with upregulated dynorphin systems that appear clearly dysphoric (Land et al., 2008) and actually
reduce separation distress and protest. This is important in explaining a key characteristic of the transition to the despair phase of the separation–depression
cascade, as animals cease protesting and “give up”
(Panksepp, Lensing, & Bernatzky, 1989; Panksepp
et al., 1991). Consistent with our hypothesis that depressive shutdown adaptively terminates a potentially
metabolically exhausting separation-protest phase in
infant mammals, there is recent work suggesting similarities between hibernation and human depression, as
antidepressants and mood stabilizers actually prevent
animals from hibernating (Tsiouris, 2005). (See Figures 1 and 2.)
Depression: An Evolutionarily Conserved Mechanism?
Figure 1. Schematic summary of the various influences and levels
of analysis that are important in analyzing the potential nature of an
integrative emotional system for social affect. (Adapted from Panksepp, 1998.)
Figure 2. Human and mammalian separation-distress systems. (Reprinted with permission of the American Association for the Advancement of Science from Panksepp, 2003a.)
Neural network perspectives: regions of interest
Functional imaging of depression
As Berton and Nestler (2006) point out, if one were
allowed to carry out brain biopsies on patients with
major depression, it is far from clear what the target re-
27
gions of interest might be for such a biopsy or, indeed,
even what one might look for in terms of fundamental
alterations in tissues. However, there is a body of
literature implicating a group of core structures, including hippocampus and both medial (cingulate) and
dorsolateral prefrontal cortex, amygdala, nucleus accumbens, hypothalamus, and multiple monoaminergic
systems. Although the fundamental neurodynamic and
neuromodulatory alterations in these structures remain
unmapped, depression appears to generate a complex
and global “change in state” in most if not all of these
systems, suggesting fundamental shifts in corticolimbic functional connectivities. Several functional imaging studies have shown hypoactivity in dorsolateral
prefrontal cortical systems (Fitzgerald et al., 2006),
shifts that presumably correlate with diminished working memory processes, including altered balances between right and left regions, perhaps biasing cognitions
more toward negative affective processing (Grimm
et al., 2008; Northoff, 2007). This is accompanied by
diminished frontal cortical size (paralleling changes
in closely connected hippocampal regions) with the
most disruption to medial frontal zones (Steele, Currie, Lawrie, & Reid, 2007), which are areas known to
be important in emotional and self-related information
processing (Northoff et al., 2006; Panksepp & Northoff, 2009). Additional support for a corticolimbic
network hypothesis about depression comes from a
recent fMRI antidepressant study (Anand, Li, Wang,
Gardner, & Lowe, 2007) showing changes in corticolimbic connectivity after six weeks of treatment with
Zoloft, with diffusion tensor imaging demonstrating
increasing cortical regulation of limbic mood-generating circuitry.
A most striking recent demonstration of intimate
relationships between depression and alterations in
corticolimbic networks has come from recent ESB
trials with individuals suffering from drug-treatment
refractory depression. Mayberg et al. (2005) suggest
that refractory depressions are typically associated
with hyperactivation of the subcallosal cingulate, and
her group found that ESB-induced disruptions of this
hyperactive subcallosal cingulate region (Brodmann’s
area 25, consisting largely of white matter tracts)
showed impressive efficacy in treating otherwise severely refractory depressions. Although this study did
not have a control group, and was clearly not even
singly blinded (which would require sham craniotomies), five out of six patients with severe refractory
depression responded positively to this form of ESB,
with four out of six showing complete remission. Several previous studies (Mayberg et al., 1999, 2000) had
shown antidepressant efficacy correlated with reduc-
28
tions in the area 25 activity. It has been known for
some time that this area of the cingulate is regarded as
the most “affective/autonomic” region of the cingulate
and that it has the richest connections of any cortical
area to a host of structures involved in separation distress in animal models, including the bed nucleus of
stria terminalis, the septal regions, the preoptic areas of
the hypothalamus, as well as several other hypothalamic regions, along with limbic thalamic areas including
medial dorsal and other midline heteromodal groups,
and periaqueductal gray (Vogt & Gabriel, 1993).
What might contribute to this refractory phenotype
in terms of either genes or life history is almost totally
unknown. However, that area 25 may exercise a role in
the transitions from separation distress to depression
is a concept that needs more empirical attention. An
attractive hypothesis from Mayberg et al. (2005) is that
in a certain percentage of patients plagued by refractory depression, area 25 becomes a kind of malignant
coordinator of refractory depression and generates a
malignant shutdown of attachment-related behaviors
and emotions. This was poignantly suggested in detailed descriptions of patient behaviors as they underwent initial brain stimulation, in which disrupting the
hyperactivity of this brain region produced immediate
phenomenologic change in the direction of prosocial
connection and antidysthymia effects. Shortly after
area 25 stimulation, treatment-refractory patients consistently described similar affective changes: “calmness or lightness,” disappearance of the “depressive
void,” a sense of increased awareness, increased interest, and increased sense of social connectedness
and caring coming from others, and even sometimes
a sudden visual brightening of the room. These effects were reversible, reproducible, and time-locked
with actual brain stimulation, but not with sham or
subthreshold stimulations. Associated with these affective/phenomenologic changes were clear improvements in psychomotor speed and output, interestingly
without discernible autonomic effects. One woman
(“A Depression Switch?” New York Times, 2 April
2006) poignantly described how her characteristic and
chronic emotional “deadness” and emptiness were almost immediately supplanted by an awareness that her
treatment team actually did care about her, suggesting
that social bonding is directly managed by area 25
networks and is not simply a result of more slowly
accumulating downstream second- or third-messenger effects (although those may contribute as well).
Although small N-case descriptions, without proper
double-blinded controls, cannot be used to frame more
than preliminary hypotheses, these descriptions suggest that the termination of depression in these refrac-
Douglas F. Watt & Jaak Panksepp
tory patients is directly hinged to the reestablishment
of a more normal sense of social connection and social
comfort. This is consistent with our core hypothesis,
and it suggests an intrinsic and intimate relationship
between termination of depressive shutdown and resumption of normal social relatedness.
These findings argue that electrical brain stimulation
in area 25 promotes disruption of a global shutdown
mechanism at the core of depression. Evidence from
other functional imaging work in humans argues that
Brodmann’s area 25 participates centrally in sadness,
the adult human homologue for infant mammal separation-distress reactions (Panksepp, 2003b), suggesting
that this is a vital region of interest for understanding the relationship between separation distress and
depressive states. How this region and its functional
states might link up with stress cascades and multiple
modulatory shifts is unclear, but we would hypothesize
that there is likely to be an intimate relationship between area 25 functional and neurodynamic alterations
in sadness reactions and depression, stress cascades,
and alterations in opioidergic and oxytocinergic transmission. We already have solid evidence that shifts in
opioidergic transmission in anterior cingulated regions
are centrally involved in sadness reactions (Zubieta et
al., 2003). Further work is required to elucidate precisely what is going on in area 25, as patients transition
from acute separation distress and sadness (short-lived
depressive responses?) into chronic depression. Our
working hypothesis is that brain regions that initially
coordinate separation-distress and sadness reactions
undergo some kind of neurodynamic shift over time to
coordinate the shutdown of separation distress and the
initiation of depression.
Neuromodulatory perspectives: affect
modulatory neuropeptides
In addition to more classical aminergic-centered
perspectives on depression, there are multiple neuropeptide perspectives, including those emphasizing
CRF/glucocorticoid dynamics (the HPA-axis hyperactivity hypothesis) as well as endogenous opioid,
cholecystokinin, dynorphin, galanin, orexin, oxytocin,
substance P, various neurotrophins (e.g., BDNF), and
multiple cytokines. Interactions between peptide and
amine systems and cytokine–neurotransmitter interactions remain incompletely mapped, even though
anatomically it is known that many neuropeptides innervate key aminergic cell groups such as the LC,
raphe, and VTA. Psychiatry is just starting to generate
sustained research initiatives into the role of neuro-
Depression: An Evolutionarily Conserved Mechanism?
29
peptides in depression and other DSM-IV syndromes
(Holsboer, 2003).
depression. The problem was that with tolerance and
the need for increasing doses, not only was addiction and abuse made more likely, but a depressive
crash following opioid withdrawal typically left patients with an intensified sense of psychic pain and
despair. Since the “opiate cure” could thus often lead
to the worsening of the depressive condition following
a most painful withdrawal process, there has been a
sustained (and in our view scientifically regrettable)
skepticism about opioids having any utility in depression. Although now there exist opiates with much less
abuse potential (mixed agonists–antagonists, such as
buprenorphine), the psychiatric community almost religiously avoids even mentioning opioids in the treatment of depression, or as a prominent candidate for
alleviating the pleasure deficits that characterize the
depressive cascade, largely out of fear of directly or
indirectly promoting addiction. In view of the power
of opioids in alleviating separation distress and in promoting feelings of pleasure and satisfaction, and the
importance of an endogenous pleasure deficit in many
forms of depression, this seems a problematic omission (Callaway, 1996). Underlining the importance of
this neglected system, recent work suggests that two
agents traditionally viewed as classically aminergic
(venlafaxine and mirtazapine) indirectly promote a
variety of opioid systems, with this potentially underpinning their increased efficacy in severe depression
(Schreiber, Bleich, & Pick, 2002).
Indeed, we would argue that the ongoing systematic neglect of the obvious implications of endogenous brain opioids for a better understanding and
potential treatment of depression is mostly driven by
an undesirable combination of big pharmacology economics and widespread addiction-phobia. One highly
informative study attempted to mitigate this neglect
by evaluating buprenorphine (a partial agonist at mu
receptors and an antagonist at kappa receptors) in an
open trial with patients who had all failed with many
other medications (Bodkin, Zornberg, Lukas, & Cole,
1995). The strikingly positive findings suggest that reexamination of opioid neuropeptide systems and their
potential role in depression is overdue. Bodkin and
colleagues found evidence that buprenorphine was an
effective antidepressant with a very low risk of addiction (because as a partial agonist, it shows antagonist
effects at higher doses) in patients with moderate to
severe depression. An open and unanswered question
around buprenorphine is whether its therapeutic efficacy in the study was due primarily to its mu agonist
effects, its kappa antagonism, or a (presumably) desirable combination of both. Also, this work needs to be
replicated using gold-standard double-blind, placebo-
Corticotrophin-releasing factor
As already noted in previous sections, the dysphoriapromoting neuropeptide that has received the most
attention in depression studies is CRF, which lies at the
very apex of the classical HPA stress response. Excessive brain release of CRF, with pituitary ACTH oversecretion, leads to chronically elevated cortisol, but
along with dysregulate cortisol feedback to the brain
effectively inhibiting the arousal of the brain stress
axis. This may lead to excessive CRF within the brain
and the promotion of anxiety, stress-related behaviors,
and dysphoric affects (Kehne, 2007; Nemeroff & Vale,
2005). However, CRF interacts with a large number of
other peptide systems in addition to activating norepinephrine arousal within the brain. For instance, some
of the affective-depressogenic and anxiogenic effects
of CRF may operate indirectly through activation of
dynorphin (Land et al., 2008) and cholecystokinin systems (Becker et al., 2008).
Opioids systems (mu opioids)
Currently, the mu-opioid system is almost totally neglected, even in excellent traditional reviews of depression (see Berton & Nestler, 2006); this neglect occurs
despite abundant long-term evidence that opioid chemistries inform nearly every aspect of pleasure in mammalian brains (Berridge, 2004; Panksepp, 1998). The
second author was the originator of the opioid theory
of social attachment (Panksepp, 1981), arguing over
25 years ago that opioids regulated social connection
and that attachment was like an endogenous opioid
addiction in which interactions with a significant other
were responsible for promoting sustained tonic opioid
release in the brain. At the top of the list of instructive
data points, mu opioids, along with oxytocin, are the
two most effective molecules in suppressing separation-distress vocalizations in animals (Panksepp, 1998;
Panksepp, Herman, Conner, Bishop, & Scott, 1978;
Panksepp, Vilberg, Bean, Coy, & Kastin, 1978; Panksepp et al. 1980), and as already noted, there is now
solid evidence that low opioid tone contributes to
separation-distress and sadness reactions in humans
(Zubieta et al., 2003) (see separation-distress system
section). Indeed, prior to the modern era of psychopharmacology starting in the 1950s, opiates were about
the only drug available that were effective in treating
30
controlled methodologies. In any event, in the open
trial conducted by Bodkin and colleagues, 10 treatment-refractory, unipolar, nonpsychotic depressed patients were treated with low doses of buprenorphine.
Of these patients, 3 terminated treatment quickly because of nausea and feelings of malaise, a not unusual problem in opiate-naïve subjects. The remaining
7 completed four to six weeks of treatment and as
a group showed clinically striking improvement in
both subjective and objective measures of depression.
Much of this improvement was observed significantly
more rapidly than with traditional monoamine agents
(which had been unsuccessful in these patients). All
showed significant improvement by the end of the first
week of treatment. Improvements persisted throughout the trial. Benefits were achieved by 4 of these 7
subjects within a few days of starting the medication
and complete remission by the end of the drug trial
(with Hamilton Rating Scale for Depression scores
less than or equal to 6), 2 were moderately improved,
and only 1 showed any kind of deterioration after a
period of improvement (this elderly patient had many
other “realistic” health and family worries).
It is worth emphasizing that this trial was conducted
on a treatment-refractory group of patients, among
whom only 7 subjects chose to complete the full drug
trial (whether patients who experience nausea might
benefit if given anti-nausea agents needs to be evaluated). It is impressive that 6 of the 7 got significant benefit, while 4 of the 7 showed complete and sustained
remissions. One suspects that any aminergic agent
able to demonstrate remotely comparable efficacy in
refractory depression (none exists!) would be vigorously promoted by pharmaceutical companies. Curiously, there has been not a single follow-up study in the
literature with full controls. One can only conclude that
“addiction-phobia” and medical economics in which
off-patent agents are seen as unattractive by large
pharmaceutical firms have seriously affected our view
of buprenorphine, which combines two desirable properties from a theoretical standpoint (partial agonism
of mu receptors, along with kappa antagonism). Use
of pro-opioidergic modulators to treat depression may
unfortunately only occur after patentable new agents
are developed. One such strategy is to enhance endogenous opioid activity by development of agents that
block their breakdown—for instance, enkephalinase
inhibitors that increase enkephalin signaling (Noble
& Roques, 2007). However, the absence of depressive
symptoms in preproenkephalin knockout mice might
speak against the critical role of changes of enkephalin dynamics in animal models of depression (BilkeiGorzo, Michel, Noble, Roques, & Zimmer, 2008) (this
Douglas F. Watt & Jaak Panksepp
seems possibly premature to conclude without knowing a lot more about how such a knockout would affect
limbic development and behavior; there could be a host
of compensatory processes recruited that might prevent
depressive phenomena in such a knockout model). Of
course, there are such a large number of endogenous
opioids in the brain that evidence against one opioid
peptide is not evidence against all. We anticipate that
deficits in the most powerful separation-distress-alleviating mu opioids—the endorphins (Panksepp, Vilberg, et al., 1978)—will prove to be more influential
in the genesis of depression. Conversely, excesses of
the most dysphoric of the opioids—dynorphins—may
promote depression.
Dynorphins
Kappa opioids have recently come under increasing
interest as mediators of depressive processes, due to
emerging evidence that they may regulate negative/inhibitory feedback on the ventral tegmental mesolimbic
dopamine system, a primary candidate mechanism to
explain global motivational shutdown and anhedonia
in depressive states. It has been known for a long time
that administration of kappa-opioid agonists produces
aversive feeling in animals, as evaluated with conditioned place-preference paradigms, and other behavioral symptoms of depression (Bals-Kubik, Ableitner,
Herz, & Shippenberg, 1993; Carlezon et al., 2006).
In humans, dynorphin agonists provoke strong, almost psychotic-like dysphoric states (Hasebe et al.,
2004), characterized by “disturbance in the perception
of space and time, abnormal visual experience, disturbance in body image perception, de-personalization,
de-realization and loss of self control” (Dortch-Carnes
& Potter, 2005, p. 195). This type of psychotic dysphoria seems to be a characteristic of all the kappareceptor agonists. For instance, Walsh, Strain, Abreu,
and Bigelow (2001) found consistent ratings of “bad”
subjective ratings in humans treated with the kappa
agonist enadoline. A characteristic description of effects was “within 10 min after receiving the injection,
he reported unusual sensations, including the floor
moving and his skin prickling. He became agitated, began swearing, mistrusting others, and accused staff of
seeking to harm him.” Clearly, these effects are much
more than depressive affect, with symptoms of strong
dissociative psychosis, and the basis for this dissociative aspect remains poorly understood.
In any event, dynorphins are very widespread in the
brain and are co-localized with many neuropeptides
that may help either alleviate or prevent depression,
Depression: An Evolutionarily Conserved Mechanism?
31
including oxytocin and orexin. Dynorphins are also
abundant along dopamine pathways, and they generally counteract the euphoria promoted by dopaminergic
arousal, even to the point where such agents have been
proposed as treatments for cocaine craving (Mello &
Negus, 2000). Dynorphins reduce the potency of brain
self-stimulation reward (Todtenkopf et al., 2004), and
they are elevated during depressive withdrawal processes, when animals are withdrawn from rewarding
psychostimulants (Hurd, Svensson, & Ponten, 1999).
Hurd et al. (1997) found evidence that messenger
RNA for dynorphin was increased in “patch” versus
“matrix” compartments of the basal ganglia system in
depressed subjects who committed suicide, consistent
with the primary peptidergic comodulation of “patch”
compartments, and with the primary role of the patch
compartments in modulating more limbic emotional
networks versus the classic sensorimotor targets of the
matrix compartments. Some of the aversive effects of
otherwise-rewarding drugs such as cannabanoids are
eliminated when dynorphin is taken out of the equation
(Zimmer et al., 2001), and the dynorphin-like neuropeptide nociceptin inhibits the rewarding effects of
most drugs of abuse (Kotlinska et al., 2003).
In other words, by promoting dynorphin-like activity in the brain, all kinds of pleasures seem to
be reduced. Thus, there is considerable excitement at
present about the possibility of evaluating dynorphin
receptor antagonists for their antidepressant effects.
Preclinical work on these compounds has been promising (Land et al., 2008; Mague et al., 2003; McLaughlin
et al., 2003). Additional support for dynorphin playing
a generative role in depression comes from the work
of Carlezon et al. (2006), who found that application
of the selective kappa agonist salvinorin A produced
depressive behavioral phenotypes in rodents, specifically behavioral depression in the forced swim test and
in self-stimulation tests, two critical behavioral tests
central to antidepressant drug design. In a complementary study, Mague et al. (2003) found that administration of a kappa antagonist generated prolonged forced
swim test behavior, suggesting increased resistance
to depression and emotional resilience. Underlining
potential intrinsic connections between kappa opioids
and stress, the evidence is that kappa opioids are promoted directly by stress cascades, possibly through a
D1 receptor interaction (Berton & Nestler, 2006).
All of this suggests close intrinsic linkages between
social comfort on the one hand and the protection
against depression (by promotion of mu opioids and
inhibition of kappa opioids), and separation distress
and depression on the other hand (by the downregulation of both mu-opioid and oxytocin systems and
upregulation of kappa opioids). These considerations
further support our primary hypothesis and suggest
that both the mild mu-opioid stimulation and kappaopioid inhibition effects of buprenorphine are ideally
suited to produce a doubly positive effect on these reciprocal pleasure-modulating chemistries of the brain.
One of the problems in pursuing such work is that currently most kappa antagonists have remarkably strong,
at times irreversible, binding to dynorphin receptors,
such that the effects of a single administration of
these agents can produce blockade for up to several
week after a single administration. However, we would
like to re-emphasize that the excellent kappa-receptor antagonism effects of buprenorphine, along with
rapid restoration of pleasure from the mu-receptor activation, may explain its ability to alleviate depression
more rapidly than do traditional agents (see above).
However, it is now important to determine, perhaps
initially through the use of animal models, how much
the drug’s therapeutic efficacy is due to its mu-agonist
effects, its kappa-antagonist effects, or—as is most
likely—the synergistic effects of both.
Cholecystokinin, oxytocin, substance P, and other
neuropeptides
There are many other neuropeptides that hold promise
as being significant vectors in contributing to depressive affect. We will only touch on them briefly, as the
amount of critical evidence remains modest. However,
considering the fact that neuropeptides add a great deal
of emotional specificity to the neurochemical control
of affect (Panksepp & Harro, 2004), these agents will
continue to attract increasing attention in the search for
better, more rapidly acting, and more specific therapeutic agents.
Cholecystokinin (CCK) has long been a candidate
as a neuropeptide that facilitates negative affect, especially of the type that is typically encapsulated by
the term “anxiety” (Harro, Vasar, & Bradwejin, 1993).
Abundant preclinical evidence has implicated changing CCK dynamics in social loss as studied in resident–intruder paradigms (Becker et al., 2001, 2008;
Kroes, Panksepp, Burgdorf, Otto, & Moskal, 2006;
Panksepp, Burgdorf, Beinfeld, Kroes, & Moskal, 2007;
Panksepp et al., 2004), but there are currently no substantive clinical data indicating that blockade of this
affectively negative neuromodulator will alleviate any
form of depression.
Oxytocin becomes a major candidate as a potential
alleviator of depression in its role of being a major
modulator of separation distress (Panksepp, 1998) and,
32
next to opiates, the best candidate for a key mediator
of social attachments (Nelson & Panksepp, 1998).
Hence, it would be anticipated that facilitation of brain
oxytocin dynamics could yield some antidepressant effects. Indeed, the three-amino-acid tail of the oxytocin
peptide (Pro-Leu-Gly) has been demonstrated to have
antidepressant effects in both animal and human studies (Ehrensing, Kastin, Wurzlow, Michels, & Mebane,
1994).
Based on the fact that substance P antagonists can
reduce separation distress (Kramer et al., 1998), it was
proposed that the receptor antagonists of this peptide
might have antidepressant properties. After some initial promising results, it was clear that such effects
were not unambiguously evident. Indeed, based on the
fact that substance P is present in the RAGE pathway
(from medial amygdala to medial and anterior hypothalamus), where it facilitates aggressive attack behavior and anger displays (Bhatt, Gregg, & Siegel, 2003),
it could be argued that the more appropriate target for
substance P antagonists might be extreme irritability
and, perhaps, explosive disorders (Panksepp & Harro,
2004).
There are probably many other neuropeptides that
figure significantly in various depressive states but
where hard data remain thin. For instance, global brain
arousal is regulated by highly localized orexin-containing neurons in the lateral hypothalamus (Harris & Aston-Jones, 2006; Jones, 2005), and the depressogenic
effects of dynorphin agonists may be partly due to suppression of orexigenic transmission. Whether orexin
agonists can ameliorate some symptoms of depression
remains to be seen.
Thyrotropin-releasing hormone is also an arousalfacilitating neuropeptide, and hypothyroid states are
commonly accompanied by depressive side effects.
Although TRH by itself has not proved to be a reliable
antidepressant, it appears capable of speeding up the
onset of affective relief with traditional antidepressants, such as SSRIs, that take many weeks to yield full
therapeutic effects (Lifschytz et al., 2006).
The molecular regulators of immune modulation, the
cytokines, are receiving ever more attention by depression researchers (De La Garza, 2005). Considering that
the “despair” response that follows prolonged social
separation may have many similarities to “sickness behavior” and may be associated with a spike of cytokine
production (Hennessy, Deak, & Schiml-Webb, 2001),
neural-immune interactions may be critical to genesis
of some depressions. Investigators have found that administration of sickness-behavior-promoting cytokines
such as interleukin-1 (IL-1) can provoke behavioral
responses in animal models that resemble the outward
Douglas F. Watt & Jaak Panksepp
symptoms of depression (De La Garza, 2005). All of
these issues suggest a multiplicity of interacting and
looping control systems affecting fundamental moodgenerating and mood-regulating machinery. Evidence
for such recursive and multifactorial control architectures can no longer be considered novel or surprising in
virtually any area of neuroscience.
Brain-derived neurotrophic factor
Several recent reviews (Kozisek, Middlemas, & Bylund, 2008; Martinowich, Manji, & Lu, 2007) have
emphasized a major paradigm shift in psychiatry regarding the treatment of depression, away from the assumption that alterations in monoamine dynamics are
directly therapeutic in depression toward an increasing
weight of opinion that these monoamine manipulations
might have their therapeutic effect generated primarily via monoaminergically mediated upregulation of
BDNF (Martinowich & Lu, 2008). The current challenge is to identify how BDNF generation and promotion of neuroplasticity might ameliorate depressive
cascades (Groves, 2007; Martinowich, Manji, & Lu,
2007; Shelton, 2007).
Neural network perspectives: BDNF and
neuroplasticity
In the late 1990s, there began to emerge an increasing
interest in conceptualizing depression in increasingly
molecular/cellular terms, as a degradation of neuroplasticity (see Duman, Heninger, & Nestler, 1997),
based on increasing knowledge of how long-term antidepressant treatments result in the sustained activation
of the cyclic AMP system in specific brain regions,
including expression of the transcription factor cyclic
adenosine monophosphate response element-binding
protein (CREB). The activated cyclic adenosine 3′,5′monophosphate system was thought critical to the upregulation of specific target genes, including increased
expression of BDNF in regions such as the hippocampus and cerebral cortex. Stress, on the other hand,
decreases expression of BDNF, leading to atrophy of
these same hippocampal neurons; this perspective is
also supported by clinical imaging studies (Kanner,
2004). Emerging evidence also suggested that the degree of hippocampal atrophy or hippocampal volume
loss is determined by the duration of the depressive
illness, suggesting that stress cascades progressively
thin out hippocampal dendritic spines (Bremner et
al., 2000; Sheline, Sanghavi, Mintun, & Gado, 1999).
Depression: An Evolutionarily Conserved Mechanism?
33
These initial probes informed an updated molecular
and cellular hypothesis of depression emerging in the
late 1990s, arguing that both stress-induced vulnerability to depression and the therapeutic action of
antidepressant treatments occur via linked intracellular
mechanisms that decrease or increase, respectively,
neurotrophic factors necessary for the survival and
function of particular neuronal populations. Recent
work argues, however, that BDNF, like the monoamines, appears to have a “permissive” or indirect
regulatory influence on mood (although, again, precise
mechanisms remain elusive), but BDNF does not appear to be a direct mediator of mood state (Martinowich, Manji, & Lu, 2007). Supporting this conclusion
is emerging evidence that genetic alterations in BDNF
signaling pathways, including alterations in its receptor (TrkB), do not readily cause any clear depressive
behavior to emerge in animal models, but they do
interfere with the effects of antidepressant drugs in
relationship to depression and chronic stress. Further
complexities involve the manner in which upregulation
of hippocampal BDNF appears behaviorally opposite
to effects of upregulation of BDNF in VTA and nucleus
accumbens, which appears prodepressive (Nestler &
Carlezon, 2006). This suggests that fundamental work
remains to untangle more precisely the various regulatory roles played by BDNF in the maintenance and
modulation of mood.
In any case, unmitigated stress cascades appear to
drive the brain’s affective systems into a dysphoric
state that can be reversed by chronic antidepressant
administration, but increased serotonergic and noradrenergic tone may be important not as primary generators of euthymia, but via promotion of cAMP–CREB
cascades, leading to increased BDNF. However, this
perspective leaves quite unspecified the putative links
between mood and such pro- versus anti-neuroplasticity factors. Why would animals and humans with
better neuroplastic/neurotrophic brain environments
and bigger hippocampi necessarily be happier? Why
would animals and humans with impaired neuroplastic capacity or “pruned-out” hippocampal dendritic
spines necessarily be depressed? While we do not
have a clear answer to this question, there may be two
dimensions to a possible set of answers. One dimension involves a functional distinction between dorsal
and ventral hippocampal systems, with clear evidence
that dorsal systems are much more involved in classic
spatial memory and learning, while ventral portions of
the hippocampus, particularly the dentate gyrus, have
classic limbic connectivities (including centrally the
nucleus accumbens, VTA, hypothalamus, bed nucleus
of stria terminalis—all systems centrally involved in
separation distress) and may play a central role in
mood regulation, including regulation of both the mesolimbic dopamine system and the HPA stress axis
(Sahay & Hen, 2007). This suggests that neurogenesis
in the ventral portions of the hippocampus may be particularly critical to mood regulation and modulation of
stress reactivity, but it should be remembered that so far
the hippocampal neurogenesis story is based largely on
correlative rather than causal evidence (for details, see
the excellent review by Sahay & Hen, 2007). Additionally, mechanistic/molecular links between impaired
neuroplasticity and brain shutdown may be intrinsic. In
other words, any global shutdown mechanism would
presumably have to affect neuroplasticity in a negative
fashion, as a shutdown brain could not possibly be optimally tuned for either affective or cognitive learning,
since this would almost be a contradiction in terms. In
that sense, we would argue that impaired neuroplasticity may be derivative of this fundamental shutdown
process—in a direct sense, a cellular–molecular manifestation of it—but this working hypothesis currently
has no direct support. One testable prediction would be
to see whether neurochemistries that seem to contribute to depressive despair, such as dynorphin and cholecystokinin, tend to generate the same stress-induced
reductions in brain plasticity associated with classic
chronic environmental stress paradigms.
Neural network perspectives: possible
neuromodulatory interactions in depression
A popular metaphor about intact adaptive brain function is that it seems to depend consistently on a “balanced symphony” of neuromodulators. In terms of this
metaphor, there needs to be a balance between percussion instruments and wind instruments, with neither of
these drowning out the string section, and so forth. Of
course, such metaphoric pictures do not give us heuristics for understanding neuromodulatory interactions
in a more precise or detailed fashion. However, there
is increasing awareness that multiple aminergic and
peptidergic systems are extensively interdigitating and,
indeed, may show a deep mutuality of regulatory influences on each other, although formal investigations
into these interactions are just starting to be undertaken
and appreciated. Figure 3 attempts to outline some of
these relationships in a schematic form.
An interesting implication of this schematic is that
we could predict that declining opioidergic and oxytocinergic tone, along with upregulation of CRF and
dynorphin, with all of these changes potentially associated with separation distress and other classic stressors,
34
Figure 3. Schematic for potential interactions between core neuromodulatory systems. Dashed lines denote inhibitory relationships, solid
lines excitatory/promoting relationships. Raphe = 5HT/serotonin; LC
= locus coeruleus/norepinephrine; VTA = ventral tegmental area/dopamine; CRF = corticotrophin-releasing factor; GABA = gamma amino
butyric acid; SP = substance P; GLU = glutamate. (Modified from
Ordway, Klimek, & Mann, 2004.)
would lead to hypotonicity of both serotonergic and
dopaminergic systems, along with potential overdriving of the LC. We also saw in our review of dynorphin in the nucleus accumbens that promotion of this
negative opioid system could feedback also on VTA to
produce declining motivation and a kind of affective
shutdown. However, this is clearly a deeply interactive
and interregulating set of neuromodulatory systems,
and such hypotheses of aminergic disruption from primary peptidergic changes, although attractive, have yet
to be clearly established. (See Table 1.)
Testable predictions from primary hypothesis
and questions on the frontier
Our review of the neuroscience literature underlines
several areas of continuing ignorance, and these include centrally the following unexplored questions and
issues, along with three predictions (see the final five
items):
1. In terms of hippocampal/HPA-axis/BDNF interactions and depression, there are many questions
about the precise relationships between monoamine systems, cytokines, BDNF, the HPA axis,
hippocampal volume, and mood. Does blocking
upregulation of BDNF in human clinical popula-
Douglas F. Watt & Jaak Panksepp
tion prevent antidepressant efficacy, even if/when
there is downregulation of serotonergic and noradrenergic receptors following classic antidepressant
administrations? Would blocking normalization of
the HPA axis and stress cascades (perhaps via a
glucocorticoid manipulation?) while allowing the
upregulation of BDNF prevent antidepressant efficacy? Is the antidepressant efficacy of BDNF
expressed more through trophic affects on ventral
hippocampus and its relationships with mood-generating systems including the hypothalamus? Conversely, would blocking BDNF expression in the
accumbens be antidepressant? Would blocking cytokine production allow more rapid normalization
of the HPA axis? Would it even be sufficient for a
full antidepressant response?
2. What role does serotonin 5-HT2 play in potentially
facilitating separation distress, given evidence that
this subset of serotonin receptors is critically involved in dysphoric states?
3. Can sustained artificial activation of the CRF within
the brain (while blocking peripheral elevation of
stress cascades) promote a depressive cascade?
4. Can the mere CNS neurochemical facilitation of
peptides that seem to figure in depression, such as
dynorphin and cholecystokinin, promote a depressive phenotype in humans?
5. What roles do pleasure-promoting molecules such
as endogenous opioids that facilitate mu- and deltareceptor activation have in the genesis and alleviation of depression?
6. To what extent are higher cognitive changes (e.g.,
dysphoric ruminations, as in right dorsolateral frontal cortical working memory fields) necessary for
sustaining depressive affect? To what extent do just
subcortical neurochemical/affective changes suffice
for sustaining depression?
7. Can one generate depression with virtually no major
changes in biogenic amine systems?
8. How do somatic therapies work to alleviate depression, especially new modalities such as transcranial
magnetic and vagal stimulation?
9. For that matter, how does ECT work? Despite piles
of correlates in terms of putative ECT effects, this
remains an unknown for our arguably single most
powerful biological therapy.
10. Predictions:
i. Joint pharmacological promotion of mu opioids and oxytocin and simultaneous inhibition
of kappa opioids and inhibition of CCK might
Depression: An Evolutionarily Conserved Mechanism?
Table 1.
35
Summary of current major treatments for depression and their primary effects
Treatment for depression
Relative effectiveness
Primary effects (?)
Tricyclics
Probably somewhat more effective than SSRIs
but with major side effects
Blocking reuptake of 5-HT and NE
MAO inhibitors
Probably somewhat more effective than SSRIs
but with major side effects
Preventing breakdown of monoamines via
MAO-A inhibition
SSRIs
Roughly 50% efficacy for any one drug,
roughly 65% efficacy after using or trying
several drugs.
Blocking reuptake of serotonin
SNRIs
Roughly 50% efficacy for any one drug,
roughly 65% efficacy after using or trying
several drugs.
Blocking reuptake of norepinephrine
Atypical antidepressants
Variable; often used as adjunctive agents, with
SSRIs/SNRIs.
Wellbutrin mostly DA reuptake;
Tianeptine ↑ uptake of 5-HT;
Mirtazapine 5-HT2 blockade, but multiple
effects?
Mixed 5-HT/NE reuptake
inhibitors
Probably somewhat more effective than “pure” Blocking of reuptake for both norepinephrine
NE or 5-HT reuptake inhibitors
and serotonin
Lithium
Regarded as adjunctive for monopolar
depression, preventative for bipolar
Many molecular effects, but therapeutic
mechanism is unknown
Electroconvulsive therapy
(ECT)
Highly effective, 80–95%, single most
effective therapy, although some patients
remain refractory; those do appear to respond
to deep brain stimulation of area 25
Unknown. Re-baselining of neuromodulatory
systems? Increased BDNF? Increased
monoamines and GABA? Promotion of delta
opioids? Hypothalamic and HPA axis rebaselining?
Regional transcranial magnetic
stimulation (TMS)
Although initial studies suggested effectiveness Inhibition versus excitation of prefrontal
on a par with ECT, a recent study did not
cortical (PFC) tissues, promoting left PFC
support this
and/or inhibiting right PFC
Vagal nerve stimulation
Regarded as adjunctive to other therapies for
refractory depression
Unknown, but presumably activates
parasympathetic nuclei in the lower brainstem,
which may promote effects on PAG & other
limbic structures
Psychotherapies
Variable. More effective in less severe
depression and in depression associated with
trauma
Empathic support promoting reduced stress,
improved regulation of negative states, and
prosocial responses? Promotion of opioid and
oxytocin systems?
Deep brain stimulation
Only one pilot study, but in severely ill and
highly refractory population, 5/6 patients
showed major benefit
Neurodynamic disruption of overactive
subcallosal cingulate (area 25)
NMDA antagonism
Rapid onset; degree of relative effectiveness
largely unknown, but presumably fairly high.
Not known, but presumably similar to
psychomimetic effect, undercutting networks
involved in affective inhibition
Exercise
Not extensively studied but may compete very
effectively with first-line antidepressants.
Grossly underutilized (esp. in view of multiple
other health benefits and no “side effects”)
Promotion of serotonin, VGF, and other growth
factors, BDNF in hippocampus, opioids, and
dopamine
36
Douglas F. Watt & Jaak Panksepp
have a more powerful and direct antidepressant effect, with a faster onset, than promotion of either serotonin and/or norepinephrine,
downstream effects on BDNF, promotion of
hippocampal trophic processes, secondary upregulation of VTA, etc.
ii. Provision of social support and empathic social
connection would augment the effects of the
above opioidergic and oxytocinergic pharmacologic manipulations, and the concurrent provision of such pharmacologic manipulation and
social supports would be more effective in the
treatment of depression than either alone.
iii. Reducing various forms of separation distress
(included its cognitive extensions in shame,
guilt, loneliness, feelings of rejection, etc.)
would be powerfully antidepressant, along with
reducing attendant feelings of helplessness in
the face of these affects. In other words, reducing a prototype driver for depression, and
increasing the subject’s sense that one can respond adaptively to these stresses, would be
powerfully antidepressant, in a way that would
exceed effects of various forms of nonspecific
support or other kinds of psychotherapy approaches. This prediction has never been tested.
We would further predict that ratings of perceived therapist empathy around these specific
issues (related to various forms of separation
distress) would have the largest correlation with
positive outcome ratings in the psychotherapy
of depression. This prediction, to our knowledge, also has never been tested.
iv. Aerobic exercise on a regular basis combined
with exploratory psychotherapy would be more
effective than any form of psychotherapy alone,
and more effective than traditional amine psychopharmacology alone. Indeed, exercise may
be the most underutilized effective intervention
in the entire armamentarium of interventions,
with virtually no downsides in terms of serious
side effects and with many other health benefits
(Ratey, 2008).
v. Area 25 hyperactivity in refractory depression
(Mayberg et al., 2005) may reflect a pathologically augmented separation-distress mechanism,
perhaps associated with CRF overdrive or additional pathogenic suppressions of opioids and
oxytocin chemistries. Accordingly, deactivation of this area in refractory depressed patients
(where there is protracted hyperactivation) with
deep brain stimulation might help recruit endogenous opioid or oxytocinergic mechanisms
of the brain—a proposition that could be tested
with receptor antagonists of these brain systems
or with radioligands for these modulators to
image these changes in refractory depression.
Unfortunately there is no currently available
animal model that we are aware of that would
mirror area-25 hyperactivity in a depressive
animal phenotype of depression.
Heuristics and theoretical integration: the
challenging multifactorial nature of depression
In a previous target article on empathy in this journal
(Watt, 2007), it was argued that although play, empathy, social bonding, contagion (the “infectiousness”
of prototype emotion), and separation distress are all
largely viewed as discrete processes currently in neuroscience and investigated quite independently of one
another, we would argue that these putatively disparate
phenomena could be considered interlocking threads,
somehow jointly forming the full fabric of a deeply
social brain. Therefore, it seems reasonable to us that
these processes were selected in an integrated manner,
by related evolutionary pressures. Each of these phenomena is part and parcel of a truly social brain, one in
which the pleasures of social connection and the pains
of social loss are first-rank motivators. Consistent with
this argument, we would also hypothesize that the
vulnerability to depression is probably intrinsic within
this complex multidimensional fabric of a social brain.
Some social brains are more vulnerable to this, some
more resilient. Individuals with fortunate genetic endowments and supportive and loving upbringings may
have intrinsic and robust protection against depression,
but even those with more resilient genetic endowments
and environmental good fortunes are never totally or
permanently protected from the reach of intrinsic depressive mechanisms. At least some degree of depression lies only a major catastrophe away for virtually
everyone.
At present, where radical reductionism and individual neurochemical vectors are receiving primary
attention in psychiatry, more integrated and “big-picture” psychobiological views of depression are badly
needed. However, typical modes of scientific analysis
are obviously not well suited for conducting the massive multifactorial studies that such integration would
require. Thus, we are left, as usual, to patch together
more holistic levels of understanding from the many
factual parts that scientific analysis can spew out in
abundance. However, the tendency to deemphasize
possible primary psychological dimensions in depres-
Depression: An Evolutionarily Conserved Mechanism?
37
sion within much of molecular psychiatry is, in our
estimation, not as likely to lead to a satisfactory integration of all the available pieces of this challenging
puzzle. After all, perhaps the major function of many
brain networks, especially those related to emotions,
is to generate various psychological processes. Put
differently, psychological processes intrinsically index complex distributed functional networks. Future
work will need to also integrate the many factors that
have been identified by existing molecular approaches
such as those summarized above, encompassing three
monoamine systems, the cholinergic system, multiple
neuropeptide systems including several opioid systems, neuroendocrine/stress axes, and immune/cytokine issues. Table 2 outlines what we currently know
about the interactions of these core factors. While it
is easy to assume from the current state-of-the-art that
these constitute all the important pieces of the puzzle,
further research may underline that even this impressive collection of issues is not the whole story. Surely,
the complexity of interactions between these factors
and the full complexity of the human brain humble
even the most brilliant and determined empirical investigations and theoretical integrations. The continuing
lesson may be that one cannot have too much humility
in the face of Nature’s virtually infinite complexities.
This brings us to another touchstone concept. In all
fairness to the field, trying to delineate unitary “first
causes” or “prime movers” in a system as massively
recursive and interactive as the brain may be a doomed
enterprise. From this perspective, the potential interactions between factors has received overall far less “air
time” in the history of writings on depression than the
many proposals promoting single- or primary-factor
theories, although, in general, recent work seems more
open to multifactorial points of view. Lessons on this
point have been very evident in modern feeding and
energy-balance research, which has exposed such a
multifactorial puzzle box, where multiple layers of
control can sustain homeostasis even when various
seemingly critical factors are deleted from the overall
equation (Horvath & Diano, 2004). Instead, it may
be more heuristic and indeed much more practical to
think in terms of an interactive matrix of factors that
can lead to depression, but where individual variability
may map onto differential loading of the various core
factors (suggesting, among other things, that future
optimal treatment of depression may require individually tuned multidimensional approaches). As Table 2
delineates, these putative core neurobiological factors
regulate and massively influence one another. This
suggests that any individual mind in a sense “lurches”
sometimes unpredictably through a complex trajec-
tory of neurochemical–neurodynamic space as these
factors cascade and reverberate in one direction or
another, in any particular instance of depression. This
multifactorial nature may also help to explain why so
many different therapies, ranging from exercise and
psychotherapy to ECT and deep brain stimulation are
antidepressant. Although we are a long way away from
being able to explain why one antidepressant therapy
works in one depressed individual and not in another,
we suspect that an answer to this also lies somewhere
in a deeper understanding of the dynamic relationships
between these primary core factors in a depressive
matrix. Although it has been long thought in psychopharmacology that “everyone’s chemoarchitecture is
different,” interactions between these core factors in
a depressive matrix may also be differentially gated
across different individuals. From such an understanding, we may eventually be able to map this unanswered
question of why one treatment works and another does
not.
Our review has sought to emphasize the oft-neglected relevance of opioids and oxytocin for understanding
depressive cascades as critical modulators for social
connection and social bonding and for how social
connection protects brains against depression-generating chronic stress states. Table 2 underlines what we
consider to be the handful of core factors constituting
this “depressive matrix.” Core factors may consist of:
(1) diminished tone in opioid and oxytocin systems associated with separation distress; (2) altered and chronic stress neurophysiology promoting upregulation of
CRF and hypercortisolemia, leading to hippocampal
atrophy, and the failure of negative feedback on the
stress axis; (3) alterations in numerous amine as well
as peptidergic neuromodulatory systems, and dysphoria-promoting CCK- and dynorphin-induced negative
affects, creating inhibitory feedback on the ventral tegmental system dopamine and other catecholamine systems that sustain “energized” goal-directed bodily and
mental activities; (4) a critical role played by the immune system, specifically cytokine generation, which
appears synergistic with stress cascades. Cytokines
may directly or indirectly promote glutamatergic overdrive and contribute to a hypotonic serotonin system as
well (Muller & Schwartz, 2007), and they further promote withdrawal, fatigue, and behavioral and affective
shutdown, impairing HPA-axis regulation by disrupting negative-feedback inhibition of CRF (Schiepers,
Wichers, & Maes, 2005). Emphasizing that all of these
factors may constitute an integrated matrix, there is evidence that social disconnection and separation distress
(associated with changes in both opioid systems) result
in potentiated stress cascades and increased cytokine
38
Douglas F. Watt & Jaak Panksepp
Table 2.
Depressive factor
Neurobiological factors forming an interactive depressive matrix?
Behavioral and symptomatic
correlates
Driven by
Producing
Increased CRF,
hypercortisolemia, CCK, and
reduced BDNF
Multifactorial limbic
influences on paraventricular
nucleus promoting activation
of HPA stress axis
Increased dynorphin,
decreased 5-HT, reduced
neuroplasticity/hippocampal
atrophy. Intensification of
separation distress. Disrupted
ventral hippocampal feedback
on core affective regions?
Dysphoria, sleep, and appetite
loss. Reduced short-term
memory, and other cognitive
deficits?
Increased acetylcholine
Reduction of social and other
rewards, opioid withdrawal,
and any other social
punishment
Facilitation of separationdistress circuitry and other
negative emotions? Effects on
other core variables?
Negative affect and excess
attention to negativistic
perceptions and thoughts?
Decreased mu opioids and
oxytocin
Separation distress, other
stressors, including physical
illness and pain
Disinhibition/release of
stress cascades; decreased
5-HT and DA; overdriven
NE. Promotion of cytokine
generation?
Anhedonia and sadness,
reduced positive affect and
reduced sense of connection?
Suicidality?
Increased dynorphin in
accumbens/VTA
Stress cascades
Down regulation of VTA and
mesolimbic DA system
Anhedonia, dysphoria, loss of
motivation
Increased cytokines
Acute but probably not chronic Promotion of stress cascades,
stress, acute reduction of
decreased serotonergic and
opioids?
increased glutamatergic tone.
Impairment of HPA-axis
negative feedback
Reduced serotonergic drive/
vulnerability
Stress, increased
corticosteroids, cytokines,
decreased mu opioids
Lowered dopaminergic and
increased noradrenergic drive.
Less functional segregation
among brain systems
Poor affective regulation?
Impulsivity. Obsessive
thought, suicidality
Diminished catecholaminergic
(DA & NE) tone
Constitutional vulnerability,
stress and poor reward
availability
Reduced “signal-to-noise”
processing in all sensory–
perceptual and motor/
executive systems.
Fatigue, diminished psychic
“energy”: appetitive
sluggishness, dysphoria.
Impaired coordination of
cognitive and emotional
information processing
generation (Hennessy, Deak, & Schiml-Webb, 2001).
We believe that these interlocking pieces of a puzzle
fit together, as differential facets of a basic depressive
cascade, although the seams between the pieces cannot
be completely stitched together at this time, especially
in humans, because practically all the basic knowledge
on which we rely has come from a diversity of animal
brain–behavior research. However, this comprehensive
review suggests that relationships between chronic
stress and changes in opioids, cytokines, glutamate,
Fatigue, malaise, and
appetitive losses. Increased
cognitive disruption.
Anhedonia?
dopamine, and other monoamine systems are intrinsic
and clearly fundamental to depressive cascades (see
Table 2).
We believe that this view of depression emphasizes
its intrinsic relationship to a prototype emotional state
found in all mammals—separation distress—and offers solid conceptual bridgework upon which to base
a search for new therapeutics. This view emphasizes
the critical importance of social support in both the
long-term protection against depression and its more
Depression: An Evolutionarily Conserved Mechanism?
39
acute and subacute therapeutic management. Our perspective underlines that social-relationship issues have
a close relationship to the fundamental neurobiology
of depression because of their intrinsic connections
to stress, cytokine promotion, and changes in multiple neuropeptide systems. We believe that the current treatment climate in psychiatry could significantly
benefit from such an emphasis, as psychotherapy and
social support have literally fallen off the radar in the
treatment of many if not most patients with depression,
due to a largely bottom-up neurochemical view of both
etiology and treatment, to the serious long-term detriment of basic patient care.
Opioids and oxytocin, maintained tonically in securely attached creatures, exercise a powerfully inhibitory effect on basic stress cascades. The protracted
downregulation of these systems in the context of
protracted separation distress may tonically facilitate
stress responsivity. The promotion of CRF and the
downregulation of opioids and oxytocin may rapidly
shift the affective state of the brain from a more euthymic to a more dysthymic one. The older view of stress
cascades failed to acknowledge their role in affective
changes, viewing these changes in the HPA axis as if
they were just physiological changes as opposed to
ones that created psychological change. For a long
time there has been comparative neglect of factors
known to regulate separation distress and social attachments—namely, opioids and oxytocin systems—in
preference for noradrenergic- and serotonergic-centered viewpoints. What was long left out of the overall
puzzle were the major peptidergic variables most intimately and directly related to mood (mu and kappa
opioids, CCK, CRF, dynorphin, and oxytocin).
Protracted stress—the most prototypical being separation distress arising from social loss—may create an
altered balance between mu, delta, and kappa opioids
and oxytocin. Promotion of dynorphin and CCK tone,
especially in the nucleus accumbens and VTA, and
the resulting loss of motivation, including centrally
the inhibition of attachment-related needs/drives, thus
potentially transform separation distress from an acute
(protest) phase to a sustained chronic (despair) form.
This shutdown is assisted by the potential fatigue/sickness-promoting effects of proinflammatory cytokines.
These parallel changes drive global inhibition of many
specific motivations, from food appetite to erotic pursuits, generating a generalized anhedonia (with active
dysphoria) and, thereby, loss of a more hopeful orientation toward life opportunities and normal reward
seeking. Altered homeostasis, particularly sleep and
appetite, may be caused not only by elevated CRF
effects on several homeostatic and circadian hypotha-
lamic systems, but also the diminished influence of
prosocial neuropeptides. Such a sustained dysthymic
mood may promote negative cognition (which may
help sustain negative mood via positive-feedback effects of sustained ruminations), and the hypofunction
in prefrontal and hippocampal systems—perhaps associated with several neuromodulatory shifts and the
effects of excessive cortisol—results in the characteristic attentional, executive, and mildly amnestic cognitive deficits of depression. The fact that such a brain
shutdown apparently is accompanied by fundamental
neuroplasticity deficits (e.g., decreased neuronal proliferation in the hippocampus and reduced dendritic
spines/connectivity) reinforces the psychic deficit. In
this context, it is important to emphasize that even the
most generous allowance for the causal role of a single
factor may not come close to explaining all the changes
that constitute a full-blown depressive episode.
The variety of brain–mind factors that can contribute to depressive affect (see Table 2) also suggest
that surely not every depression is precipitated simply
by attachment losses, or even by “symbolic” or social-status losses. Anhedonia and dysphoria can have
various causes, including endogenous neurochemical
imbalances of the brain as well as withdrawal from
various drugs of abuse. Polymorphisms of multiple
genes involved in the neurochemical underpinnings
of affective homeostasis can also presumably modify
the thresholds for the induction of the various stress
and affective cascades. However, it is now also eminently clear that early separation distress can promote
lifelong dysregulation of hedonic homeostasis, leading to the disinhibition of negative affective processes
and associated stress cascades. This combination of
incompletely mapped genetic and somewhat betterunderstood early environmental factors results in the
potentiation of future depressive processes that may
be more easily triggered by any severe chronic form
of stress besides its classic precipitation by various
forms of separation distress. In fully considering the
long-term consequences of early stress, we can envision how the whole system of regulatory controls over
intrinsic depressive mechanisms becomes more fragile
over the entire life span. The precise manner in which
that happens remains as important chapters for both
future animal-brain research and for human neuropsychoanalytic developmental research. Of course, we
must stay open to there being several distinct types of
unipolar depression that are not yet being adequately
differentially diagnosed.
Just as the neurobiological correlates of depression appear very multifactorial, developmental issues
contributing to lifetime vulnerability in depression
40
appear equally so. Recent developmental modeling
(Kendler, Gardner, & Prescott, 2002) confirms this
multifactorial nature of developmental pathways into
depression, outlining a host of “outside-the-skin” factors that presumably interact with multiple “inside-theskin” neurobiological variables in a fashion still poorly
plotted. Kendler and colleagues, using a sophisticated
statistical algorithm, found that roughly half of the
variance for major depression in males could be explained by 18 factors and their interactions: genetic
risk, low parental warmth, childhood sexual abuse, parental loss (early-childhood factors), neuroticism, low
self-esteem, early-onset anxiety, and conduct disorder
(early-adolescence factors), low educational achievement, lifetime traumas, low social support, and substance misuse/abuse (late-adolescence factors), history
of divorce and past history of major depression (adult
factors), and factors taking place in the last year (lastyear marital problems, other personal difficulties, and
stressful life events). How these are all interrelated
in the brain remains uncertain. Similar modeling was
done for females in an earlier study, with slightly more
than 50% of the variance explainable in terms of a similar complex of factors (Kendler, Gardner, & Prescott,
2002). Given that even with such a complex matrix of
predisposing variables they could only explain slightly
less than 50% of the variance further underlines the
challenging heterogeneity of depression in terms of
its multifactorial developmental pathways. In addition
to the risk factors outlined in these models, it seems
obvious that chronic pain as well as perhaps numerous other chronic illnesses can be powerfully depressogenic, presumably by virtue of chronic activation
of stress and immunological/cytokine cascades and
relative hypoactivation of mu-opioid systems that may
require not just social comfort and secure attachment
but also general physical wellness for their maximum
tonic promotion.
Although the present formulation, with its focus on
the separation-distress and attachment processes of
the mammalian brain, may not explain every aspect of
depression, it aspires to integrate diverse lines of basic brain, affective neuroscientific, and psychological
thought into a theoretically coherent view of one major
subtype of depression that can promote new lines of
inquiry. It may also potentially help explain striking
findings such as the rapid antidepressant effects of glutamate receptor antagonists such as ketamine (Zarate
et al., 2006), since the separation-distress response
is rapidly diminished with glutamatergic antagonists
(Panksepp, 1998). Conversely, it is known that separation distress and other negative emotions can be dramatically intensified by increased glutamatergic drive
Douglas F. Watt & Jaak Panksepp
(see Panksepp, 1998, Figs. 14.7 & 14.8), suggesting a
possible mechanism for the antidepressant efficacy of
NMDA antagonists. The rich cornucopia of integrative
thought in this area that is provided by an affective
neuroscientific understanding of the primary emotional
processes that help construct the mammalian social
brain provides a novel and heuristic framework for the
further study of depression. Hopefully this review will
facilitate such research efforts.
Conclusions: psychotherapeutic and
neuropsychoanalytic implications
Freud was deeply interested in the problem of depression, and his classic work on “mourning and
melancholia” (1917e [1915]) began a long-term psychoanalytic interest in the subject. Although a detailed
summary of the psychoanalytic literature on depression is beyond the scope of this article, several points
are worth highlighting. Consistent with a Helmholtzian mechanistic–hydraulic image of drives that has
clearly not been neurobiologically validated, early
psychoanalysis tended to gravitate toward classically
simple metaphors for affective states, in terms of putative dysfunction in drive systems, such as the notion
that anxiety was “dammed-up libido,” while depression reflected “aggressive drives directed against the
self.” These ideas have received little empirical support. A larger, more recent thread within psychoanalytic literature, however, has emphasized the close and
intrinsic relationships between depression and object
loss (Bowlby, 1969), between helplessness and the
frustration of narcissistic needs related to the maintenance of self-esteem (Bibring, 1953), and between
a basic vulnerability to depression in adult life and
early attachment trauma involving object loss, neglect, or abuse (Jacobsen, 1964, 1971). We believe
that low self-esteem may derive from the total amount
of “psychic pain” an individual endures, associated
with an overactive separation-distress/PANIC system
and underactive or disregulated SEEKING urges. (For
a more recent discussion of brain and self, following
psychoanalytic object-relations theory, see Panksepp
& Northoff, 2009.) These pathways may constitute a
developmental foundation for vulnerability to depression, as psychoanalytic perspectives have emphasized
for many decades that low self-esteem is associated
with early exposure to neglect/abandonment, maternal
or early rejection, excessive induction of shame and
guilt, abuse, or variable combinations of the above.
In this sense, low self-esteem might be a structural
derivative of various forms of separation distress as-
Depression: An Evolutionarily Conserved Mechanism?
41
sociated with recurrent empathic and attunement failures, through critical periods of development (Schore,
1994; Watt, 2007).
These areas of the psychoanalytic literature, including results from early observational and developmental
work on children, offer genuine insights. In Bibring’s
classic monograph (Bibring, 1953), he argued that
depression came from the “helplessness of the ego to
achieve goals necessary for the maintenance of selfesteem,” including, prototypically, helplessness in the
face of emotional/attachment losses and loss of love.
This monograph was significant in terms of its movement away from the simplistic hydraulic/electrical
drive metaphors of earlier metapsychology and toward
a more ego-psychological/object-relations perspective,
even though Bibring himself was not an object-relations theorist per se, and for its emphasis specifically
on helplessness, self-esteem, and attachment relatedness. Bibring’s thinking in a sense presaged later work
by Bowlby and major reviews by Allan Schore (1994),
all of which reaffirmed the central importance of the
rupture of social connection in depression.
We will not here attempt to formulate a coherent bridge between the abundant neuroscience data
summarized above and implications for the psychotherapeutic “arts,” but simply note that the database
indicating how various psychotherapies can modify
brain functions has been growing rapidly (Etkin, Pittenger, Polan, & Kandel, 2005; Roffman, Marci, Glick,
Dougherty, & Rauch, 2005). Some of the basic science
of separation distress that emerged three decades ago
when Bowlby’s synthesis was emerging (Panksepp et
al., 1978a, 1978b, 1980) has now been translated into
human brain imaging (Swain, Lorberbaum, Korse, &
Strathearn, 2007) and psychiatric conceptualizations of
panic disorders (Preter & Klein, 2008) and of grief dynamics (Freed & Mann, 2007). It is likely that certain
individuals are much more susceptible than others to
the psychic pain of separation distress, some because
of genetic sensitivities (Barr et al., 2008) and others
because of early-life vicissitudes (Heim & Nemeroff,
1999). The separation-distress sensitivity variant of the
mu-opioid receptor allele C77G has a potential counterpart in humans, the A118G variant (Barr et al., 2008). It
would be most interesting to see whether humans with
this allelic variant are more susceptible to the psychic
pain of separation distress and, if so, whether they
are overrepresented in depressed populations seeking
therapy. If this is the case, will this type of individual
respond better to certain psychotherapeutic modalities
than will individuals who are more resilient to the effects of this primal affect? Given possible alterations
in mu-opioid dynamics, would these individuals be
strong candidates for a drug like buprenorphine? There
is no empirical work (yet) on which to make such a
judgment.
We would also briefly note that fMRI studies are
beginning to provide insights about how higher brain
dynamics in depression interact with the more primal
mechanisms of self-referential information processing
(Northoff & Panksepp, 2008; Panksepp & Northoff,
2009). These techniques now allow better integration
between third-person neuroscientific and first-person
psychodynamic perspectives (Northoff, Bermpohl,
Schoeneich, & Boeker, 2007), with special insights
in the study of depression. Depressive disorders show
more distinct changes in the subcortical–cortical midline system (the so-called default mode network) than
in other brain regions (Grimm et al., in press), with
a shift from more externally focused left dorsolateral
prefrontal working memory networks to affectively
self-centered right-sided “self-worrying” networks
(Grimm et al., 2008). Thereby, depressed patients commonly show increased self-focusing, with profound
social withdrawal, negativistic ruminations, and lack
of engagement with provocative environmental challenges (Northoff, 2007).
Since this article is already quite long and detailed,
we will not attempt to provide any comprehensive
overview for the increasingly neglected psychotherapeutic aspects of treating depression; rather, we wish
to throw this critical issue open for discussion among
commentators. We would simply say that our own
bias is to envision psychotherapy to be very dependent
on both patient and therapist characteristics, and we
would affirm that an evolutionary hierarchical vision
of brain–mind functions is essential for progress on
these issues (Lane & Garfield, 2005). In our vision
of hierarchical structures, which can incorporate both
bottom-up and top-down perspectives, with continual
two-way circular causality (see Gallagher, 2008), it
is important to have some clear distinctions between
levels of control, especially primary-process affective
levels (as summarized in Panksepp, 1998), secondary-process levels (basic mechanisms of learning and
memory, as summarized in LeDoux, 1996), and tertiary-process levels (all the higher cognitive-thoughtful
processes that are largely impossible to study in animal
models, about which psychoanalysts and other clinicians have written in great length and depth). Indeed,
psychodynamics, emphasizing notions of defense as a
form of “stop-gap affective regulation,” may be a kind
of global shorthand for how complex corticolimbic
systems that must span such a hierarchy of levels might
work (see Watt, 1990). How one might better integrate
all of this neurobiological understanding with the art
42
of psychotherapy is still largely unmapped. We would
throw this matter open for discussion among our expert
panel of discussants.
No one from a psychodynamic or psychoanalytic
background needs any convincing that psychodynamics must play a huge role in orchestrating how attachments play out, with an uncanny capacity for repetition
of earlier scenarios in current attachments—what
Freud (1914g, 1920g) termed “the repetition compulsion.” Freud’s insights about repetition compulsions
could prove to be very scientifically productive, although unfortunately this concept got tied to problematic metapsychology, in terms of notions about
a “death instinct,” instead of it being considered as
simply intrinsic to brain–emotional habit systems (aka
limbic basal ganglia) and to the natural tendency to
gravitate to the familiar. No one doing long-term psychotherapy would need any convincing that the trajectory of patients’ lives often show, in some sense, a kind
of “structuralizing” of early experiences of abandonment and loss and attunement failure, with repetition of
key scenarios over and over again. Indeed, we would
argue that the concept of the repetition compulsion has
been given short shrift in developmental thinking in
general. It underlines how we are all, in a sense, trying
to win battles we lost a long time ago and that present
events that recapitulate past traumas are going to be
powerfully mobilizing of the most painful negative
affects. Contemporary biological psychiatry is paying precious little attention to such issues, having lost
touch with any notion about “the mental apparatus,”
as the onslaught of molecular options provided apparently easier answers to human problems than did any
meeting of human minds to explore mind and emotional dynamics. Currently, psychotherapy in any form
has become seriously underutilized in the treatment of
many clinical depressions (see STAR*D work: Rush,
2007).
At the same time, let us share our biases concerning
the therapeutic arts. There has been an almost “ideological” elevation of cognitive behavioral therapy and
to a lesser extent interpersonal psychotherapy as the
only appropriate psychotherapies for patients with major depression. A basic problem in all psychotherapy
research is the assumption that the putative dynamics
of the psychotherapy “type” actually truly describe in a
comprehensive way how clinicians actually work with
patients. We would emphasize that an emotionally supportive but still exploratory psychotherapy approach
to depression is, in our judgment, seriously clinically
underutilized. Judicious and careful empathic exploration of hurtful losses in which patients feel fundamentally helpless to mitigate the loss or attendant feelings
Douglas F. Watt & Jaak Panksepp
of rejection or abandonment precipitating depressive
shutdowns, and the presentation to the patient of realistic options beyond “giving up,” may constitute the
most essential elements of effective psychotherapy in
depression. We would simply propose that reducing
helplessness and any attendant sense of isolation in the
face of almost any deeply painful experience is likely
to be powerfully and prototypically antidepressant, in
any form of psychotherapy, as it directly undercuts any
sense of hopeless loss. Indeed, empathic social support
was perhaps the original antidepressant (along with
playfulness) long before we had neurochemical modulators, or even much psychological or psychoanalytic
theory.
Such psychotherapeutic work will be most difficult
when the most relevant life vicissitudes occurred very
early in life before symbolic processing had emerged.
In these situations, the maladaptive processes may be
so deeply ingrained in presymbolic modes of coping
and operating in the social world, such as ingrained
repetition compulsions, that it will be essential for
clinicians to pay attention to more deeply affective and
preconscious currents expressed in interpersonal behavior, but rarely if ever in words, and bring them back
into the realm of human discourse. Ultimately pluralism has to become a way of life for all skillful therapists, and therapists must become at least somewhat
conversant in both the neurochemical complexities of
affective processes and the vast menageries of higher
awareness and other mental processes with which they
interact. How shall we bring these many different
kinds of perspectives toward a more fruitful union? We
welcome all insights and critiques that our commentators would wish to share.
APPENDIX
Animal models of depression
Recent work argues that there are probably four major
animal models for depression: a separation-distress
model (discussed in the main body of the paper), a
social-status loss model, an olfactory bulb resection
model, and a large variety of learned-helplessness and
chronic-stress models. There is remarkably little integration across these four types of models in the animal
literature in terms of putative mechanisms, although
we would argue that the separation-distress model is
the closest to the human clinical condition and, additionally, that the social-status loss model and the separation-distress model are very close cousins and that
stress models are a general class of models intrinsically
related to separation distress as a prototype stressor.
Depression: An Evolutionarily Conserved Mechanism?
43
There is an implicit if not explicit assumption in much
of the clinical literature that all of these models may
be inadequate in relationship to human clinical depressions, because none of them can adequately model
the changes in cognitive state or recreate our characteristic depressive cognitions. However, we would
argue that because depression, at least in some form,
is a conserved mammalian-brain mechanism, and because there are remarkable homologies with respect to
the basic affective machinery in mammalian and human brains (Panksepp, 1998), all of these models are
still invaluable and have proven their value over and
over again in heuristic antidepressant drug design and
are especially useful in dissecting the endophenotypic
brain changes that characterize depression (McArthur
& Borsini, 2006). This suggests that the states referenced in these four models are likely to be important
animal analogs to human depression.
The social-status loss model is an ethological model
with a great deal of face validity (Panksepp, Moskal, Panksepp, & Kroes, 2002). It typically consists
of the resident–intruder aggression paradigm, where
an intruder placed into the environment occupied by
a paired male and female rapidly gets attacked and
typically loses (Malatynska, Rapp, Harrawood, & Tunnicliff, 2005). There are a variety of neuropeptide and
genetic changes in the animals that have lost in such
social encounters, yielding various candidate vectors
for the depressive cascade (e.g., Kroes et al., 2006;
Panksepp et al., 2004, 2007), with the most comprehensive analysis having appeared recently characterizing the massive gene-expression changes in the
brain that result differentially in varying degrees of
“resilience” to this classic stress paradigm (Krishnan et
al., 2007). Unfortunately, in Krishnan and colleagues’
superb study, the actual aggressive behavior of animals
was not monitored, thus we do not know whether the
“resilient” animals were paired in less aggressive encounters than were the “nonresilient” mice.
The olfactory bulb model indeed seems the furthest
from human clinical concerns, but it is a robust depression analog in terms both of behavioral state and of response to chronic antidepressant administration (Cai &
Leonard, 2006). We would argue that it is an exceptionally cruel and perhaps in some sense even an unethical
model. It is very difficult for most humans, with their
relative lack of dependence on olfaction, to appreciate
the truly devastating impact that loss of olfaction might
have on the brain, where the primary afferent/sensory
inputs into a host of limbic system structures are olfactory. Loss of olfaction (in target rodent species) probably removes a/the primary afferent driver from a host
of limbic system structures and is presumably at least
as devastating to an animal with a heavy reliance on
olfaction as would loss of hearing and eyesight be to a
heavily exteroceptive creature like ourselves. Indeed,
since our exteroceptive distance-related sensory modalities of hearing and vision only gain access to limbic
structures after a host of intermediate relays through
idiotypic–unimodal–heteromodal–paralimbic cortical
connectivities,4 it may be a more intrinsically affectively devastating brain lesion than an adult human
losing both vision and audition. Because of this fundamental architectural difference between our brains
and those of “lower” mammals, it is probably difficult
for human beings to appreciate how depressing such a
loss of olfaction is for olfactory animals, but it is probably intrinsically more depressing than our losing all
our exteroceptive abilities. In this sense, olfactory bulb
loss may recruit whatever endogenous “shutdown”
mechanisms are embedded in mammalian limbic architectures, because those architectures are no longer
in a position to process critical world inputs and in a
real sense may have “very little to do.” Stripped of any
ability to make value judgments about the desirability
or undesirability of various afferent stimuli, animals
suffering from olfactory bulb resection are in a real
sense “limbically blinded.” Consistent with this, animal models for olfactory bulb resection do show signs
of hypercortisolemia and promotion of stress cascades,
and one would also predict decreased central mu-opioid
and increased kappa-opioid processes, although to our
knowledge this has not yet been empirically described.
Thus, although this animal model for depression seems
very far from our central hypothesis, we would argue
indeed that it is deeply consistent with the idea of an
endogenous shutdown mechanism embedded in limbic
reticular relationships, because such a devastating loss
of afferent inputs presumably would recruit exactly
those endogenous shutdown mechanisms, as a kind of
“system default.”
Learned-helplessness animal models for depression,
4
There are presumably some neurodynamically significant brainstem
sensory–limbic connectivities operating also in humans, such as interactions between the superior colliculus and PAG, and other subcortical pathways such as the “fast” thalamic–amygdala pathway made famous by Joe
LeDoux’s (1996) research. However, it is likely that sensory information
in humans reaches paralimbic and limbic system structures primarily after
extensive cortical relays, with the exception of olfactory information, which
has direct access to influencing emotional states. Olfaction is obviously a
chemical sense modality, but it may have intrinsic codes in terms of primary
access to prototype emotional systems in subcortical/limbic architectures
(for example, rodents appear to have a genetically coded aversion to the
smell of cat fur, capable of activating strong fear states). This kind of intrinsic value coding of olfactory stimuli, while obviously modifiable through
learning and new experiences, would make species heavily dependent on
olfaction especially susceptible to depression when olfactory bulbs are
damaged.
44
chiefly consisting of subjecting animals to uncontrollable foot shocks or other aversive events such as forced
swimming or enforced bodily restraint for which there
are no available salvation contingencies, have found
evidence for changes in both serotonergic and noradrenergic systems, along with upregulation of CRF. All
of these models have been extensively reviewed recently (see Neuroscience and Biobehavioral Reviews,
2006, vol. 29) and will not be detailed here.
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Sidney J. Blatt & Patrick Luyten
Depression as an Evolutionarily Conserved Mechanism to Terminate Separation
Distress: Only Part of the Biopsychosocial Story?
Commentary by Sidney J. Blatt (New Haven, CT) & Patrick Luyten (Leuven, Belgium)
Keywords:
depression; personality; attachment; trauma; stress; neurobiology
The article by Douglas Watt and Jaak Panksepp provides a much-needed opportunity to attempt to bridge
the gap between psychological and biological processes in depression research. In addition, their article provides the opportunity to address critically Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV:
APA, 1994) assumptions that may hinder rather than
facilitate current research concerning depression (Blatt
& Luyten, in press-a; Luyten & Blatt, 2007; Luyten,
Blatt, Van Houdenhove, & Corveleyn, 2006). Moreover, the article illustrates the relevance of a number
of areas that are highly interesting for psychoanalysis—such as animal models and contemporary stress
research—but until now have been relatively neglected
by the psychoanalytic community.
In this commentary, we respond primarily from a
clinical perspective to the important and extensive
contribution by Watt & Panksepp on their biological
perspective of depression as an evolutionarily conserved mechanism that terminates separation distress.
In particular, Watt & Panksepp consider depression as
an evolutionarily adaptive mechanism that terminates
the protest phase of distress—a process of resignation
that becomes removed from adaptive control. While
we agree about the importance of early trauma, especially the impact of early separation and loss, on the
development of depression and psychopathology more
generally, we argue that extensive research indicates
that issues of separation and loss account for only a
relatively limited subset of patients in the development of depression. Thus, we stress the need to integrate the extensive investigation of neurobiological
dimensions in psychopathology, especially based on
animal models and contemporary research on stress,
with understanding achieved through systematic investigation with humans of normal and disrupted psychological development. In this context, we also note
that although it is important to attempt to bridge the
gap between biological and psychological perspectives
Sidney J. Blatt: Departments of Psychiatry and Psychology, Yale University, New Haven, CT, U.S.A; Patrick Luyten: Department of Psychology, University of Leuven, Leuven, Belgium, and Yale Child Study Center,
New Haven, CT, U.S.A.
in investigations more broadly, but especially in the
study of depression, important limitations are imposed
on such integration by aspects of the DSM that hinder
research on clinical phenomena, especially depression
(Blatt & Levy, 1998; Blatt & Luyten, in press-a; Luyten & Blatt, 2007).
Hence, this commentary focuses primarily on the
heterogeneity of dimensions that are at issue in depression and the need to include developmental and clinical
perspectives that include the role of the content and
cognitive structural organization of meaning systems
(i.e., mental representations or interpersonal cognitive–affective schemas of self and others) in comprehensive biopsychosocial models of depression and of
psychopathology more broadly.
The heterogeneity of depression: anaclitic and
introjective dimensions of depression
It should be noted that Watt & Panksepp’s central
assumption that depression is an evolutionarily conserved mechanism that terminates separation distress
has a long history in clinical research on depression.
In fact, it was Rene Spitz (1946) who first identified
what he called an “anaclitic depression,” in his discussions of the consequence in young infants of early loss
and separation from primary caregivers. In particular,
he noted in these babies a condition similar to Watt &
Panksepp’s description of depression as a mechanism
that terminates separation distress, in that these babies
showed clear feelings of sadness, tearfulness, loss of
appetite, and loss of weight after a period of protest.
These important clinical observations by Spitz not
only documented the occurrence of a particular form
of depression in infants and children and of apathy and
lethargy as central expressions of this form of depression, but they also identified a research agenda to investigate pathways from early adversity in the first few
months of life to later psychopathology in adolescence
and adulthood (Luyten, Vliegen, Van Houdenhove, &
Blatt, in press). Others elaborated Spitz’s observations,
including Bowlby (1980) in his work on attachment,
Engel and Reichsman (1956) in their classic paper on
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
baby Monica’s gastric fistula, and early research on the
impact of separation and loss in animals (e.g., Harlow,
1958) and children (e.g., Freud & Burlingham, 1944;
Provence & Lipton, 1962; Robertson & Robertson,
1971).
In addition, and importantly, Watt & Panksepp’s
suggestion to consider depression as an evolutionary mechanism that may have adaptive value was
already anticipated by George Engel, the spiritual father of the biopsychosocial model, who noted that
“the bulk of depressive reactions encountered in clinical practice are more indicative of ‘giving up’ and
do not include as a major component morbid guilt
and aggression turned toward the self” (Engel, 1962,
p. 96). Moreover, Engel (1962) argued that “depression–withdrawal” should be considered, together with
anxiety, as a basic affect and a basic “building block”
of psychopathology. Yet according to Engel, this depression–withdrawal reaction primarily served important adaptive purposes and thus was not maladaptive
as such, because it led to hypoactivity of psychological as well as physiological and biological systems, a
kind of “hibernation” state, anticipating contemporary
theories about hypothalamic–pituitary–adrenal (HPA)axis hypoactivity as an adaptive response to regulate
chronic stress (Fries, Hesse, Hellhammer, & Hellhammer, 2005; Van Houdenhove, Van Den Eede, & Luyten, 2009). According to Engel—and this is where
the resemblance with Watt & Panksepp’s argument is
clearly evident—this depression–withdrawal reaction
is not simply a passive reaction, but an active coping
strategy to increase the “stimulus barrier” so as to decrease the painfulness of feelings of loss and separation. Likewise, Sandler and Joffe (1965) argued that
depression in the first place should be seen as “a basic
psycho-biological affective reaction” (p. 90) that is in
itself adaptive but can become maladaptive when it
becomes a habitual reaction to stress of the organism.
Bibring (1953) added to this, long before Seligman’s
(1975) seminal work on depression, that the helplessness of the ego was the hallmark of most depressions
and thus constituted a “giving-up” response.
Yet despite this long line of predecessors, neither the
psychiatric nor the psychoanalytic world considered
these types of “simple depressions” to be the prototype
of depression in adults. Rather, for decades, self-critical or guilt-ridden depression, referred to alternatively
as melancholic or manic-depressive psychosis, was
considered to be the true prototype of depression (e.g.,
Abraham, 1911; Fenichel, 1945; Freud, 1917e [1915];
Gero, 1936; Lorand, 1937; Nacht & Racamier, 1960;
Rado, 1928; Rochlin, 1953).
Research in subsequent years has shown that both
53
approaches were correct in some respects, as studies from several strands of research, including both
psychodynamic and cognitive-behavioral approaches,
over several decades, have identified two fundamental
dimensions in depression (Arieti & Bemporad, 1978,
1980; Beck, 1983, 1999; Blatt, 1974, 1998, 2004; Blatt,
D’Afflitti & Quinlan, 1976; Blatt, Quinlan, Chevron,
McDonald, & Zuroff, 1982): an anaclitic1dimension
and an introjective2 dimension (Blatt & Maroudas,
1992). The anaclitic dimension involves feelings of
loneliness, abandonment, and neglect, emphasized in
the research on “simple depression.” In contrast, the
introjective dimension involves feelings of failure,
worthlessness, and guilt, as emphasized in research
on melancholic depression and manic-depressive psychosis.
Several research instruments have been developed
that assess systematically these two dimensions of
depression, including The Depressive Experiences
Questionnaire (DEQ: Blatt, D’Afflitti, & Quinlan,
1976, 1979), the Dysfunctional Attitudes Questionnaire (DAS: Weissman & Beck, 1978), the Sociotropy–Autonomy Scale (SAS: Beck, Epstein, Harrison, &
Emery, 1983), and the Personal Styles Inventory (PSI:
Robins & Ladd, 1991).
Extensive research with these instruments not only
documents the validity of this clinical distinction, but,
importantly, has also shown the predominance of the
introjective type of depression in both clinical and
nonclinical samples (for a summary of this research,
see Blatt, 2004). Importantly, extensive research with
both nonclinical and clinical samples indicates the
particularly insidious nature of introjective (self-critical) depression. Anaclitic qualities, in contrast, seem
to have both adaptive and maladaptive consequences
for intrapersonal and interpersonal functioning. For
example, although individuals with anaclitic depressive features are more vulnerable for depression after
experiences of loss or separation, they often struggle
to maintain interpersonal contact—contact that sometimes provides them with constructive social support.
Introjective depression, in contrast, not only involves
high levels of self-criticism and self-devaluation, but
also is associated with a “degeneration” of the interpersonal world, leading to social isolation that seems
1
Anaclitic depression has been described by investigators as “dependent” (Blatt, D’Afflitti, & Quinlan, 1976; Blatt et al., 1982), “dominant
other” (Arieti & Bemporad, 1978, 1980), or “sociotropic” (Beck, 1983)
depression.
2
Introjective depression has been described as “self-critical” (Blatt,
D’Afflitti, & Quinlan, 1976; Blatt et al, 1982), “dominant goal” (Arieti &
Bemporad, 1978, 1980), or “autonomous” (Beck, 1983) depression.
54
to contribute to the pernicious nature of this type of
depression (e.g., Blatt, 1995; Shahar, 2006).
Extensive research (see summaries in Blatt, 2004;
Blatt & Zuroff, 1992; Luyten, Corveleyn, & Blatt,
2005) documents the validity of the anaclitic–introjective distinction and has identified early, as well as current, life experiences that contribute to the emergence
of these two types of depression, the personality and
clinical characteristics associated with these two types
of depression, and their differential response to various
types of therapeutic intervention.
In this context, it is important to note that issues
of separation distress discussed by Watt & Panksepp
seem particularly relevant to anaclitic depression but
are of only limited relevance to introjective depression. Thus, it must be clear that clinical research that
fails to make this distinction among depressed patients
is likely to find only limited support for the possible
neurobiological mechanisms extensively considered
by Watt & Panksepp. In addition, establishing animal
models of introjective depression seems to pose much
more of a challenge than establishing animal models
for anaclitic depression, in part because introjective
depression probably involves more symbolic and cognitive issues. Thus, animal models, though useful in
providing possible leads for studying separation distress in anaclitic depression, may have very limited
applicability in the investigation of the more insidious introjective type of depression, in which there is
also significantly greater possibility of suicide (Beck,
1983; Blatt, 1995; Blatt & Shichman, 1983; Blatt et
al., 1982; Fazaa & Page, 2003).
For instance, as Watt & Panksepp note, much
contemporary research focuses on the relationship
between stress, as mediated by the HPA axis, and
depression. Yet results concerning the relationship between HPA-axis functioning and depression may be
seriously biased if they do not distinguish between
the different psychological dimensions in depression.
In particular, increasing evidence indicates that atypical depression—characterized by interpersonal rejection sensitivity, a core feature of dependency—is
associated with hypoactivity of the HPA axis. Melancholic depression, in contrast, is more characterized by irritability and hostility—typical introjective
traits—associated with HPA-axis hyperactivity (Gold
& Chrousos, 2002; Thase, 2007). Studies have indeed
found that individuals diagnosed with atypical depression are characterized by strong needs for reassurance, feelings of abandonment, rejection, loneliness,
an inability to rely on other people, anxiety and mood
swings, crying, oral behaviors (e.g., smoking, drinking
Sidney J. Blatt & Patrick Luyten
alcohol), and the use of self-consolatory coping strategies (such as spending money)—characteristics that
empirical studies have shown to be typical of anaclitic
depression (e.g., Blatt et al., 1982; Parker, 2007). Introjective depression, in turn, tends to be more characterized by feelings associated with defeat and failure,
such as feelings of failure, self-hate, guilt, anhedonia,
and loss of interest in others (Blatt, 2004; Luyten et
al., 2007). Hence, different sets or configurations of
depressive symptoms seem to be related to different
HPA-axis dysfunctions. Thus, results in this area may
have been confounded depending on the relative distribution of patients with introjective versus anaclitic
qualities (for a similar example regarding trauma and
depression, see Heim, Plotsky, & Nemeroff, 2004).
Moreover, concomitant symptoms such as hyperphagia and hypersomnia in anaclitic depression are
probably best considered as coping strategies aimed
at restoring homeostasis, rather than core symptoms.
This has important implications for studies aiming
to establish correlations between specific depressive
symptoms and genetic or neurobiological factors, because some symptoms may be core symptoms of depression, while others reflect coping strategies.
Similarly, research based on animal models that
study the role of attachment and the dopaminergic
system in depression, briefly noted by Watt & Panksepp, should also take this heterogeneity of depression into account. For instance, a considerable body
of research has related anaclitic issues to attachment
anxiety, while introjective traits are most closely associated with attachment avoidance (Luyten, Corveleyn,
& Blatt, 2005; Sibley, 2007). Attachment anxiety, in
turn, has been associated with attachment-hyperactivating strategies in response to (separation) distress,
while attachment avoidance is associated with attachment-deactivating strategies under stressful conditions
(Mikulincer & Shaver, 2007). These individual differences in the use of hyperactivating versus deactivating
strategies under stress are likely to impact on neurobiological findings such as studies using fMRI to map
attachment-related neurocircuits in depression. At the
very least, large individual differences in the activation of specific neurocircuits may be expected. Current fMRI studies on attachment, however, rarely take
such individual differences into account (e.g., Bartels
& Zeki, 2004).
These findings not only challenge the purely descriptive approach of the DSM, which defines subtypes
of depression based on symptoms and not on etiological concepts, but they also have important implications
for studying the genetic and neurobiological under-
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
pinnings of these two dimensions more generally, as
anaclitic issues render individuals vulnerable not only
to depression, but to disorders that involve dysregulated emotional and self-consolatory responses more
broadly (Parker, 2007), just as introjective issues render individuals more vulnerable for psychopathology
that involves issues of autonomy and control (Blatt,
2008; Blatt & Shichman, 1983). Hence, both in psychosocial and in neurobiological research, the focus
should be on pathways to different disorders, rather
than on any single disorder such as depression, because
it is highly unlikely that one specific biological system,
such an evolutionarily conserved mechanism that terminates separation distress, would be only involved
in one specific disorder. In particular, much current
evidence indicates the need for studies considering
vulnerability to spectra of disorders that share similar
biological and psychosocial mechanisms rather than
for research focusing on vulnerability for one specific
disorder (Luyten et al., in press).
The importance of a developmental model and
mental representations
The importance of distinguishing between anaclitic
and introjective depression raises the broader issue of
the limitations of a disease- or symptom-centered approach, exemplified by the DSM-IV (Blatt, 2008; Luyten & Blatt, 2007). Most current mainstream clinical
research, diagnostic assessment, and treatment focuses
on specific psychiatric disorders defined primarily by
manifest symptoms within an atheoretical categorical
system—the DSM. This disorder-centered approach
should be differentiated from a more fundamentally
person-centered approach to diagnosis (such as the
anaclitic–introjective distinction in depression) that
focuses on the dynamics and life experiences that
contribute to psychological disturbance (Luyten et al.
in press). The growing concern about the high comorbidity among psychiatric disorders has led some
investigators to consider a person-centered approach to
psychopathology as an alternative to the atheoretical,
symptom-based, categorical system of the DSM (Blatt,
2008; Blatt & Shichman, 1983).
Some of these investigators have stressed the need
to include developmental considerations and hierarchical models in the classification and treatment of
psychopathology as a way of dealing with the vexing
problem of comorbidity caused by equifinality and
multifinality in the development of disorders—that a
given clinical end-state can be the result of different
55
developmental paths, and that similar developmental
factors may lead to different clinical outcomes. For instance, findings from various strands of research—in
the neurosciences and genetic research in particular—
suggest that early adversity leads to vulnerability to a
wide variety of psychiatric and (functional) somatic
disorders (Luyten & Blatt, 2007; Luyten et al., in
press). This rediscovery of the importance of early
experiences has contributed to the recognition of
the need for a broad developmental perspective in
studying intact as well as disrupted psychological development—a perspective that also emphasizes the
importance of symbolic processes and meaning-making in understanding and treating patients with a history of early adversity (Blatt & Luyten, in press-b;
Luyten & Blatt, 2007; Luyten et al., in press).
Current biological research on depression, and on
psychopathology more generally, is often flawed by its
tendency for biological reductionism—that is, the danger of not appreciating the importance of mental structures and meaning-making in the relationship between
biological and psychosocial outcomes. In particular,
contemporary accounts of vulnerability and resilience
tend—implicitly or explicitly—to deny the importance
of meaning and subjectivity (Fonagy, 2003; Luyten et
al., in press). For example, current accounts tend to
describe the vulnerability of children who have experienced physical and/or sexual abuse, or other forms
of early adversity, in terms of the impact these experiences have on their developing stress system, which
is supposed to put them at increased risk for later psychopathology. To put it more bluntly: these children
are described as being vulnerable not because of the
impact these experiences have had on their developing
sense of self and others, and particularly their sense of
trust in others, but because their HPA axis is dysregulated. A similar trend toward reductionism is apparent
in many contemporary genetic accounts, despite their
current emphasis on the importance of gene–environment transactions (Moffit, Caspi, & Rutter, 2005).
Although Watt & Panksepp try carefully to avoid
such reductionism, and stress the need to bridge the
gap between the biological and psychological, their
extensive essay does not include consideration of what
is, in our opinion, the vital link between the biology
and psychology of depression—namely, a consideration of the mediating role of mental representations
or cognitive affective schemas and meaning structures
more generally. This is somewhat surprising because
psychoanalysis can provide an important correction
in this context as the discipline par excellence that is
occupied with the study of meaning and subjectivity.
56
Fonagy (2003), for instance, has convincingly argued
that psychiatric geneticists have for the most part studied the “wrong” environment—namely, the objective
environment. However, studying the subjective environment as it is experienced and constructed by individuals might be as important, if not more important,
because it is the process of meaning-making—or the
lack of meaning-making—that probably explains most
of the impact of the environment. Returning to our
example of stress research, a crucial mediating variable in the association between early childhood abuse
and the developing HPA axis is the meaning system
of the child—that is, the impact of the abuse on the
child’s basic sense of trust and self-worth and on his
or her representations of self and others (Blatt, 1974;
Blatt, Auerbach, & Behrends, 2008; Fonagy & Target,
2000). Fonagy, Gergely, Jurist, and Target (2002) have
coined in this context the concept of an interpersonal
interpretive mechanism to refer to a mental system or
processing structure for the self and significant others
in terms of a relatively stable and generalized set of
beliefs, desires, intentions, and affects that are based
on interactions with significant others.
Recent psychoanalytic theorizing and research provide an exciting window into this meaning-making
system, focusing on the role of narrative, narrative coherence, mentalization, and the organization of mental
representations in dealing with adversity in life (Blatt,
2008; Blatt, Auerbach, & Behrends, 2008; Fonagy
et al., 2002; Hauser, Golden, & Allen, 2006). These
studies have convincingly shown that the capacity to
mentalize is an important mediator explaining why
some individuals are able to work through adversity,
including early adversity, leading to so-called earned
secure attachment or resolved trauma, as opposed to
unresolved trauma (Hauser, Golden, & Allen, 2006;
Roisman, Padron, Sroufe, & Egeland, 2002). These
findings shed a particularly interesting light on patients
with a history of abuse or trauma, as these patients
often show considerable difficulties in reconstructing
their life history, expressed in narrative incoherence
and in unresolved (Roisman et al., 2002) and hostile/helpless (Lyons-Ruth, Yellin, Melnick, & Atwood,
2005) states of mind, resulting in problematic transference and countertransference reactions, characterized
by attraction–rejection and idealization or denigration.
What is important to stress in this context is that
these findings point to the fundamental interpersonal
nature of psychopathology, including depression. This
tends to be almost completely overlooked in contemporary mainstream accounts, especially in neurobiological accounts (Luyten et al., 2007), although there are
Sidney J. Blatt & Patrick Luyten
important exceptions to this trend as exemplified by the
growing interest in the role of attachment in neurobiological research on stress (Gunnar & Quevedo, 2007).
Yet it is a central tenet of most psychoanalytic accounts
that distress, including separation distress, leads to the
activation of cognitive-affective schemas of self and
other, in an attempt to regulate such distress. Hence,
any model of separation distress should at the same
time be an interpersonal as well as an intrapersonal
model and should be able to account for both of these
influences on responses to (separation) distress—that
is, how, developmentally, stress was first regulated in
the context of an interpersonal matrix and how these
experiences have led to the internalization of such
experiences in terms of cognitive–affective schemas or
working models of self and others. These cognitive–affective schemas are referred to in different psychodynamic traditions as mental representations, internal
working models, representations of interactions that
have been generalized, good or bad inner objects, or
internalized object relations (Blatt, Auerbach, & Levy,
1997), but the basic thrust of all these approaches,
despite their different terminology, is that it is the representational world and the capacity to reflect on one’s
subjective experiences that mediate stress responses
(Luyten et al., in press).
Implications for research
Such a developmental perspective that emphasizes
mental representations and meaning-making structures
also suggests an alternative to the predominant clinical
resarch model that investigates neurobiological correlates of particular disorders defined in terms of the
DSM system. One alternative to deal with the somewhat fuzzy diagnostic categories of the DSM, as exemplied in our consideration of depression, is to seek
further refinements within the diagnostic distinctions
in the DSM. Another alternative approach to this topdown and post-hoc seeking of biological, psychological, and social correlates of particular disorders with
the hope of discovering etiological factors is to take a
bottom-up developmental approach that considers how
early disruptions in development can lead to different
forms of psychological disturbance. Such an approach
would study the impact of particular life experiences
on the development of adaptive as well as disrupted biological and psychological systems—the recursive interactions among life experiences, biological systems,
and the meaning structures (e.g., concepts of self and
others) that are central to psychological development.
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
These formulations stress the importance of studying the etiology, nature, and treatment of psychological disturbances from a biopsychosocial dynamic
interactionism model that seeks to identify recursive
interactions among biological, psychological, and
sociological factors in the etiology of psychological disturbances (e.g., Luyten, Blatt, & Corveleyn,
2005; Ursano, 2004). Recursive interactions among
biological, psychological, and social-context factors
in the etiology of psychopathology are most effectively studied from a theory-based comprehensive
model that specifies well-established developmental pathways from infancy to adulthood (Blatt, 2008;
Charney et al., 2002) rather than the orientation characteristic of much of psychiatric research based on
post-hoc attempts to reconstruct etiological factors
that could have contributed to the various disorders
identified in a clinical context. These post-hoc efforts
may resemble the proverbial seeking the needle in
the haystack. The many conditional and provisional
statements in Watt & Panksepp’s article, in our view,
point to the problematic nature of such an endeavor.
Such post-hoc analyses are plagued by the fact that
similar symptoms can emerge from different etiological pathways (equifinality) and, depending on a variety of factors and circumstances, can be expressed
in different disorders (multifinality). In contrast, a developmental approach to psychological development
and psychopathology provides a prospective longitudinal approach to the investigation of the etiology of
various forms of psychopathology as variations and
disruptions of well-specified processes in normal psychological and biological development.
Research on the development of secure and insecure
attachment patterns (e.g., Ainsworth, Blehar, Waters,
& Wall, 1978; Fonagy, Steele, & Steele, 1991; Steele,
Steele, & Fonagy, 1996), for example, clearly demonstrates the impact of a mother’s attachment style on the
early development of her child’s personality organization and how the mother’s attachment style derives
from her relationship with her own mother. In addition,
there is emerging evidence how attachment affects
the development of the stress system in both animal
models and humans (Gunnar & Quevedo, 2007). Recent evidence (Besser & Priel, 2005) documents how
these attachment and personality patterns are transmitted across at least three generations of women—from
grandmother, to mother, to daughter.
Recent research (Beebe et al., 2007), in fact, demonstrates how a mother’s personality organization influences the infant’s development of self- and interactive
regulation as early as 4 months of age. Using the DEQ
57
(Blatt, D’Afflitti, & Quinlan, 1976, 1979), Beebe and
colleagues assessed, 6 weeks post-delivery, the extent
to which primiparious mothers of a healthy first-born
child in an ethnically diverse, low-risk sample of welleducated women experienced feelings of dependency
or disturbances in self-worth and self-criticism—anaclitic and introjective issues we discussed earlier as
central in depression. Beebe and colleagues also examined the impact of feelings of dependency and selfcriticism on interactive play patterns in these mothers
and their infants 4 months after the infants’ birth. Using
well-established microsecond split-second analysis of
mother–infant interactions, Beebe et al. (2007) found
that elevated maternal scores on DEQ dependency and
self-criticism 6 weeks postpartum both significantly
predicted lower infant self-regulation at 4 months of
age. These two dimensions also predicted very different patterns of mother–infant interactive regulation
at 4 months. Dependent (or anaclitic) mothers had
heightened facial and vocal coordination with their
infants—an “attentional vigilance” that was accompanied by heightened emotional activation of the infants.
Infants of these dependent mothers showed a similar
emotional vigilance and an intense reactivity to shifts
in their mother’s affectivity. This heightened vigilance
and dyadic symmetry of mother and infant indicates
excessive maternal concern about the infant’s availability that limits the infant’s individuation and affect
regulation. In contrast, mothers with elevated scores on
self-criticism (introjective issues) had difficulty sharing their infant’s attentional focus and emotional variations. These mothers appeared to try to compensate
for their disengagement with their 4-month-old infants
by touching them more frequently, a more neutral
type of engagement than sharing facial expressions,
voice quality, or visual gaze (Beebe et al., 2007). In
response to the disengagement of self-critical mothers,
their infants seemed to disengage from their mother by
withdrawing vocal-quality coordination. This distancing and disengagement in self-critical mothers and
their infants appears to be the precursor of dismissive
insecure attachment. The intense involvement of dependent mothers and their infants, in contrast, appears
to be the precursor of preoccupied or anxious–ambivalent insecure attachment. It remains for subsequent
research to examine the relationship of these early
interpersonal interactive patterns observed at 4 months
of age and in the attachment patterns observed in the
second year of life to the later development of anaclitic
and introjective forms of personality organization and
psychopathology.
Yet the research paradigm established by Beebe
58
et al. (2007), investigating the impact of personality
variations in a nonclinical sample of first-time mothers
on infants’ early interpersonal engagement, provides a
structure for examining systematically the impact of
neurobiological and genetic dimensions on psychological development. Infants at 4 months of age have
begun to establish pre-representational schemas of self
and others that become increasingly consolidated in
the symbolic representational structures associated
with secure and insecure attachment patterns observed
in the second year of life. The identification of the
emergence of the behavioral, cognitive, and interpersonal expressions of these representational structures
can be used to establish extensive research paradigms
to evaluate the impact of neurobiological and genetic
aspects of mothers on their caring patterns and the
impact of these on the neurobiological development,
particularly the development of the HPA axis (Claes
& Nemeroff, 2005; Levinson, 2006), of their infants
and its role in their subsequent biological and psychological development. As noted recently by Gunnar and
Quevedo (2007), individual differences in the social
regulation of neurobiological reactions to stress observed in mother–infant interactions can provide a lens
for examining questions about the impact and management of stress throughout development.
Rather than the post-hoc searching for specific genetic and neurobiological markers of particular psychiatric diseases or disorders seen in the clinical context,
an approach plagued by complex issues of the equifinality and multifinality of symptoms and of etiological
pathways—the developmental approach to personality
development and psychopathology, as exemplified by
the research by Beebe et al. (2007)—has considerable
promise but will require extensive, long-term, longitudinal, developmental research. But as suggested by
the impressive findings of Beebe and colleagues, this
approach has considerable potential.
This paradigm might also lead to a more fruitful approach to study the interaction between biological and
psychosocial processes in adulthood. Several studies,
for instance, have shown that not only subjective but
also psychophysiological and biochemical stress are
contingent on the “fit” or congruence between personality and the nature of the stressor (Allen, Horne, &
Trinder, 1996; Ewart, Jorgensen, & Kolodner, 1998;
Gruen, Silva, Ehrlich, Schweitzer, & Friedhoff, 1997;
Sauro et al., 2001; Wirtz et al., 2007). Gruen et al.
(1997), for instance, found that introjective, but not
anaclitic, traits were associated with changes in plasma
homovanillic acid, the primary dopamine metabolite
in humans, during exposure to an induced failurestressor.
Sidney J. Blatt & Patrick Luyten
Conclusions
The article by Watt & Panksepp is a remarkable attempt to develop a comprehensive theoretical model of
depression drawing on animal models. However, this
commentary illustrates the need to coordinate animal
models and research with clinical experience and research with humans. In particular, in this commentary
we focused primarily on the heterogeneity of dimensions that are at issue in depression and the need to
include clinical and developmental perspectives that
include the role of the content and cognitive structural
organization of meaning systems (i.e., mental representations of interpersonal cognitive–affective schemas
of self and others) in comprehensive biopsychosocial
models of depression and of psychopathology more
generally.
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Is Sadness an Evolutionarily Conserved Brain Mechanism to Dampen Reward
Seeking? Depression May Be a “Sadness Disorder”
Commentary by Peter Freed (New York)
Keywords:
sadness; depression; attachment; emotion; yearning; incentive salience
Douglas Watt and Jaak Panksepp’s article addresses
two fundamental questions in behavioral neuroscience:
1. How is the protest phase of separation distress adaptively terminated?
2. What is the evolutionary purpose of depression?
Their innovative response is to use each question to
answer the other. Separation distress is terminated by
depression, and depression evolved to terminate separation distress.
In analyzing this appealing, if somewhat circular,
argument, I will draw contrasts between it and a model
addressing the same questions recently published by
myself and John Mann (Freed & Mann, 2007), to
which it bears many similarities, but from which it
departs in several key aspects.
Freed and Mann suggest that the core problem in
separation distress is the persistent incentive salience,
or reward-value, of the missing love object. This incentive salience drives four key features of the protest
phase: (1) attention toward reminders of the missing
attachment, (2) yearning for the missing attachment,
(3) motivation to seek out the missing attachment, and
(4) crying behavior.
In our model, the opportunity cost of protest is its
most serious downside. While a period of heightened
incentive salience may adaptively promote reunion
Peter J. Freed: Division of Neuroscience, Columbia University Medical
Center, New York, NY, U.S.A.
with a missing object, attention/yearning/seeking/crying comes at the expense of pursuing other strategies
toward adaptive fitness. At a certain break-point the
opportunity cost of protest becomes too high relative
to other avenues toward regaining function, and, for
adaptive fitness to be maximized, it must be downregulated.
As in the Watt–Panksepp model, Freed and Mann
suggest that the despair phase of separation distress is
a likely candidate for facilitating the downregulation of
protest. But which parts of despair are targeting which
aspects of protest? Rather than suggest that the entire
despair phase performs some function with respect to
the entire protest phase, we focus on the core “positive
symptom” of despair—sadness—and its relationship
to the core positive symptom of protest—yearning. We
hypothesize that sadness may be a subjective correlate
of neural events in which dopaminergic yearning and
seeking mechanisms, geared toward obtaining oxytocin and opioid rewards, are downregulated. We suggest
that sadness facilitates the rapid onset of what I will call
the adaptive “negative symptoms” of despair: amotivation, immobility, introversion, depressive affect, and
anhedonia. We summarize our model as follows:
When the desire for reunion with a deceased loved
one is both overpowering and maladaptive, a mechanism that inhibits reward seeking and downregulates
yearning and attentional bias [towards the attachment]
is useful. Sadness may be such a mechanism. However, if sadness does not perform such a function, further inquiry is needed into the mechanisms by which
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
62
Peter Freed
bereaved persons decouple outdated stimulus–reward
associations. [Freed & Mann, 2007, p. 32]
As reviewed below, Watt & Panksepp have nominated
depression where we put forth sadness.
Finally, as with Watt & Panksepp, we suggest that
adaptive hope-renouncing mechanisms in the human
brain—in the case of our model, sadness—can become
disordered, giving way to depression.
If sadness is shown to reduce incentive salience and
the neurocircuitry of minutes-long episodes of sadness
overlaps with that of sustained periods of depression,
it may be plausible that depression is in part a “sadness
disorder” in which incentive salience, hopefulness,
motivation, and goal-directed activities are all reduced
as a result of the inappropriate triggering of this sadness mechanism. [Freed & Mann, 2007, p. 32]
In short, the Freed–Mann and Watt–Panksepp models
both are concerned with how protest is dampened
when it becomes maladaptive; both suggest that despair plays some downregulatory role; and both suggest that despair can become disordered and give way
to depression. Furthermore, both emphasize that attachment figures provide homeostatic regulation and
are experienced as rewarding and that the dampening
of reward seeking and return of homeostasis must be
end products of any adaptive process in despair. Given
these many similarities, readers may wonder how the
two models differ. Watt & Panksepp do not address this
question in their article, and in fact for unclear reasons
our paper and model are only referenced in passing. As
such, I must offer my own analysis of the distinction
between their framework and ours—I look forward to
learning whether they agree with it.
In my view, the core difference is that Freed &
Mann attribute to the emotion of sadness the same
protest-dampening functions that Watt & Panksepp
attribute to depression, a term they use to describe the
despair phase of separation distress.
Before examining their model in detail, I would emphasize that the overriding reason that Freed & Mann
did not suggest that depression (despair) per se was
adaptive is that in our view despair is a heterogeneous
state combining adaptive and maladaptive features of
various etiologies. As such the phase cannot be usefully attributed a singular function as a whole and instead, we believe, must be broken down and analyzed
in terms of distinct processes (e.g., helplessness, anhedonia, stress). This point is implicit in our suggestion
that attachments provide homeostatic regulation and,
therefore, that when they die, dysregulation of the organism maladaptively follows, including a protracted
stress response and neurovegetative symptoms. This
dysregulation takes time to emerge and does not appear prominently during protest. The term “phase” in
the phrase “despair phase” gives the false impression
that all the characteristics of this phase are somehow
orchestrated, when in fact many are likely homeostatic
breakdown pathologies that take time to emerge.
However, implicit in our model is also the idea that
despair does contain adaptive processes which can be
conceptually parsed from the maladaptive ones. In particular, we believe it is downregulation of the incentive
salience of the deceased that is the crucial adaptive
process during the despair phase.
This brings me to the positive hypothesis of our
article, which is our answer to the question “how does
downregulation of incentive salience occur?” Here we
suggest that sad emotion—a minutes’- to hours’-long
actively generated state—plays a key role in reducing
incentive salience. I emphasize here that we purposely
focus on this brief emotion because it helps to explain
the defining temporal signature of normal grief: “pangs
of grief.” Pangs of grief may be loosely defined as brief
but intense amalgams of yearning, sadness, anhedonia,
and preoccupation with the missing object.
Of crucial importance, these pangs are interspersed
with periods of normal function. Following in a long
tradition of analytic thinking from Freud onwards, we
emphasize that this sinusoidal nature of grief bestows a
singular, and incalculably beneficial, adaptive function
over that attributed to depression in Watt & Panksepp’s
article. It is this: grief permits the maintenance of normal social function and all the adaptive benefits that
attend it. To argue that depression is the evolutionarily
conserved process by which protest is dampened is,
implicitly, to argue that it bestows some adaptive advantage that is greater than the loss of social function it
requires, relative to grief.
In contrast to Watt & Panksepp, we believe that
chronic negative affect is rarely adaptive, while brief
bursts of negative affect that rapidly alter an organism’s orientation, priorities, and behaviors are. This
is seen with normal versus pathological anxiety and
anger, and we see no reason that this should not also
be the starting assumption about sad emotion as well.
We therefore start by hypothesizing that any adaptive
negative affect during despair should be rapidly reversible, thereby granting the organism maximal behavioral flexibility.
Pangs of grief grant behavioral flexibility. The
hours- to days-long periods of euthymia in grief allow
the mourner to continue to maintain his or her work
and social relationships, to continue to provide value to
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
any group he or she is a part of, to continue to eat and
sleep and pursue the activities of daily living, and to
retain access to peak cognitive functioning. However,
the acute pangs themselves facilitate important decathexis. Importantly, we believe the burst-like nature of
the decathexis in grief is likely more adaptive than the
tonic and global decathexis in which all pleasure and
normal social function is lost in depression.
Having now outlined the Freed–Mann model and
its overall differences from the Watt–Panksepp model,
I now proceed to analyzing their model per se. I will
subsequently critique the Freed–Mann model in the
hope of anticipating (and in several places I suspect
agreeing with) their critiques. I will close with a suggestion that the two models may be usefully combined
in an effort to find a way forward to understanding the
important but mysterious connections between mourning and melancholia.
Summary of Watt & Panksepp’s argument
Watt & Panksepp’s work embodies an inspirational
and sorely needed conviction that a review of “bottom-up” brain changes in depression, combined with
a sophisticated “top-down” evolutionary and psychological model, may meet in the middle to create an integrated model of depression. They correctly note that
only such a broad model can hope to do justice to the
lived experience of the disorder and its neuroanatomy.
Furthermore, only such a model can point the way to
new research paradigms and novel treatments for depression. Their focus on dynorphin, a product of their
review, is an example of the concrete progress that can
come from such an effort.
The authors are rightly critical of pure bottom-up
models, which they demonstrate to be insufficient to
produce an explanation of depression. They review
the inadequacy of models based purely on findings
regarding norepinephrine, serotonin, dopamine, opioids, GABA, glutamate, dynorphin, substance P, CRF,
BDNF, cortisol, and many other small molecules. Each
is shown to contribute important elements to an understanding of the DSM-IV symptoms of depression,
but to be insufficient on its own to explain the illness.
They perform a similar review, though less extensive,
of brain regions involved, including PAG, PFC, amygdala, and ACC (including BA25). Throughout they
emphasize that the brain may be too complex to allow
depression to be explained by any single overriding
theory.
However, despite these caveats, and consistent with
63
the article’s bold title, they seek to combine key features of the data to create an organizing model of depression. In addition to the model implied by the title,
to my reading they imply two other models. Because
these are presented separately, and briefly, and are not
explicitly reconciled to one another, I shall discuss
them separately.
All three models begin with a common set of observations. First, attachment is pleasurable, is mediated
by oxytocin and opioids, and promotes homeostasis
with low allostatic load. Separation from caregivers
deprives the organism of this pleasurable attachment
and homeostatic regulation, leading to high allostatic
load. A stress cascade ensues that is metabolically
demanding and gives rise to many of the symptoms of
the protest phase of separation distress. To name but a
few highlighted by the authors, the HPA axis is activated, with cortisol and CRF having various effects on
cognition, anxiety, and mood. Dysphoria is produced
as a function not only of the reduction of oxytocin
and opioids, but of the effects of CCK and dynorphin.
Brain regions involved in executive functions become
hypoactive and may process negative stimuli more
readily, while limbic and paralimbic regions such as
BA25 demonstrate increased processing that may be
related to negative affect. Brain regions implicated
in separation distress, and regulated by oxytocin and
opioids, are also active, including the PAG and BNST.
They note that “normal” separation distress is adaptive
but, if not self-limiting, can progress to depression.
They are not specific about what criteria help to define
when an organism has crossed the line from adaptation to pathology. Nevertheless, they make clear that
over time the distress response becomes pathological.
BDNF decreases, there is atrophy of hippocampus and
other brain regions, social function suffers, and the
metabolic demands placed on the organism are inconsistent with optimal health.
It is from these data that each of the three models
takes their cue.
What might be called their “decathexis” model,
and the topic of the paper’s title, follows the uncited
Freed–Mann model closely, although it is possible
that my reading of their model is unduly influenced
by my familiarity with my own. However, as I read it,
it explains the data above by focusing on the adaptive
risk of remaining attached to a caregiver who no longer
provides care. Decathexis is necessary when caregivers are absent. For this purpose, the despair phase of
separation distress (which the authors appear to describe as depression at some points) evolved to “shut
down” attachment seeking seen in protest. This model
64
accounts for the decline in opioids and oxytocin and
for the dysphoric effects of dynorphin. It also makes
sense of psychoanalytic contributions, described at the
article’s close, in which depression reflects an inability
to attain goals. It is also consistent with theoretical
work on goal renunciation done by Nesse (2000) and
others. Watt & Panksepp state that the despair phase
lasts long enough to accomplish the decathexis goal,
at which point it “self-limits”; people with deficits in
this self-limiting mechanism, possibly as a function
of early-life difficulties, may be prone to pathology.
As discussed below, they are not specific about when,
why, and how this self-limitation occurs.
What might be called the “social brake” model—
though less developed than the decathexis model—
suggests that subtypes of depression may be adaptive
shutdown mechanisms for other social emotions besides separation, including sex, play, and status. Status
is the best explained of these. They suggest that when
efforts to climb status gradients are assessed to be too
dangerous, despair may save the physical body from
attack by others, even as it renders the psyche sorrowful. Again, a loss of motivation and pleasure experiences are adaptive in this context.
Finally what might be called a “stress model” appears in pieces throughout the article and seems to be
only partially overlapping with the separation-distress
model. Here, Watt & Panksepp imply that if adaptive,
the despair phase should dampen rather than increase
the stress of protest. I was not sure they explained how
the despair phase might do this; most of their emphasis
was on the dangers of stress, rather than its downregulation.
Critique of the Watt–Panksepp model
Having summarized their model as I understand it, I
now highlight four trouble spots that require clarification.
What separates the despair phase from
depression?
First, the term “depression” seems sometimes to be
used to describe the apparently adaptive despair phase
of separation distress and at other times to describe
frank psychopathology, consistent with the DSM. Because the premise of the article requires despair to
be an evolutionarily conserved adaptation, I think it
would be advisable to avoid conceptual drift by clearly
Peter Freed
segregating it from psychopathology. I believe their
argument would be greatly clarified if they were to use
two words (“despair” vs. “depression”) to describe the
distinct adaptive and pathological conditions to which
they now apply the single term “depression.” This
would require that the title of their article be changed
to “Despair: an evolutionarily conserved mechanism
to terminate protest; depression: a pathology of despair?”
Terminology aside, the question arises as to what,
exactly, divides despair from depression. Throughout
the article the authors refer to the “self-limiting” nature
of despair, but they do not describe the mechanism of
limitation. The details of this limitation are a crucial
piece of the puzzle that needs more clarification. I
think that three questions should be answered:
1. What precisely is the brain mechanism that terminates despair and returns the person to normal function?
2. How does the brain “decide” when to trigger this
mechanism? What process must be complete (e.g.,
decathexis) before it is triggered, and how is this
completion detected?
3. What pathologies (e.g., early initiation, late termination, excessive intensity) of this mechanism may
permit pathological depression to develop?
Depression as decathexis: turning off one bulb
by blowing every fuse in the house
It is possible that the article’s main argument embodies something of a logical fallacy. Let us say that it
is true that depression terminates separation distress.
Does this mean that this is its purpose? I think some
improvements to the argument might attend a discussion of all the candidate processes by which protest
might be terminated, followed by a review of the
relative strengths and weaknesses of each. As implied above, I think such a review would reveal that
grief—a process hardly discussed in this article—is
an excellent candidate to which depression must be
compared. I will discuss this more below. However,
as the heading of this section indicates, while depression dampens all reward seeking—akin to blowing every fuse in the house—is it possible that some
other process might more elegantly reduce yearning
for the missing attachment, while preserving general
reward processes crucial to survival—akin to turning
the switch on a single lamp?
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
The problem of stress
I was not sure that the stress story was a complete
one, as presented. The authors offer two pieces of
what I think needs to be a three-piece model explaining the role of stress in depression. First, they show
that attachment is protective against stress, and, consistent with this, separation from caregivers triggers
stress that characterizes the protest phase. Second, they
show—and do so admirably—that stress is a gateway
into depression and, indeed, that control of stress at the
biological level may in the future play a crucial role in
resolving pathological depression.
But at this point they face a choice, and I was
not sure that they made one. One option is that they
can show that the despair phase of separation distress
adaptively terminates protest-phase stress. This would
provide an evolutionary purpose for despair distinct
from decathexis. If this is the case, we need more detail, as the vast bulk of their review of this topic indicates that stress worsens, rather than improves, during
despair. The second option is that, given that stress
worsens in despair, it represents a pathological component of the despair phase. This then puts pressure
on their model to adjust to the fact that the despair
phase, per se, does not have an adaptive function but,
rather, must be subdivided into adaptive and maladaptive components.
Subtypes of depression
A final critique is over the “social brake” model of
depression, which though mentioned briefly deserves
a foundational place in the neuroscience of depression.
The authors raise the provocative—and for psychoanalysts, laudable—idea that depression terminates forms
of social reward other than attachment reward. For
followers of Sidney Blatt’s work on introjective versus
anaclitic depression (Blatt, 2004), the suggestion that
depression may facilitate disengagement from status
conflicts and be experienced subjectively as a failure
of the self—rather than the loss of an object—was
quite welcome, and a harbinger of a hopefully fruitful
intellectual collaboration between psychoanalysis and
neuroscience. However, I thought that this suggestion
inadvertently poses problems for the decathexis model,
as it takes the purpose of despair—which in the article
is presented as a response to protest—as possibly being to address problems that are not related to protest
at all. This raises the question of whether despair is
an “independent module” not inextricably tethered to
65
attachment. The details of this will be important. For
example, are oxytocin and opioid systems the final
common pathway for status pleasure?
Critique of the Freed–Mann model
The Freed–Mann model makes three claims that the
Watt–Panksepp model may correctly dispute; empirical study will be necessary to do so.
The first is that sadness, the “positive symptom”
of despair, triggers depression, which I believe can
be considered the “negative symptoms” of despair—
amotivation, anhedonia, anergia, introversion—as
they represent the absence of normal function. Watt
& Panksepp describe these as a fundamental loss of
hopefulness in the face of adversity. In our model,
these symptoms are brief—on the order of minutes to
hours—and dissipate rapidly, allowing the return of
normal function. Therefore, our focus is on functional
brain changes rather than on neurobiological ones. I
think this is a matter for empirical study, and critics
would be well within their rights to argue that the positive and negative symptoms of despair are not causally
connected. I suspect that this is what Watt & Panksepp
believe, and I think that if this is the case, they have
clinical evidence on their side: many periods of depressive affect consist, simply, of the absence of normal
function, without the involvement of sad affect. If this
is the case, then work must be performed separately on
sadness and depressive affect.
Second, we clearly locate sadness in the despair
phase of separation distress. However, I believe that
critics—and personal conversation with Panksepp and
a review of his work leads me to believe he is one
of them—might place sadness squarely in the protest phase of separation distress. In the Freed–Mann
2007 article, we suggest that this question should become an item for empirical study. However, if sadness
is properly understood as a protest-phase behavior,
then it is likely that some other process in depression
accomplishes the decathexis of stimuli from reward
predictions—which is to say, negative reward–prediction errors. A region not discussed by Watt and
Panksepp—the habenula—is currently emerging as
just such a candidate region; it may detect the absence
of predicted rewards and dampen VTA production of
dopamine, thereby reducing incentive salience and encoding negative reward-prediction errors.
The third and final claim—and the one closest to
psychoanalysis proper—that may be disputed is that
pangs of grief allow the targeted decathexis of love
66
objects while preserving normal reward seeking in
other areas of life, thereby preserving normal social
function. Watt & Panksepp may believe that depression—which essentially produces a decathexis field
that robs the reward value of any stimulus entering it,
be it sexual, nutritive, aspirational, interpersonal—is
necessary to accomplish the decathexis task. Here,
however, I believe the burden remains on those suggesting that depression is adaptive to prove that grief
does not produce the main effect needed without the
nasty side effects of depression.
In closing, I want to draw attention to a crucial difference between grief, including episodes of sadness,
versus depression, that deserves a longer exposition.
Negative emotion during grief comes in waves. These
waves of intense pangs of yearning, sadness, and thinking about the deceased are interspersed with prolonged
period of relative euthymia. During these periods the
bereaved person is able to prosecute normal social relationships in a way that promotes integration with his
or her social world, increases his or her attractiveness
to others, and keeps available rewards within reach.
This stands in contrast to the extended dysfunction of
depression, in which social dysfunction and reward
insensitivity are interminable. What makes the waveform of grief possible is the brain’s capacity to rapidly
dampen—just as it rapidly generates—strong negative
affect. I think for these reasons, and as elaborated on
above, grief—and in particular, sadness—must be considered the most likely natural process for terminating
separation distress.
Phasing out phases?
I want to suggest that, moving forward, we should discard the phase model of separation distress and substitute in its stead a task framework. This would have the
immediate benefit of allowing us to rapidly distinguish
between adaptive and maladaptive features of despair,
rather than seeking to explain the phase as a whole. Instead, we should ask what tasks must be accomplished
Peter Freed
by a person who has lost the homeostatic regulation of
an attachment figure and for whom protest has failed.
In the Freed–Mann model reviewed here, the answer is
that the rapid encoding of negative reward-prediction
errors, leading to a downregulation of dopaminergic
seeking/incentive salience, is necessary, as it can free
the bereaved person from the mandate to pursue opioid
or oxytocin rewards in the form of the deceased and,
instead, to seek them elsewhere. Or as Freud would
call it, decathexis. Or as Watt & Panksepp would call
it, the loss of hopefulness in the face of adversity. Key
questions that then remain are these:
1. whether this loss of hopefulness, which certainly
occurs at some point during despair, occurs as a
result of sadness or regardless of it;
2. whether the loss of hopefulness occurs in bursts
seen in pangs of grief or requires a sustained period
of depression;
3. how the loss of hopefulness is itself terminated—
whether through adjustment to a negative rewardprediction error, as in my own thinking, or some
other mechanism.
On these questions depends the manner in which the
known biological and emerging functional changes in
depression should be interpreted. Watt & Panksepp’s
clarion call for synthetic bottom-up plus top-down empirical-evolutionary models is sorely needed and with
little doubt represents the way forward on this tricky
problem.
REFERENCES
Blatt, S. J. (2004). Experiences of Depression. Washington, DC:
American Psychological Association.
Freed, P. J., & J. J. Mann (2007). Sadness and loss: Toward a
neurobiopsychosocial model. American Journal of Psychiatry, 164 (1): 28–34.
Nesse, R. (2000). Is depression an adaptation? Archives of General Psychiatry, 57: 14–20.
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
67
Depression as a Mechanism for Terminating Separation Distress: A Critical
Review
Commentary by Paul E. Holtzheimer (Atlanta)
Keywords:
depression; mood disorders; animal models; separation distress; phenomenology
Douglas Watt and Jaak Panksepp present a very thorough, thoughtful, and thought-provoking review of
the neurobiology and treatment of depression. Based
on this review, the authors propose an overarching
hypothesis of depression as an evolutionarily selectedfor mechanism in mammals for terminating separation
distress. This hypothesis is offered as a potential explanatory model for the available and diverse neurobiological findings in depression research; furthermore,
the authors hope this model can serve as a guide for
future investigation into the neurobiological underpinnings of depression and antidepressant-treatment
development.
The authors’ argument relies on several premises:
1. Separation-distress behaviors (e.g., crying) in response to social loss occur in most mammals, including humans.
2. Mechanisms to inhibit separation-distress behaviors exist in mammals.
3. These mechanisms have been evolutionarily selected for since the inability to inhibit such behaviors in
infants would have an untenable survival/reproductive cost.
4. In susceptible individuals, these inhibitory mechanisms—what the authors refer to as a fundamental shutdown process—are not properly regulated,
leading to a protracted abnormal state; this protracted state is what is clinically referred to as depression.
The authors provide support for this argument by citing a wealth of data relating depression to social loss/
stress. Additionally, the authors show that the response
of animals to a separation-distress testing paradigm has
significant phenomenological overlap with the clinical
depressive syndrome in humans. Finally, the authors
note that separation-distress responses in animals are
Paul E. Holtzheimer: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, U.S.A.
associated with changes in biological systems (endocrinological, immunological, etc.) similar to those tied
to human depression. While the proposed model has
much to support it—and does indeed provide a novel
framework to guide future depression research—there
are several questions that need to be addressed to
strengthen this work. In this brief commentary, I will
summarize three main questions for further discussion.
Question #1: Does the natural history of separation
distress in humans and other mammals support
such an explanatory model for human depression?
Conversely, if adult human depression represents an
evolutionarily conserved process, what is its analogue
and prevalence in other adult mammals?
The authors’ principal argument is that mechanisms
involved in suppressing certain separation-distress behaviors in infant mammals are conserved and available to adult mammals, including humans. To support
this premise, it would be reasonable to describe in
more detail the natural history of separation-distress
mechanisms in mammals, including humans. Specifically, some discussion of the normal operation of
these processes in adult mammals would be helpful.
Are the authors suggesting that all adult mammals
continue to engage these processes (e.g., bereavement), or are they suggesting that these mechanisms
are inherently abnormal when present in adulthood
(e.g., depression)?
Along these lines, one wonders what the animal correlate of adult human depression might be.
If human depression is based in an evolutionarily
conserved neurobiological system, then it must be
necessarily presumed that this system exists and operates in nonhuman mammals. Thus, one would expect that other mammals, especially the nonhuman
primates, should have some incidence of a depressive-like syndrome. Although there are multiple animal models for depression, it is not clear what the
prevalence of “depression” is in nonhuman adult
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
68
mammals in the wild. Presumably, if it was on the
order of 7%–15% (as in humans), there would be a
description of this in the literature. The authors might
strengthen their argument by a more thorough discussion of this issue. If the presence of a depressive-like
syndrome is not found in other mammals, or is much
less prevalent than in humans, this would argue that
human depression is unique in some fundamental way
(and that the separation-distress model may not be
most appropriate).
This discussion is critical since it helps establish the
degree to which human depression is simply the expression of neurobiological processes present in other
mammals versus being a condition unique to humans
because of their unique neurobiology. For example,
one might argue that neuroanatomical studies (including numerous imaging studies) support a primary role
for the prefrontal cortex in the pathophysiology of
depression. Given that humans have a much-expanded
prefrontal cortex compared to any other mammalian
species, one could then argue that disorders involving
the prefrontal cortex, such as depression, are unique to
humans. If this holds, then any animal behavior-based
model of depression (such as the separation-distress
model proposed by the authors) is at best incomplete as
it cannot necessarily account for disorders or features
of disorders that result from biological processes only
present in humans.
Question #2: If depression fundamentally results from
brain mechanisms related to social-loss separation
distress, how are nonstress-related depressive episodes
explained?
The model presented by Watts & Panksepp relies on
social loss as the link to evolutionary mechanisms
related to separation distress. However, not all depressive episodes occur following social loss. Many episodes of depression follow stress that is not inherently
social (traumatic brain injury, stroke, loss of a primary
body function such as sight or hearing, loss of a limb,
etc.). One might then conclude that some other feature of stress (beyond its relationship to separation/social loss) may underlie its depressogenic properties.
An example supporting this can be found in one of
the more interesting primate models of depression:
variable foraging demand (VFD: see Coplan et al.,
1996). In this model, mother–infant monkey dyads
are exposed to one of three different foraging conditions over time: high food availability (predictable),
low food availability (predictable), and variable food
Paul E. Holtzheimer
availability (unpredictable). Separation time between
mother and infant is controlled; however, infants in
the variable-foraging condition develop a depressivelike syndrome not seen in the other conditions. Furthermore, it is notable that it is primarily the mother
that experiences the stress directly (i.e., the infant
receives adequate nutrition regardless of condition),
but the depressive syndrome occurs in the infant. This
argues that some other aspect of this stress beyond
separation (unpredictability? uncontrollability?) may
be associated with depression. The authors might
comment on the alternative hypothesis that depression results from disruption of stress response systems
more generally, with social loss/separation distress as
a special case.
Beyond this, it is well-known that many depressive
episodes occur de novo without any apparent trigger. It
would seem that any model for depression would need
to account for these episodes as well. However, the
authors’ hypothesis as presented does not provide an
easy explanation for how depression could arise in the
absence of any stressor (including social loss).
These points argue that persistence of social-loss
separation-distress mechanisms in adulthood may underlie some forms of depression—but not all. If the
authors are proposing that their model applies to a
specific subset of depressed patients, this might be
stated explicitly. Alternatively, they could discuss how
their model, as proposed, might relate to depression
unrelated to social loss or to any other stressor/environmental trigger.
Question #3: Does human depression (from a
neurobiological perspective) correspond to the state
of physiological shutdown associated with separation
distress or with the abnormal regulation of this process?
That is, is depression “sadness” or “the inability to
regulate sadness”?
Throughout the article, the authors appear to equate
depression with sadness—and both with the separation-distress “despair” phase. However, like separation
distress in young animals, sadness is a very normal human emotional state. One presumes that some degree
of sadness is appropriate following social loss even in
adulthood—for example, bereavement following the
loss of a loved one. What appears to distinguish the
clinical disorder of depression is not sadness itself, but
(1) the presence of sadness in the absence of a known
trigger; (2) a degree of sadness and associated emotions/cognitions (e.g., guilt, anxiety, hopelessness, sui-
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
cidal ideation) more extreme than would be expected
given a known trigger; and/or (3) the persistence of
sadness beyond presumably normal limits. Thus, it
seems depression may be better defined as the inability
to terminate/suppress sadness rather than the simple
presence of sadness; in other words, depression is abnormal negative-mood regulation rather than negative
mood per se.
Related to the authors’ thesis, one can then ask
whether depression (in their view) is essentially equivalent to the physiological shutdown associated with
separation distress or whether depression is actually
the disturbed regulation of this (otherwise normal)
process. This is a critical distinction since it provides a
subtly different framework for understanding the neurobiological findings in depression reviewed in this article. If one accepts that depression is not sadness but,
rather, the disordered regulation of sadness, then the
majority of neuroscience findings in depression (where
data from currently depressed subjects are compared
to those from nondepressed controls) become even
more (!) confusing: these findings may then represent
neurobiological changes/differences associated with
being sad (which could be the correlates of normal
sadness) and changes/differences related to disrupted
mood regulation (the inability to not be sad—i.e., the
“real” biology of depression). Concerning treatment,
understanding depression as dysfunctional negative
mood regulation might explain why certain successful antidepressant treatments (e.g., SSRIs) have few, if
any, effects in nondepressed individuals—that is, these
are not mood-elevating but, rather, mood-regulating
treatments. Or, this might explain why certain acute
and subacute treatments for depression (ECT, sleep
deprivation, and perhaps ketamine) are also associated
with such a high relapse rate: these treatments may be
“shifting” the patient’s state from sadness to euthymia
but doing nothing to address the underlying deficiency
in mood regulation.
Such a redefinition of depression has further implications for what are considered depressive symptoms.
If sadness (and its associated symptoms) are viewed as
“normal,” and the inability to regulate these is considered abnormal, then one could argue that the current
DSM-IV criteria for depression do not adequately highlight the behavioral correlates of depression. Instead,
it could be proposed that symptoms representative of
dysfunctional negative-mood regulation (negative cognitive bias, hopelessness, helplessness) are more central to the diagnosis than are other symptoms (stated
mood, sleep and appetite changes, etc.) that are essentially epiphenomena.
69
Clearly, a full discussion of this is beyond the authors’ intended scope. However, it would be instructive
if they could comment on whether they view depression, from a neurobiological standpoint, as referring to
the state of shutdown itself or the disrupted regulation
of the shutdown process. The answer to this question
has specific relevance to the validity of separationdistress and other models of depression: “depressivelike” behaviors exhibited by animals may actually be
analogs of normal sadness—not the disrupted mood
regulation inherent to depression. If the authors agree
that depression, at least in part, results from disrupted
mood regulation, then some discussion of how this
might relate to their primary hypothesis would be warranted.
Summary
Watt & Panksepp are commended for offering such an
impressive review of the depression neuroscience literature coupled with an intriguing hypothesis to guide
future research. As a clinical neuroscientist, I especially welcome their thoughts and suggestions concerning treatment development and agree that modulators
of the opioid and oxytocin neurotransmitter systems
(among others) should be more aggressively pursued.
As a practicing psychiatrist (specializing in the medication management of patients with treatment-resistant
depression), I also strongly agree that psychotherapy
(including behavioral, cognitive, and psychodynamic
approaches) is an extremely important antidepressant
therapy that should be recommended for most, if not
all, depressed patients. In line with the discussion
above, psychotherapy may be able to fundamentally
alter and potentially normalize mood-regulatory neural systems, thereby “curing” depression in a manner
that somatic treatments may never be able to achieve.
I disagree somewhat with the authors’ view that the
recommendation and use of psychotherapy have been
primarily constrained by a bottom-up neurobiological view and pressure from “Big Pharma”—rather, I
think the inequity in mental health coverage by thirdparty payers, especially for psychotherapy, has played
a much larger role.
Watts & Panksepp have gone further than most in
proposing an explanatory model for depression that
fully integrates a diverse and often confusing neurobiological database. Given the current state of the
field, it is unlikely that any model for depression will
be easily accepted by the neuroscience and psychiatric
community—however, this particular model appropri-
70
Ilia Karatsoreos & Bruce S. McEwen
ately lends itself to testing via a number of resultant
hypotheses. Perhaps more importantly, this approach
to depression opens the door a bit more to novel and
exciting potential collaborations between previously
(mostly) unrelated schools of thought—for example,
psychodynamic theory and basic neuroscience. Such
a wide-reaching collaboration promises many exciting
and paradigm-shifting discoveries.
REFERENCE
Coplan, J. D., Andrews, M. W., Rosenblum, L. A., Owens, M.
J., Friedman, J. M., et al. (1996). Persistent elevations of
cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life
stressors: Implications for the pathophysiology of mood and
anxiety disorders. Proceedings of the National Academy of
Sciences, USA, 93 (4): 1619–1123.
Depression: What Is the Role of Physiological Dysregulation and Circadian
Disruption?
Commentary by Ilia Karatsoreos & Bruce S. McEwen (New York)
Keywords:
circadian rhythm disruption; glucocorticoids; hippocampus; prefrontal cortex; amygdala; clock genes; mood
Douglas Watt and Jaak Panksepp have provided an
excellent and wide-ranging review that analyzes what
is missing in current theories of the etiology of depression, and they effectively present the notion that
depression is a state that is rooted in misuse of an
adaptive and normal response—namely, the termination of separation distress. They suggest that multiple
neural systems react in order to suppress the distressful
feelings associated with separation of the infant from
the mother. In adulthood, according to their view, this
same system acts to prevent an organism from continuously seeking out a goal that is unreachable and
thus prevents a pointless waste of resources. In their
view, depression can be thought of as the inappropriate
engaging of this system. Thus, improper activation of
the neural systems that terminate separation distress, or
perhaps an incomplete shutdown of these systems, can
lead to a pathological impairment of normal behavior,
resulting in the individual withdrawing.
Potentially even more important is their view that
depression involves the malfunction and desynchronization of multiple interacting neural and neurochemical systems. We propose that separation distress is an
example of a more global dysregulation of the organism’s neural and systemic ability to adapt, based on
the concept of allostasis and the build-up of allostatic
overload. In particular, the dysregulation of circadian
rhythms can lead to an allostatic state, resulting in the
Ilia Karatsoreos & Bruce S. McEwen: Laboratory of Neuroendocrinology, Rockefeller University, New York, NY, U.S.A.
dysfunction of many of the same systems that Watt
& Panksepp highlight in their more specific focus on
separation distress.
Adaptation, allostasis, and allostatic load
Adaptation is key to survival. This is true for the
lowliest unicellular organism, all the way through the
phylogenetic tree to humans. Selective pressures have
resulted in organisms that possess exquisitely tuned
systems that regulate the functions of life. In some
instances, these systems are relatively “simple” biochemical cascades (e.g. the electron transport chain).
In others, such systems are a complex orchestration
of multiple tissues and organs toward a singular result
(e.g., digestion). Regardless, these systems are crucial
to survival of the individual and are tuned to meet the
particulars of a given environmental niche.
Maintaining viability in the face of ever-changing
environmental pressures is termed homeostasis. Homeostasis amounts to maintaining the right conditions
for various physiological and biochemical systems to
operate within optimal parameters (Box 1). The problem of maintaining homeostasis is not a simple one.
For instance, many systems are engaged in maintaining
body temperature within its optimal range (in humans,
this is approximately 36.8°C ± 0.7°C). When body
temperature begins to climb, we begin to perspire to increase heat loss from the skin, and blood vessels dilate
to increase heat dissipation. When body temperature
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
begins to fall, blood vessels constrict to reduce heat
loss, we begin to shiver uncontrollably to generate
more heat, and piloerections attempt to reduce heat
dissipation from the skin.
While apparently simple, and totally automatic,
these responses are the result of multiple neural and
endocrine (and exocrine!) systems working together
for the purpose of a single goal: maintaining the body
within its optimal range by a process referred to as
allostasis, or “maintaining stability through active intervention” (Boxes 1 and 2). It is the mediators of
allostasis (e.g., adrenalin, cortisol, cytokines) that are
mobilized to maintain homeostasis, whereas those parameters essential to survival (e.g., body temperature,
pH, oxygen tension) are not themselves used for this
purpose (Box 1).
However, the mediators of allostasis may respond
to a sustained external challenge or to internal factors
(e.g., chronic anxiety) by becoming elevated into an
allostatic state beyond the normal range (Box 2). In
an allostatic state, other mediators of allostasis that
operate in a nonlinear network (McEwen, 2006) are
also forced to operate out of their range (e.g., elevated
inflammatory cytokines leading to elevated cortisol
and often accompanied by imbalance of sympathetic
and parasympathetic activity) (Goldstein et al., 2007;
Sloan et al., 2007a, 2007b).
While short-term allostasis can help to overcome
acute challenges and, in a sense, ensure survival of the
organism by forcing systems to function outside normal ranges, long-term allostasis can result in problems
resulting from “wear and tear.” In a sense, allostatic
states are “borrowing” against a system’s integrity in
Allostasis—the active process of maintaining/
re-establishing homeostasis, when one defines
homeostasis as those aspects of physiology (pH,
oxygen tension, body temperature for homeotherms)
that maintain life. Allostasis refers to the ability of the
body to produce hormones (like cortisol, adrenalin)
and other mediators (e.g., cytokines) that help an
animal adapt to a new situation/challenge.
In contrast to the mediators (of allostasis) that actively
promote adaptation, those features that maintain life
(using the restricted definition of homeostasis above)
are ones that operate in a narrower range and do not
change in order to help us adapt—that is, they are not
the mediators of change.
Box 1. Allostasis and homeostasis
71
Homeostasis: essential parameters of life
Allostasis: active process of maintaining homeostasis
Allostatic state: elevated level of mediators (e.g.,
increased blood pressure, hypercortisolemia)
Allostatic load: cumulative change (e.g., body fat;
remodeling of neuronal circuitry)
Allostatic overload: wear and tear, pathophysiology
(e.g., atherosclerosis; neuronal damage and cell
loss)
Box 2. Terminology
the short term to ensure long-term viability, under the
(somewhat anthropomorphic) notion that such states
of indebtedness will be ameliorated quickly when the
environment returns to normal. But when the environment does not cooperate and return to baseline, or the
regulatory systems underlying allostasis fail to properly
engage, a situation of “allostatic overload” may result,
which involves wear and tear on body systems and
pathophysiology (e.g., atherosclerosis or obesity and
Type 2 diabetes). A lesser degree of cumulative change
(e.g., putting on body fat for winter in bears prior to
hibernation), referred to as allostatic load (Table 2), has
adaptive advantages (McEwen & Wingfield, 2003).
Allostatic states occur in the brain in terms of internal neurotransmitter systems and the actions of
elevated levels of external factors, such as circulating hormones that affect brain function and structure.
Adaptive plasticity of the dendritic and synaptic structure of neurons in hippocampus, amygdala, and prefrontal cortex is one of the consequences of prolonged,
uncontrollable stress (McEwen, 2007), and the failure
of the reversal of such plasticity and/or increased vulnerability to irreversible damage is an example of allostatic overload. Such consequences are related to states
of chronic anxiety, depressed mood, and neural damage—for example, after stroke or seizures, or neurodegenerative diseases. Restated, allostatic states allow
for flexibility of physiological systems when environmental pressures require. Allostatic overload can occur
if the allostatic state is maintained for too long, forcing
mediators normally promoting adaptation to become
dysregulated and to operate outside of their optimal
ranges for a protracted period of time. This leads us to
a major biological factor involved in maintaining balance of allostasis, failure of which leads to allostatic
overload—namely, the circadian timing system of the
brain and body.
72
Ilia Karatsoreos & Bruce S. McEwen
Circadian timing: brain and body clocks
Circadian rhythms and allostasis
Perhaps the most salient environmental cue for terrestrial organisms is the alternation of light and dark that
defines the solar day. The rotation of the earth about
its axis allows for a temporal framework of life. It
provides a level of predictability that allows organisms
to anticipate daily-recurring events and adjust their
physiology and behaviors to meet these changes. For
instance, daily rhythms in glucocorticoid secretion are
tightly controlled by the circadian clock, and in both
nocturnal and diurnal animals, plasma corticoids reach
their peak just before the onset of daily activity (i.e.,
just before dusk in a nocturnal species, and just before
dawn in a diurnal species). A master circadian clock
generates these rhythms, which in mammals is located
in the suprachiasmatic nucleus (SCN) of the hypothalamus. This brain region is comprised of neurons
that are cell-autonomous oscillators—in other words,
individual cells that contain the genetic and molecular
machinery to generate circadian rhythms. Importantly,
the unique tissue-level organization of these cells into
a complex network of different functional components
ensures that the SCN clock is able to maintain circadian rhythmicity, even in vitro, without any external
inputs. The neural network of the SCN is important
to consider, as the molecular “gears” of the clock
(clock genes and clock-controlled genes) are present in
myriad cell types throughout the brain and body. These
“peripheral clocks” lose their synchronous rhythmicity
rapidly when decoupled from the SCN, in that while
individual cells may remain rhythmic, the tissue itself
no longer shows a coherent rhythm as individual oscillators have drifted out of phase with each other. Thus,
timing in peripheral clocks seems to be an intrinsic
property of these cells, but extrinsic synchrony must
be imposed by the master clock in order for coherent
tissue-level rhythms to be expressed.
We propose that disrupted circadian timing—namely, altered phase-relationships between cellular oscillators throughout the brain and body—leads to an
allostatic state and eventually to allostatic overload.
Many studies have shown that depression is a condition in which circadian timing is altered (Wirz-Justice,
2006). We go further to propose that circadian disruption is not just a symptom of depression, but is perhaps
one of the precipitating causes of depression. Thus,
disrupted circadian timing results in a real or perceived
threat to homeostasis and can lead to the engagement
of protective systems that attempt to remove the threat.
Depression may be, as Watt & Panksepp propose in
terms of termination of separation distress, one of these
defense mechanisms.
Anticipation of daily events is a key benefit of having
an optimally functioning circadian system. The SCN
regulates rhythms in myriad physiological systems
through a combination of neural and humoral connections, and sometimes both. Moreover, at the level of
the target brain region (or peripheral organ or gland),
local clocks also contribute to the exquisite timing
of the system. Such a wide reach through neural and
diffusible signals places the SCN and the circadian
system in a position to regulate multiple systems both
homeostatically and also in times of allostasis. In a
sense, circadian rhythms may be one of the driving
forces to restore normal homeostasis after a period of
allostasis.
Disruption of circadian rhythms, both environmentally and genetically, can lead to many physiological
problems. These effects are felt on a regular basis during
transmeridian air travel (i.e. jetlag), and by shift-workers. Symptoms include a general “malaise,” sometimes
accompanied by specific physical complaints (such
as gastrointestinal problems and weakened immune
function), as well as psychological manifestations of
poor concentration, attention, and memory. In animal models, numerous studies present compelling data
showing that chronic circadian dysfunction can lead
to subsyndromal mental and physical characteristics
of “bad aging” and even, in some cases, a decrease in
lifespan (Costa, 2003; Davidson et al., 2006). Interestingly, it has been difficult to disentangle the effects of
circadian disruption from effects of sleep deprivation,
though we propose that it is an important distinction
and that circadian disruption is the key component in
the development of depressive syndrome.
Clock-gene expression and glucocorticoids
Peripheral oscillators, both within the brain and in the
rest of the body, make use of the same suite of clock
genes as the central clock in the SCN. The SCN then
imposes the proper phasing of these oscillators and
actually maintains their rhythmicity, through different
pathways—some neural and some humoral. The daily
surge of glucocorticoids before waking is an essential
synchronizer of circadian rhythms in organs and tissues
in the periphery and potentially in the brain. Almost all
tissues express circadian clock genes, and the rhythms
of these genes are synchronized through humoral signals like corticosterone (Balsalobre, 2002; Balsalobre
et al., 2000), as well as direct neural connections (Buijs,
van Eden, Goncharuk, & Kalsbeek, 2003; Buijs et al.,
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
2003), and even through feedback from daily behaviors (e.g., feeding). This means that circadian rhythms
in the periphery are imposed by the master brain clock
on the rest of the body through numerous mechanisms.
Examined in this light, dysfunction in circadian timing
has many downstream effects on peripheral organs and
eventually on the brain. As the peripheral effects can
be as wide ranging as changes to metabolism, obesity,
and even in extreme cases decreased life span (Hurd
& Ralph, 1998; Turek et al., 2005), it is likely that the
effects on the brain can be as great in breadth and as
serious in consequences.
Interestingly, not all peripheral oscillators reach
their peaks and troughs at the same time, but the phase
relationship between some of these oscillators has been
determined. For instance, while PER2 expression in
the dentate gyrus and the basolateral amygdala peak at
the same time, the central amygdala peaks later in the
day (Segall, Perrin, Walker, Stewart, & Amir, 2006).
The significance of such phase relationships of clock
genes in different brain regions is unclear, but it is
important to note that some of these extra-SCN brain
oscillators can be reprogrammed by glucocorticoids,
while others, including importantly the SCN, cannot
(Lamont, Robinson, Stewart, & Amir, 2005; Segall et
al., 2006). This organization may lead to the potential
for dysregulation between the SCN clock and other
brain (and body) oscillators due to altered glucocorticoid signaling. What does this mean for general physiology and for specific downstream control of some of
the neurochemical mediators Watt & Panksepp refer to
in their review?
Circadian regulation of neurochemical systems can
occur through direct mono- or multisynaptic projections from the SCN, through diffusible SCN signals,
or through local control by circadian clock-gene expression in those brain regions. The most dense neural
projection of the SCN is to the subparaventricular
zone, particularly the ventral aspect. This intermediate
way-station then sends extensive projections to the locus coeruleus noradrenergic systems, the serotonergic
system of the midbrain raphe nuclei, and the rostral tip
of the cholinergic periaqueductal grey (PAG), to name
only a handful (Kalsbeek et al., 2006; Watts & Swanson, 1987; Watts, Swanson, & Sanchez-Watts, 1987).
Interestingly, the PAG also expresses prokineticin-2
receptors, which respond to prokineticin, a peptide
that plays a role in transmitting circadian signals from
the SCN (Cheng, Leslie, & Zhou, 2006; de Novellis et
al., 2007). Whether or not these different brain nuclei
have the molecular machinery necessary to be considered peripheral oscillators is unclear. However, the
raphe show clear rhythms in tryptophan hydroxylase-2
73
activity that are driven by the daily surge of adrenal
corticosteroids (Malek, Sage, Pevet, & Raison, 2007).
In short, many of the key brain regions that Watt &
Panksepp discuss receive inputs, both neural and humoral, from the circadian clock and would possibly
be affected by circadian dysregulation. The issue of
reciprocal feedback from these regions to the SCN
clock is also an important one, and there are multiple
lines of evidence suggesting they communicate back to
the SCN (Watts & Swanson, 1987; Watts, Swanson, &
Sanchez-Watts, 1987). How such cross talk influences
the function of the SCN is unknown, but it clearly sets
the stage for multiple mechanisms by which circadian
disruption could alter essential emotional processing
circuitry and for how limbic and brainstem regions can
potentially feedback and influence clock function.
While we focus on how circadian dysfunction may
be a cause of depression, or at least may contribute to
its development by placing the brain and body into
an allostatic state, it is important to note that such a
hypothesis also provides for potential paths to treatment. Restoring a cohesive circadian system may be
a beneficial treatment in some depressed individuals.
The most obvious case of a circadian basis and a circadian treatment in a depressive syndrome is seasonal
affective disorder (SAD). The primary treatment for
SAD is bright-light therapy delivered in the morning
just after the individual awakes, in order to mimic a
bright sunrise. However, there are many treatments for
depressive disorders that incorporate, or at least impinge upon, circadian rhythms. For instance, exercise
has shown to improve depressive symptoms in some
individuals, and the animal literature clearly shows that
exercise can shift the circadian clock (Buxton, Lee,
L’Hermite-Baleriaux, Turek, & Van Cauter, 2003).
Also, it has been shown that brief (i.e. single night)
REM sleep deprivation has the puzzling benefit of being antidepressant (reviewed in Wu & Bunney, 1990).
Such a stimulus may serve as a “jump start” to the
circadian system, providing a reset switch of sorts to
reinitialize and resynchronize rhythms. This, however,
is speculative and requires further experimentation.
Conclusions
In the model proposed by Watt & Panksepp, the system
for reducing separation distress is rooted in mesolimbic emotional regulatory regions upstream from homeostatic regulatory processes, but downstream from
higher cognitive processes. Watt & Panksepp suggest
that engaging of these mood systems may then result in the disruption of the “subordinate” homeostatic
74
systems, as well as of the “supraordinate” cognitive
systems. We propose an alternative, although in some
ways parallel, pathway in which homeostatic disruptions result in altered mood systems and eventually
in depressive symptoms through a disruption of the
timing of clock genes in different brain regions and
body organs. These effects are mediated, at least in
part, through the actions of glucocorticoids. Moreover,
we further suggest—as did the late Edward Sachar
(Sachar et al., 1973), referring to glucocorticoid secretion—that the state of being “depressed” is in itself
stressful and thus amplifies circadian disruptions and
leads to allostatic states and allostatic overload, further
resisting the restoration of normal allostasis.
We would like to expand upon the Watt–Panksepp
hypotheses surrounding the mesolimbic structures that
regulate separation–distress and other “basal” emotional responses. As separation–distress is inherently
“stressful,” then it may be useful to think that mesolimbic systems are acting in a way to protect homeostasis by reducing the distress. Orchestration of such
a response requires the recruitment of multiple brain
regions, and disruption of this recruitment may lead
to dysfunction in the system. We hypothesize that in
attempting to operate in a way to mitigate separation
distress, perhaps the circadian clocks in these mesolimbic systems are being disrupted and dysregulated
by stressful experiences. This leads to dysregulation of
normal communication between brain regions and to
an allostatic state that eventually causes the buildup of
allostatic overload in the brain and eventually in other
body organs. Considered in this light, any set of stimuli
that pushes an organism into an allostatic state—in this
case, separation distress—will cause “wear and tear”
even while the brain attempts to maintain homeostasis.
Thus, protection of homeostasis is the primary role
of such mesolimbic systems. Any perceived threat to
homeostasis, be it external or internal in origin, could
result in the engagement of such systems. Disruption
of circadian timing may serve as one of these triggers
and may potentially lead to further circadian disruption
and add to the allostatic load.
Watt & Panksepp’s review thoughtfully highlights
the multifactorial nature of depression. It is this manyfaceted quality of depression that makes it so difficult
to treat. Approaching the disorder in a multipronged
assault may accomplish more than attempting a unitary
solution. Perhaps a truly “holistic” approach, by which
we mean a “whole-organism” approach to treating
depression, will be more successful—for example, by
treatments such as exercise, social engagement, and
some form of cognitive behavioral therapy, which help
Ilia Karatsoreos & Bruce S. McEwen
re-establish coordination of dysregulated neural and
body circadian systems. By narrowing down the main
neural systems that are dysfunctional, such a holistic
approach will be more possible. Accepting the notion
that depression may arise, as Watt & Panksepp propose, from a primary dysfunction in midline brain nuclei far more ancient than the cortex, we may be more
able to address the problem from a primal “emotional”
perspective and perhaps from the perspective of circadian disruption.
In addition, we posit that allostatic states through
circadian disruption are a key contributor to the dysfunction of such ancient brain systems. These states
may occur spontaneously, but they are more likely
caused by a “stressor.” Such a stressor can be a salient
experience, but it could also be an internal stressor, one
generated due to improper or inappropriate functioning
of physiological systems, or resulting from anticipatory anxiety or rumination. According to this view, dysfunctions in circadian rhythms may be a central player
in such internal stresses, as circadian clocks organize
physiology and behavior and ensure that different tissues and organs function optimally and in a coordinate
fashion with each other.
Whether or not such an important role for circadian
rhythms exists at the level of different brain nuclei is
still unclear, though there is ample evidence that circadian clock “genes” are present and oscillate in many
different brain regions. Most remain under tight control of the central brain clock in the SCN, though some
are able to be independently synchronized by external
environmental cues arising from circulating glucocorticoids (Balsalobre et al., 2000; Hastings, Reddy, &
Maywood, 2003) and even dissociated from the SCN
clock.
The emotional ramifications of dysfunctional circadian synchronization within the brain, and throughout
the body, are largely unknown, though one of the most
common, and invasive, symptoms of many depressive
syndromes is sleep and rhythm dysregulation. Because
such complaints include both insomnia and hypersomnia, “sleep deprivation” cannot be invoked as a global
catchall, and it reflects a more fundamental problem
with homeostatic circadian control. Thus, dysfunction
at the level of circadian rhythms can lead to changes in
allostatic states that, if maintained, can have deleterious effects on the mental and physical well-being of
the organism in the form of allostatic overload. Much
as Watt & Panksepp suggest that basal emotional processing is compromised in depression, we propose that
another potential cause of depression is basal physiological dysregulation.
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
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76
Otto F. Kernberg
An Integrated Theory of Depression
Commentary by Otto F. Kernberg (New York)
Keywords:
attachment; guilt; mourning; symbolic structure; abandonment; cognitive framing
Douglas Watt and Jaak Panksepp’s elegant, comprehensive, and thought-provoking essay provides not
only an up-to-date review of neurobiological systems
involved in depression, and a clear and convincing relationship between these mechanisms and those involved
in the panic/separation-distress system, but convincing evidence throughout the painstaking analysis of
the interaction of the various neurobiological systems
involved that strengthens their overall thesis—namely,
“that depression is an evolutionarily conserved mechanism in mammalian brains, selected as a shutdown
mechanism to terminate protracted separation distress
(a prototype mammalian emotional state), which, if
sustained, would be dangerous for infant mammals.”
Following Bowlby’s (1980) terminology, the separation/distress syndrome is described as a series of psychological responses to social loss on a continuum
from protest to despair and, finally, to detachment. The
broad spectrum of depressive syndromes results from
an exaggerated activation and persistence of this mechanism, particularly the transition phase between protest
and despair. A genetic predisposition to an excessive
activation of this biological constellation, particularly
a genetically determined hypersensitivity combined
with excessive negative affect in response to the loss
of social support—abandonment by essential sources
of physical and psychic security—would reflect the
biologically determined vulnerability to depression.
This vulnerability becomes reinforced by psychological experiences that further augment the threat of social
loss or psychological abandonment and constitute the
psychodynamic disposition to depression.
In my view, the authors’ thesis fits harmoniously
with contemporary psychodynamic thinking regarding
depression, particularly with respect to the intrapsychic mechanisms that determine the experience of loss
of support not only from external objects, but also as
a consequence of pathological internalization of early
object relations and their role in dysfunctional regulation of self-esteem and of the confirmation of selfOtto F. Kernberg: Weill Medical College of Cornell University, New
York; Personality Disorders Institute, The New York Presbyterian Hospital,
Payne Whitney Westchester, White Plains, NY; Columbia University Center for Psychoanalytic Training and Research, New York, U.S.A.
regard by the internalized value systems represented
by the superego and its ego-ideal component.
In exploring this thesis further, there are two reasons for caution. One is the risk posed by the attempt
to fit neurobiological systems into the procrustean bed
of psychoanalytic theories; the other is the risk of a
reductionistic effort to link specific psychic functions
to specific neurobiological structures, a danger that
Panksepp himself (2008) has warned against, by stressing the epigenetic, in contrast to the genetic, source of
organization of psychic functions. In other words, from
a general viewpoint, neurobiological functions permit
the development of the psychic structure of primary affects and their cognitive contextualization. But further
elaboration of affective disposition, which reflects the
development of symbolic thinking, depends on this
structure formation at the level of symbolic functions
and not directly on the underlying neurobiological
structures and functions. What follows, I trust, will
illustrate my efforts to respect these two reasons for
caution.
“Mourning and Melancholia” (1917e [1915]) is
Freud’s first and fundamental contribution to the psychoanalytic understanding of normal and pathological mourning, the psychopathology of major affective
disorders, and the psychodynamic determinants of depression.
Freud described fundamental differences between
normal and pathological mourning processes. In normal mourning, he proposed, there are no guilt feelings
regarding the lost object. The work of mourning culminates in the introjection of the lost—external—object;
the narcissistic gratification of being alive contributes
to the successful working through of the mourning
process. In melancholia, in contrast, the ambivalent
relation to the lost object arouses intense guilt feelings
and leads to the turning of the unconscious aggressive
attack on the external object into an internal attack on
a part of the ego identified with the lost object. This
attack on the self prevents the narcissistic gratification
of being alive and thus intensifies and prolongs the
pathological mourning process.
Melanie Klein (1940) postulated the splitting, in the
mind of the infant, of idealized and persecutory relations with its mother and the generation of guilt and de-
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
pression when integration of these split segments of the
ego or self and of the corresponding internal objects
would bring about the infant’s awareness that its own
aggression was directed against the ideal mother: this
is the depressive position. Klein pointed to the normal
consolidation of the good internal object and the ego
when aggression is not excessive and described how
conditions promoting marked dominance of aggressive over libidinal investments prevent such a normal
integration. The result is intolerance of ambivalence
and lack of assurance of one’s own goodness, creating the predisposition to pathological mourning and
melancholia.
In contrast to Freud, Klein felt that in normal mourning there was an unconscious process of reinstating
the early good internal object and that ambivalence
characterized normality as well as pathology. Normal
mourning, she proposed, includes unconscious guilt
feelings related to the reactivation of the depressive
position, together with the activation of reparative
urges, gratitude, and longing for the lost good object,
but also by the reinstatement of the good internal one.
Pathological mourning is characterized by the failure to
work through the depressive position due to the sadism
and cruelty of the superego, its demands for perfection,
and its hatred of instincts. In melancholia, Klein stated,
this hatred has destructive consequences for both the
internal and the external good objects, leading to a
sense of internal emptiness and loss. Because of the
attack on and the destruction of the idealized object,
a vicious circle of guilt evolves, with an attack on the
bad self, not on the internalized object. Suicide would
be an unconscious effort to destroy the bad self and
rescue the good object.
Edward Bibring (1953) described depression as the
result of acknowledgment of the loss of an ideal state
of self in the context of a severe discrepancy between
the ideal self and the real self. This pointed to the affect
of depression as an ego potential predating the differentiation of the superego from the ego. In contrast to
the Kleinian view that depression necessarily involves
superego mechanisms, Bibring stressed the early emergence of the loss of an ideal state of self under conditions of severe failure of the protective environment,
thus foreshadowing, I suggest, the catastrophic reaction to prolonged early separation described by Bowlby (1969) in the pathology of attachment. A potential
for depressive affect, triggered by the loss of an ideal
state of self, may be caused by early maternal failure as
well as by a later internal, superego-determined attack
on the self. The basic mechanism is a loss of an ideal
state of self related to the loss of an ideal object. In my
view, the potential for the affective reaction of depres-
77
sion to loss of an ideal ego or self state is compatible
with Melanie Klein’s description (1946) of the depressive position when the aggression stemming from the
self can be acknowledged, when ambivalence can be
tolerated, and when the implicit comparison between
a past illusory, split-off, idealized self and the realistic,
integrated, present one signals the loss of that ideal self
state.
Edith Jacobson’s analysis (1971) of normal, neurotic, borderline, and psychotic depression mapped
out a comprehensive psychoanalytic theory of the psychopathology of depression. In describing the dyadic,
internalized object relations reflected in the affective
connection between libidinally invested self and object
representations and the corresponding aggressively invested self- and object-representations, she originated
what I consider the contemporary object-relations theory model in psychoanalysis. I believe that she accomplished this independently from, although at the same
time as, Ronald Fairbairn (1954) in Scotland. Jacobson
described the originally fused or undifferentiated units
of self- and object-representations in both the libidinal and the aggressive domains of experience and the
defensive refusion of libidinal self- and object-representations under conditions of psychotic regression. In
psychotic depression, this regressive refusion would
affect the aggressively invested self- and object-representations in the ego and would also involve a refusion
of the earliest aggressive superego precursors with
the later idealized ones. It is the regressive fusion of
persecutory and idealized object representations in the
superego, she proposed, that brings about the sadistic
demand for perfection and the typical cruelty of the
superego in melancholia. The attacks of this sadistic
superego are directed toward the units of fused aggressive self- and object-representations in the ego. In the
process, the frail remnant of the idealized segment of
the self that was overwhelmed in the total refusion process occurring in the ego succumbs to the generalized
activation of guilt, despair, and self-accusation. As a
consequence, the nihilistic, hypochondriacal, and selfdevaluing delusions of psychotic depression evolve.
Jacobson proposed that in borderline conditions the
boundaries between self- and object-representations
in both libidinal and aggressive domains of internalized object relations persist, facilitating the defensive
processes of dissociation, depersonalization, and projection that help these patients avoid the sadistic superego attacks characteristic of depression. In neurotic
depression, a sufficiently well-integrated self relating
to integrated representations of significant others still
experiences the attacks of the superego in the form of
exaggerated, pathological guilt and self-devaluation,
78
but such a self suffers neither the fusion processes that,
in melancholia, transform guilt into a total delusional
devaluation of the self-identified with the object nor
the primitive defenses characteristic of borderline conditions.
In all these psychoanalytic theories of depression
except Bibring’s, depressive affect emerges as the connection between the basic experience of loss of an ideal
state of self as the result of the loss of an object and the
assumption that the loss of the object itself was caused
by one’s own aggression. The empirical research of
John Bowlby (1969) and his followers on normal attachment and its pathology and their description of the
stages of protest, despair, and detachment as a result
of catastrophically prolonged separation of the infant
from mother provided a fundamental link between the
psychoanalytic theory of depression, on the one hand,
and the reaction to early separation, on the other. Depressive affect as a basic psychophysiological reaction
is triggered by early separation from the mother, if excessive or traumatic, and similarly by an internal sense
of loss of the relation between the self and the good internal object derived from the superego’s attack on the
self. Early separations provoke depressive affects—a
chain reaction of rage, despair, and despondency, and
their neurohormonal correlates, in humans as well as
in other primates (Suomi, 1995). This link between felt
emotion and neurochemical response begins to connect the psychoanalytic theory of internalized object
relations with biological research into the genetic and
neurobiological determinants of aggressive and depressive affect.
Prolonged separation of the infant from its mother
powerfully activates the affects of rage first, despair
later, and, under extreme circumstances, despondency
and reduction of the capacity for object-relatedness.
Neurobiological studies in both humans and other
mammals have confirmed the corresponding activation
of the hypothalamus–pituitary–adrenal (HPA) axis, the
resulting hypercortisolemia, and, more recently, the
resulting long-range consequences in terms of lowered blood cortisol, excessive stress response to later
traumatic stimuli, and reduction in the hippocampal
volume, the brain structure most directly involved in
explicit affective memory (Panksepp, 1998).
The mechanisms by which the HPA stress response
activates the basic affective responses of rage, panic,
and depression probably are still insufficiently elucidated, although the brain structures mediating rage
and pain have been circumscribed more clearly. As
Panksepp (1998) points out, the complexity of affect activation demands the simultaneous analysis of
the brain structures involved—the generally activating
Otto F. Kernberg
biogenic amines (particularly, in the case of depression, the serotonergic and noradrenergic systems), but
also particular neuropeptides related to specific affect
systems that are as yet only partially known—in the
context of the analysis of behavioral manifestations
and subjective experience. Basic autonomous vegetative functions of affects involve the hypothalamus, the
amygdala, and the periaqueductal gray; early emotional experience involves the amygdala, the hippocampus,
and the ventral striatum; but mature emotionality, with
the development of complex later emotions, involves
the prefrontal cortex along with cognitive control of
emotions mediated particularly by the orbital, frontal,
and cingulated cortex.
At this time, psychoanalysis and neurobiology are
still too far apart in their focus and methodology to
permit any satisfactory integration. I believe, however,
that it is reasonable to assume that the psychopathology of depression is determined by a complementary set of etiological factors. These include, on the
biological side, an abnormal, genetically determined,
and neurochemically controlled activation of the affect of depression under conditions of early separation
and object loss, most probably mediated by abnormal
biogenic amine systems. Early, severely traumatic circumstances, particularly failed or insecure attachment,
further contribute, triggering not only an exaggerated
stress response but a disposition to later excessive
activation of negative, particularly depressive, affect,
mediated by the corresponding hypercortisolemia and,
presumably, by the loss of the modulating influence
of the hippocampus—affective memory—on deeper
affect-activating centers.
On the psychological side, depressive affect is activated by loss of the ideal state of self when anxiety
is aroused by need, and seeking gratification fails to
produce the expected maternal response, and, later,
when active rejection by an ideal object is no longer
perceived as an external attack but resonates with the
internal build-up of archaic superego structures. Here,
what is relevant is the build-up of complex affective
memory structures that are symbolically manipulated
and integrated unconsciously, leading to the concepts
of self and the world of internalized object representations. The extraordinary richness of the human neocortical brain structures constitutes the basis for this
evolution of psychological structures. In short, on the
psychological side, the development of pathological
ego and superego structures in response to the aggressive affects activated by a hostile, depriving, abusive
environment, with the consequent threat to the normal
dominance of libidinally invested internalized object
relations in ego and superego over those invested with
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
aggression, determines the potential for pathological
depression.
The work of Melanie Klein and Edith Jacobson
has enriched the analysis of normal and pathological depressive reactions by delineating the role of the
primitive defensive operations of splitting, idealization, projection and introjection, projective identification, denial, omnipotence, and devaluation. Both
authors described a vicious cycle of early aggressive
response to frustration, the infant’s tendency to project
its own aggression onto the frustrating object, and the
re-internalization of that aggressively perceived object
into the basic layer of the early superego in the form
of persecutory internalized object representations. A
constitutional disposition to excessive depressive affect may contribute significantly to the intensity of
depressive response to superego-mediated attacks on
the self.
Perhaps the major theoretical formulation initiated
in “Mourning and Melancholia,” transcending the subject of depression, is the concept of identification. This
concept is relevant for the understanding of the relation between affect activation and the internalization
of object relations, the consistent contextualization of
affects in relation to self- and object-representation.
Here, I believe, the work of Fairbairn (1954) and of
Jacobson (1964), who arrived independently at remarkably similar conclusions regarding this essential
mechanism, provides major contributions to Freud’s
original observations in “Mourning and Melancholia.”
Briefly summarizing how I conceptualize the contemporary view of identification, I would stress as a central
concept the definition of identification as the internalization of a representation of the object interacting
with a representation of the self under the impact of an
intense affect. The more intense the affect, the more
significant the object relation; the more significant the
object relation, the more intense the affect state. This
theory of identification overlaps with the theory of the
centrality of depressive affect in normal and pathological mourning: the more intense the predisposition to
react with depressive affect to separation or loss, the
more powerful the identification with an abandoning
object and with an abandoned self. The more profound
the experience of rejection or loss of a good external
or internal object, the greater the potential for depression.
Returning once more to the determinants of normal
and pathological depression, we can now conceive of
a genetic disposition to pathological activation of aggressive affects that will be integrated into the aggressive drive in the form of a structured sense of self or
object as victim or persecutor, self and object bound by
79
affects of fear, rage, and despair. The result is proneness to the excessive activation of rage, anxiety, and
despair under conditions of frustration and object loss.
It is important to keep in mind that the stress response
mediated by the activation of the HPA axis includes
intensive rage and panic as well as the disposition to
depression. In fact, the combination of an intense rage
response and panic may be the origin of the later structured internalized relation between a rageful self and a
frustrating, sadistic object. The projection of rage onto
the object intensifies the fear and wish to destroy the
persecutory object, thus transforming rage into hatred,
a complex affect that will later constitute the core affect of the aggressive drive. Here, I refer to my theory,
spelled out in earlier work (Kernberg, 1992), that the
libidinal and aggressive drives are hierarchically superordinate integrations of the libidinal and aggressive
affects, respectively, and that affects constitute the primary motivational systems first and, later, the signals
of the drives in terms of the affective quality of reactivated internalized object relations. I believe that this
theory does justice to the convincing clinical implication of Freud’s dual-drive theory and to the emerging
knowledge of the fundamental motivational functions
of affects in neurobiology.
Temperament as a genetically determined, constitutionally given disposition to a certain intensity,
rhythm, and threshold of affect activation links the
innate disposition to aggression with the traumatic
impact of early separation, trauma, and frustration on
the internalization of object relations. By far the most
important determinant of the internalized object relations expressed in the tripartite psychic structure is the
earliest mother–infant interaction. Severe frustration
and trauma in this early interaction, with consequent
excessive activation of aggressive and depressive affect, would then give rise to the structural consolidation of a psychic apparatus with a “hypertrophic”
superego and the predisposition to react with depression to relatively minor triggering factors from the
environment. An extremely severe inborn disposition
to depressive affect would exacerbate the development
of such pathological structures. At the other extreme,
even without any genetic disposition, the structural
consequences of severe frustration and trauma, with a
consequent activation of excessive aggression, would
contribute to the build-up of a severely pathological,
though well-integrated, superego structure predisposing to depression in later life.
A depressive–masochistic personality structure predisposes to characterological depression and to a loss
of normal self-esteem, determined by the superego,
under conditions of multiple sources of unconscious
80
guilt. This is the counterpart to the activation of anxiety
as nonspecific manifestation of danger derived from
unconscious intrapsychic conflict (Kernberg, 1992).
Anxiety, in fact, also may function as a warning of the
impending danger of unconscious guilt and object loss
leading to depression.
Once depressive affect is structured into an internalized object-relations frame that reflects the relationship between a guilty, internally abandoned self and
an idealized, abandoning or critical object, it would
seem reasonable to hypothesize that any critique, disqualification, or abandonment in everyday life would
immediately activate depressive affect as part of such
an object relation. And vice versa: when, given such
a structured internalized object relation, depressive
affect is triggered or accentuated by a constitutional
disposition to pathological affect activation, the entire
constellation of intensive guilt feelings, self-devaluations, and the experience of abandonment will be activated as well.
The major emphasis in this discussion has been on
the attempt to integrate the psychoanalytic approach
to depression with evolving knowledge regarding the
neurobiology of depression. For neurobiology, contemporary psychoanalytic theory offers an instrumental approach to higher symbolic functions that cannot
be reduced to neocortical circuitry. For psychoanalysis, neurobiological progress offers the challenge of
reexamining older theories of drives, the impact of
neurobiological structures on stress and trauma, and
the mutual relations of unconscious interpsychic conflict and the genetic and temperamental disposition to
depressive affect as causes of depression.
This completes my outline of the organization of the
psychodynamic features that contribute to the development both of normal mourning and grief reactions on
the one hand and of clinical depression—from characterologically determined chronic dysthymic reaction to
major affective illness—on the other. From a clinical
psychiatric viewpoint, it is possible to differentiate the
milder, chronic dysthymic reactions from major depression because of the lesser degree of depressive symptoms in the former and the stronger presence in those
cases of particular environmental triggers and specific
characterological predispositions, in contrast to the
greater degree of clinical severity, the prominence of
neurovegative symptoms, and the alteration of biological rhythms evident in major depressive disorder. Genetic factors predominate in major depression, while
intrapsychic and environmental factors predominate in
chronic dsythymic disorders. In general, psychopharmacological (and electroconvulsive) treatments are the
treatment of choice in the major depressions, while
Otto F. Kernberg
characterologically determined depression responds
optimally to psychotherapeutic treatments, often combined with medication.
Finally, from a general viewpoint of the interaction
of biological and intrapsychic predisposing features,
it is of great interest that the psychological impact
of a grave loss of social support may trigger the entire constellation of the neurobiology of depression,
while, equally, a strong genetic disposition to depression reflected in the activation of the corresponding
neurobiological systems may trigger the entire complexity of psychodynamically structured, psychological symptomatology of depression, including severe
and unrealistic self-attack and self-devaluation. The
study of the intimate mechanisms of these interactions
between symbolic thinking and genetic disposition,
and between genetic and epigenetic structures, is a
major task ahead, and Watt & Panksepp have advanced
fundamentally in this direction.
REFERENCES
Bibring, E. (1953). The mechanism of expression. In: Affective
Disorders, ed. P. Greenacre. New York: International Universities Press, pp. 13–48.
Bowlby, J. (1969). Attachment and Loss, Vol. 1: Attachment.
New York: Basic Books.
Bowlby, J. (1980). Attachment and Loss, Vol. 3: Sadness and
Depression. New York: Basic Books.
Fairbairn, R. (1954). An Object Relations Theory of the Personality. New York: Psychoanalytic Quarterly Press.
Freud, S. (1917e [1915]). Mourning and melancholia. Standard
Edition, 14: 237–258.
Jacobson, E. (1964). The Self and the Object World. New York:
International Universities Press.
Jacobson, E. (1971). Depression. New York: International Universities Press.
Kernberg, O. (1992). Aggression in Personality Disorders and
Perversion. New Haven, CT: Yale University Press.
Klein, M. (1940). Mourning and its relation to manic-depressive states. In: Contributions to Psychoanalysis, 1921–1945.
London: Hogarth Press, 1948, pp. 311–338.
Klein, M. (1946). Notes on some schizoid mechanisms. International Journal of Psycho-Analysis, 27: 99–110.
Panksepp, J. (1998). Affective Neuroscience. New York: Oxford
University Press.
Panksepp, J. (2008). Commentary on “Is There a Drive to
Love?” Seeking the epigenesis of romantic love. Neuropsychoanalysis, 10 (2): 166–169.
Suomi, S. J. (1995). The influence of attachment theory on ethological studies of biobehavioral development in nonhuman
primates. In: Attachment Theory: Social, Developmental
and Clinical Perspectives, ed. S. Goldberg, R. Muir, & J.
Kerr. Hillsdale, NJ: Analytic Press.
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
81
An Evolutionarily Conserved Depression Mechanism: Are There Implications for
Psychotherapy?
Commentary by Harold W. Koenigsberg (New York)
Keywords: depression; separation distress; psychotherapy; epigenetics; separation-distress shutdown; evolutionarily conserved
mechanism
Increasingly sophisticated research, accessing state-ofthe-art neurochemical, neuroendocrine, pharmacologic, molecular genetic, and neuroimaging methods has
generated a densely populated landscape of biological
correlates of depression. Douglas Watt and Jaak Panksepp masterfully survey this rich and complex landscape and observe that what is sorely lacking in our
understanding of depression is a model that integrates
the disparate biological findings and links them to the
core psychological and behavioral features of depression. They propose that such a model of depression
may be derived from an examination of the separationdistress behavioral system, common to so many animal
species. A separation-distress motivational system that,
in the event the young animal is separated from its
caregiver, prompts the animal to send out a distress
signal and to actively seek out the caregiver is adaptive
and evolutionarily conserved. However, continued activation of this distress system after an extended period
of time, when there is little likelihood for reuniting
with the caregiver, could expose the young animal to
predators and exhaustion. Thus a mechanism for terminating the separation-distress response is also necessary and would be evolutionarily conserved as well.
Watt & Panksepp propose that this separation-distress
shutdown system, however, is vulnerable to hypertrophy and excessive activation, providing a biological
substrate for depression.
With ongoing phylogenetic development the separation-distress shutdown (SDS) system likely came to
serve additional but related functions—for example,
the inhibition of protest to other types of losses such
as losses of social attachment, social status, comfort,
other rewards, and possibly even other disruptions to
homeostasis such as those caused by physical illness
or chronic pain. Thus the system could be triggered by
the range of stressors known to precipitate depression.
Once activated, it would close down seeking-behaviors
Harold W. Koenigsberg: Mount Sinai School of Medicine, New York;
James J. Peters VA Medical Center, Bronx, NY, U.S.A.
and initiate an energy-saving mode in the organism,
which would give rise to many of the biological and
behavioral stigmata of depression.
A low threshold for activation of the SDS system or
a failure of its homeostatic regulation could account for
various forms of clinical depression. Factors likely to
influence the threshold for activation and the homeostatic properties of the SDS system include inheritance,
early rearing experience, and early, late, or cumulative
exposure to trauma, neglect, or stress.
While it may be too soon to conclude that dysregulation of the SDS system is sufficient to explain all or
most forms of depression, the model is of considerable
appeal and has important heuristic value. By identifying an evolutionarily conserved behavioral system
implicated in depression, this conceptualization offers
the possibility that studying the neurochemical and
functional neuroanatomic pathways activated during
separation-distress shutdown can direct us to the neural
systems most relevant to human depression. This could
help us to understand how the multiple biological concomitants of depression are interconnected. Such an
integrative model could aid in drug discovery. Beyond
this, however, understanding depression in terms of an
evolutionarily conserved behavioral system provides
the potential for linking the neurobiologic features of
depression with the characteristic behavioral correlates
of the disorder. This is crucial because depression is
so intimately connected to human behavior and the
psychology that organizes and regulates that behavior.
Changes in interpersonal behavior patterns can be both
the precipitants and the sequelae of depressions.
Psychotherapy is a mainstay in the treatment of depression; it has been shown to be as effective as medication, and the combination of psychotherapy with
pharmacotherapy is more effective than either alone.
Enhancing the efficacy of psychotherapy for treating
depression could therefore be of enormous benefit.
Thus it is relevant to ask whether a biobehavioral model such as the one proposed by Watt & Panksepp could
contribute in any way to refining psychotherapeutic
approaches to depression.
© 2009 The International Neuropsychoanalysis Society
• http://www.neuropsa.org
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Implications for psychotherapy
A first test of the relevance of the SDS model for psychotherapy is whether psychotherapeutic approaches
known to be effective for depression are consistent
with the model. This is in fact the case. Many effective individual psychotherapies for depression devote
considerable energy to the focus on relevant losses
(separations)—losses of real objects, of internalized
objects, of aspirational goals, or those reflected in
unmet demands (Arieti & Bemporad, 1978). For example, the Interpersonal Psychotherapy of Depression
(IPT: Klerman, Weissman, Rounsaville, & Chevron,
1984), a well-studied and highly effective treatment for
depression (Klerman & Weissmann, 1987; Weissman,
2007), stands on a theoretical foundation derived in
part from the work of John Bowlby on attachment and
separation. Two of the four basic paradigms of depression that IPT targets involve losses: unresolved grief
and role transitions. It treats depression by helping
the patient to consciously process the often conflictual
conscious and unconscious feelings engendered by significant losses and by encouraging the patient to find
new satisfying interpersonal substitutes for them. Psychodynamic and psychoanalytic treatments for depression, though less operationally described as IPT, also
typically address conscious and unconscious conflicts
related to losses and separations, taking into account
relevant aggressive impulses.
Can the SDS model suggest novel psychotherapeutic strategies for depression? The model suggests that
depression involves the hyperactivation of a shutdown
system that, while turning off the separation-distress
response, is ultimately maladaptive by encouraging
“giving-up” attitudes and behaviors. This would imply
that diminishing the need to shut down the separationdistress system might actually release key behavioral
and biological systems from operating in the depressive mode. Could a treatment approach be devised
that would enable a patient to disengage the shutdown
system? If this were possible, the model suggests that
the patient might be able to reactivate motivational
and seeking systems that had been shut down. This
reactivation could temporarily restore motivation and
future-orientation and could even decrease the fatigue
and sickness feelings induced by proinflammatory
cytokines associated with the shutdown state. This
would give the patient the wherewithal, now with the
therapist present to help and guide, to bring to bear
native adaptive and problem-solving capacities that
had been shut down, providing the patient resources
to overcome the distressing losses and develop new
replacement sources of gratification. How could one
Harold W. Koenigsberg
intervene psychotherapeutically to diminish activation
of the shutdown system to achieve these potential dividends? Perhaps an effective strategy would be to reinforce the sense of agency in the patient by encouraging
thinking and behavior that could adaptively substitute
for the desperate seeking for the lost object that characterizes the separation-distress reaction. For example,
one might encourage the patient to take on, as his or
her own, a cause important to a deceased object (e.g. a
favorite charity or special interest) or to actively plan
a memorial for that person. As the patient functioned
in this way, there might be a decreased activation of
the separation-distress shutdown process. This line of
thought is highly speculative, but it is presented here in
the interest of modeling a way to connect psychotherapeutic practice with predictions from the separationdistress shutdown conceptualization of depression.
Another implication of the SDS model relates to
the timing of interventions. Since the model posits that
the shutdown does not occur at the time of loss but,
rather, somewhat later, after a period of seeking for
the lost object, this suggests that early interventions
soon after the loss might have a primary preventative
effect. Providing support immediately after the loss
could permit the individual to engage his or her own
coping mechanisms before the depressive shutdown
occurred. While these ideas require further elaboration
to develop them into operational treatment approaches,
they illustrate concretely how the SDS model might
influence psychotherapeutic strategy. Further examination of the ethological data on separation distress and
its shutdown should yield additional ideas relevant to
the psychotherapy of depression, which could then be
subject to test.
A paradigm shift for psychopharmacology
Another approach to the enhancement of psychotherapy for depression that could derive from a biobehavioral model would be to employ medication to
facilitate the process of psychotherapy itself. Can the
effectiveness of psychotherapy be enhanced by a medication administered during the therapy session? In
the area of anxiety disorders, recent work has shown
that the NMDA partial agonist, D-cycloserine (DCS),
which improves extinction learning in animal models,
enhances behavior therapy for a number of anxiety
disorders including social anxiety, acrophobia, specific
phobia, and panic disorder (Norberg, Krystal, & Tolin,
2008). These observations signal a paradigm shift in
pharmacotherapy—that is, the use of medication not
to directly influence symptoms but, rather, to enhance
Depression: An Evolutionarily Conserved Mechanism? • Commentaries
the psychotherapeutic process itself. Such an approach
could leverage the power of psychotherapy and do this
at a rather low cost in terms of medication side effects,
because medication exposure would be for limited
time periods.
To date we do not know whether there are pharmacological agents that might facilitate the psychotherapy of depression or could influence modalities of
psychotherapy other than behavior therapy. The separation-distress model suggests that oxytocin, a neuropeptide that modulates the separation-distress response
in animals, might play such a role. Watt & Panksepp
point out that oxytocin may have some direct antidepressant properties, and they cite work demonstrating
that its three-amino-acid tail has antidepressant effects.
Apart from its potential direct antidepressant effects,
however, oxytocin has been shown to influence attachment-related behaviors in humans. It is a mediator of
prosocial behavior in many species including primates.
In humans, it has been shown to enhance the ability
to accurately read the emotions of others by looking
at their eyes (Domes, Heinrichs, Michel, Berger, &
Herpertz, 2007), to enhance the recall of positive social
percepts (Guastella, Mitchell, & Mathews, 2008), and
to increase trust in social interactions (Baumgartner,
Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008). In
a direct study of the effect of oxytocin upon two-person
interactions, couples were observed as they discussed
a previously selected conflict-laden topic. Those who
had received intranasal oxytocin 40 minutes before
the discussion showed a higher ratio of positive social
behavior (e.g., emotional self-disclosure, agreement,
curiosity/care, eye contact) to negative behavior (e.g.,
defensiveness, belligerence, contempt) than did those
who had received placebo (Ditzen et al., 2008).
This work raises the possibility that oxytocin could
facilitate psychotherapy. It might enable a withdrawn
depressed patient to develop a positive attachment to
the therapist earlier in the course of therapy than might
otherwise be the case. This would lead to an enhanced
therapeutic alliance, a nonspecific factor known to facilitate psychotherapy. In addition, however, oxytocin
enhancement could have a specific effect by fostering
the more rapid development of a positive interpersonal
experience that would lessen the intensity of the separation-distress state underlying the depression. This
in turn could lead to a downregulation of the separation-distress shut-off system and allow the patient to
mobilize to re-engage with others and to call into play
adaptive coping strategies sooner.
In some depressed individuals, however, responsiveness to oxytocin itself may be decreased. A study
of a group of young men who had sustained parental
83
separation before the age of 13 years showed a reduced sensitivity to intranasal oxytocin as measured
by cortisol response, in comparison with young men
without early parental separation (Meinlschmidt &
Heim, 2007). Thus depressed patients with histories
of early separations may not show a direct response
to oxytocin. For oxytocin to aid the psychotherapy for
such individuals, it may first be necessary to restore
function of the central oxytocin system. This observation illustrates that an assessment of the interpersonal
and developmental history of the patient can be critical not only in order to formulate a psychotherapeutic
strategy, but also to plan a psychopharmacological
approach.
Adverse early experience, epigenetics, and
treatment implications
The susceptibility of the separation-distress shutdown
system to dysregulation in a given individual may
derive from a genetic predisposition, early-life exposure to trauma or neglect, later exposure to significant stress, or the interaction of these factors (for an
example of how these factors interact in depression,
see Caspi et al., 2003). One way in which early experience can set the stage for later depression is epigenetically—that is, through alteration of the expression
of the genome. Adult rats, who as pups received low
levels of maternal licking and grooming (LG) in the
first week of life, demonstrated exaggerated fear-conditioning under stress, compared to adult rats who
received high LG as pups. This effect is mediated by
differential effects of cortisone on hippocampal plasticity, resulting from differences in the expression of
glucocorticoid receptors (GRs) and mineralocorticoid
receptors (MRs) between high- and low-LG-raised
animals (Champagne et al., 2008). These differences
appear to be epigenetic, arising from differences in
gene expression as a consequence of differences in
DNA methylation and acetylation at the hippocampal
GR promoter site (Weaver, Meaney, & Szyf, 2006).
In particular, a transcription-factor binding site on the
GR promoter is rendered less active in the low-LGraised animals than in the high-LG-raised animals because the DNA is methylated and hypoacetylated in
the low-LG rats. Thus differences in maternal care
in the first week of life alter the conformation of the
animal’s DNA, leading to differences in the expression of GRs on hippocampal neurons in the adult, ultimately predisposing to differences in vulnerability to
stress. Recent studies have extended these findings to
the brains of human suicide victims, showing hyper-
84
methylation of DNA in subjects with histories of early
childhood abuse or neglect (McGowan et al., 2008).
This line of research is of striking importance because
it demonstrates how early experience may be stored
and transduced into biological (neuronal) changes in
the adult, predisposing to psychopathological reactions.
Particularly intriguing, however, is the possibility
that these stored effects of adverse early-life experiences may be modified in the adult by altering DNA
methylation or acetylation. The treatment of adult offspring of low-LG mothers with intracerebroventricular
infusions of the histone deacetylase inhibitor trichostatin-A (TSA) reversed the effect of the low-LG earlylife experience (Weaver, Meaney, & Szyf, 2006). The
TSA-treated low-LG animals showed a normalization
of performance on the open-field test, a measure of
anxiety in a stressful situation, compared to controltreated low-LG animals. This raises the question of
whether pharmacological interventions could specifically reverse the effects of epigenetically encoded detrimental early-life experiences and enhance resilience
to depression. However, epigenetic therapy based on
DNA remodeling may never achieve the specificity
of psychotherapy, in which specific memories are recalled and recontextualized. Moreover, substances that
alter DNA methylation or acetylation are likely to have
widespread effects at many loci, possibly giving rise
to unwanted consequences. Thus, it remains to be seen
whether pharmacologic interventions to alter epigenetic effects will have clinical application. Nevertheless, research in this area is worthy of pursuit. Perhaps
a combination of re-accessing of memories by means
of psychotherapy and affecting their reconsolidation
with medication will combine the specificity of psychotherapy with the mutative power of pharmacologic
intervention.
Watt & Panksepp have provided us with a sophisticated review of the current state of knowledge of
the biology of depression and have proposed a model
linking it to an evolutionarily conserved behavioral
system that terminates the separation-distress reaction.
This is a powerful model with considerable heuristic
value. It has the potential to direct us to new pharamacological treatments for depression, to help us to better understand the relationship of depression to losses
and stress, to help better understand the interaction
of genetic and environmental factors in determining
vulnerability and resilience to depression, and possibly
to inform the development of new psychotherapeutic strategies as well. This model, whether ultimately
confirmed or disconfirmed, is likely to guide new and
Harold W. Koenigsberg
productive directions for integrative research on the
causes and treatment of depression.
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Arieti, S., & Bemporad, J. (1978). Severe and Mild Depression:
A Psychotherapeutic Approach. New York: Basic Books.
Baumgartner, T., Heinrichs, M., Vonlanthen, A., Fischbacher,
U., & Fehr, E. (2008). Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron, 58:
639–650.
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W.,
Harrington, H., et al. (2003). Influence of life stress on
depression: Moderation by a polymorphism in the 5-HTT
gene. Science, 301: 386–389.
Champagne, D. L., Bagot, R. C., van Hasselt, F., Ramakers,
G., Meaney, M. J., de Kloet, E. R., et al. (2008). Maternal
care and hippocampal plasticity: Evidence for experiencedependent structural plasticity, altered synaptic functioning,
and differential responsiveness to glucocorticoids and stress.
Journal of Neuroscience, 28: 6037–6045.
Ditzen, B., Schaer, M., Gabriel, B., Bodenmann, G., Ehlert,
U., & Heinrichs, M. (2008). Intranasal oxytocin increases
positive communication and reduces cortisol levels during
couple conflict. Biological Psychiatry, 65: 728–731.
Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz,
S. C. (2007). Oxytocin improves “mind-reading” in humans.
Biological Psychiatry, 61: 731–733.
Guastella, A. J., Mitchell, P. B., & Mathews, F. (2008). Oxytocin enhances the encoding of positive social memories in
humans. Biological Psychiatry, 64: 256–258.
Klerman, G. L., & Weissmann, M. M. (1987). Interpersonal
psychotherapy (IPT) and drugs in the treatment of depression. Pharmacopsychiatry, 20: 3–7.
Klerman, G. L., Weissman, M. M., Rounsaville, B .J. & Chevron, E. S. (1984). Interpersonal Psychotherapy of Depression. New York: Basic Books.
McGowan, P. O., Sasaki, A., Huang, T. C. T., Unterberger, A.,
Suderman, M., Ernst, C., et al. (2008). Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the
suicide brain. PLoS ONE, 3: e2085.
Meinlschmidt, G., & Heim, C. (2007). Sensitivity to intranasal
oxytocin in adult men with early parental separation. Biological Psychiatry, 61: 1109–1111.
Norberg, M. M., Krystal, J. H. & Tolin, D. F. (2008). A metaanalysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biological Psychiatry, 63:
1118–1126.
Weaver, I. C., Meaney, M. J. & Szyf, M. (2006). Maternal care
effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proceedings of the National Academy of Sciences,
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Depression: An Evolutionarily Conserved Mechanism? • Commentaries
85
Depression and the Brain’s Input: Intrinsic Brain Activity and Difference-based
Coding
Commentary by Georg Northoff (Magdeburg, Germany)
Keywords:
depression; coding; glutamate; imaging; seeking
In their impressive target paper, Douglas Watt and Jaak
Panksepp aim to consider the “psychological properties of the brain and its adaptive mandates” in the
pathophysiology of depression. They argue that depression is “fundamentally connected to social attachment,” the neurobiology of which they consider to be
related to the separation-distress mechanism. In this
commentary I do not want to go into the neurochemical
and neuroanatomical details of their impressive hypothesis but will briefly focus on one particular aspect
of the brain’s input. I want to raise the question for the
kind of coding mechanisms that must be presupposed
by the brain in order to link its intrinsic activity and the
brain’s input to the stimulus-induced activity. In doing
so, I will briefly indicate how an abnormally altered
brain’s input may yield the kind of changes observed
in depression.
How is it possible that the brain’s internal separation-distress mechanisms can impact stimulus-induced
activity? This occurs only if the neurobiological underpinnings of the brain’s internal separation-distress
mechanisms modulate and impact stimulus-induced
activity in an abnormal way. In these circumstances,
withdrawal from the social environment, together with
the consecutive increased self-focus that is one of the
hallmarks of depression, are generated. Hence, we
must presuppose that the pathologically altered separation-distress system apparently decreases stimulusinduced neural-activity changes from the environment.
The question I want to raise here concerns the kind of
neural coding that must be presupposed in order for the
brain (and its input) to have such disastrous effects on
stimulus-induced activity. How must the brain code its
neural-activity changes in order, first, to link its own
input to the intrinsic activity and, second, to link the
stimulus-induced activity to the environment?
Watt & Panksepp seem to remain unclear about the
exact mechanisms of the interaction between the organism’s separation-distress disposition and the external stimulus’s salience attribution. How the organism’s
Georg Northoff: Department of Psychiatry, University of Magdeburg,
Magdeburg, Germany.
internal separation-distress disposition and the external
factors interact, and are linked together, remains unclear. There must be some kind of common currency,
or coding, since otherwise interaction and linkage remain impossible. What, then, is the common currency
between intrinsic separation-distress disposition and
the degree of salience of external stimulus? Is there a
special instance for coordinating and translating intrinsic separation-distress disposition and the salience of
the external stimulus? Or are both coded in a common
currency that makes the assumption of some kind of
additional coordination and translation superfluous?
It is at this point that the concept of relational coding as difference-based can be introduced. As in the
case of mental and social-context stimuli (described
above), the external stimulus is coded in relation to the
organism’s intrinsic stimuli—that is, the activity and
stimuli reflecting the organism’s separation-distress
disposition. What the brain’s intrinsic activity (and
hence its separation-distress disposition) provides is
the neuronal “context” for how the brain can encounter
(i.e., get excited by, engage in, and approach) external stimuli—that is, potentially rewarding stimuli, and
their triggering of possible neuronal activity changes.
How can the brain’s intrinsic activity and the neuralactivity changes related to the stimulus be linked and
coordinated with each other? Rather than assuming
some additional coordination or translation, I claim
that such linkage is made possible by coding the difference between both: the gap between the level of
the brain’s intrinsic seeking disposition, and the potential neuronal activity changes related to the degree
of salience of the stimulus. Hence, it is the difference
between the brain’s intrinsic resting-state activity level
and the stimulus-induced activity changes that is coded
in the brain’s actual activity level. Thus, the degree of
possible neuronal activity changes that the stimulus can
induce is set from the very beginning in relation to the
brain’s actual intrinsic activity level—the latter serves
as reference, standard, or measure for the former.
Such inclusion of the brain’s intrinsic level of activity, as a neuronal context in difference-based coding,
makes the question for possible coordination and integration superfluous. The question need not even be
© 2009 The International Neuropsychoanalysis Society
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raised, because there is coordination and integration
from the very beginning of the process. Thus, by virtue of difference-based coding, brain and stimulus no
longer need to be coordinated and linked, because the
neural-activity changes themselves mirror the relation
between the brain’s intrinsic activity level and possible
stimulus-induced neuronal activity changes.
If we wish to understand the pathophysiological
mechanisms of depression, we must reveal the kind
of neural coding that links the brain’s intrinsic activity
to the stimulus-induced activity. My hypothesis is that
the intrinsic brain activity is abnormally high, which in
turn may make it impossible for the external stimulus
to induce any change in the brain’s intrinsic activity
level. Accordingly, the difference between the brain’s
intrinsic activity and the potential stimulus-induced activity is shifted to one extreme—resulting in an imbalance—with the predominant impact being the former
(intrinsic activity) at the expense of the latter (events in
the external world).
If this holds true, one would expect that external
stimuli can no longer induce changes in neural activity
in those regions that show high resting-state activity,
such as the cortical midline structures that are also involved in constituting self-relatedness. This is at least
indirectly supported empirically by imaging studies
from others (Grecius, Krasnow, Reiss, & Menon, 2003;
Grimm et el., 2003, 2009, in press; Mayberg, 2003;
Mayberg et al., 1999.) and from our group, showing
(1) an abnormally high resting-state activity in subcortical and cortical midline structures in depression and
(2) that this variable no longer parametrically modulates stimulus-induced activity from either external
emotions or self-relatedness in any fine-grained way.
Watt & Panksepp’s proposal may well be a testable
hypothesis that can be investigated both in animals and
Georg Northoff
in humans with depression. This may help to explain
why, metaphorically speaking, relational coding seems
to mute into self-referential coding in depression, with
circulating and ruminating affects and cognitions that
refer almost exclusively to the self rather than to the
environment, resulting in what can be described as
increased self-focus.
REFERENCES
Greicius, M. D., Krasnow, B., Reiss, A.L., & Menon, V. (2003).
Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proceedings of the
National Academy of Sciences, USA, 100 (1): 253–258.
Grimm, S., Beck, J., Schuepbach, D., Hell, D., Boesiger P.,
Bermpohl, F., et al. (2008). Imbalance between left and
right dorsolateral prefrontal cortex in major depression is
linked to negative emotional judgment: An fMRI study in
severe major depressive disorder. Biological Psychiatry, 63:
369–376.
Grimm, S., Boeker, H., Beck, J., Bermpohl, F., Heinzel, A.,
Boesiger, P., et al. (2009). Abnormal functional deactivation
in the default-mode network in depression. Neuropsychopharmacology, 34: 932–943.
Grimm, S., Ernst, J., Boesiger, P., Schuepbach, D., Hell, D.,
Boeker, H., et al. (in press). Increased self-focus in major
depressive disorder is related to neural abnormalities in
subcortical–cortical midline structures. Human Brain Mapping.
Mayberg, H. S. (2003). Modulating dysfunctional limbic–cortical circuits in depression: Towards development of brainbased algorithms for diagnosis and optimised treatment.
British Medical Bulletin, 65: 193–207.
Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S.,
Mahurin, R. K, Jerabek, P. A., et al. (1999). Reciprocal
limbic-cortical function and negative mood: Converging
PET findings in depression and normal sadness. American
Journal of Psychiatry, 156: 675–682.
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
87
Response to Commentaries
Douglas F. Watt & Jaak Panksepp
Keywords:
depression; neuropeptides; HPA axis; opioids; cytokines
Response to Sidney J. Blatt & Patrick Luyten’s
commentary
The challenging heterogeneity of depression
Sydney Blatt and Patrick Luyten provide a useful
overview of their insightful parsing of psychologically distinct forms of depression. Since our target
article well exceeded recommended word limits, we
could not mitigate our neglect of the psychological
aspects of depression, in preference for the more bottom-up neuroscience views. Additionally, we felt that
tackling the heterogeneity of depression (one of its
most difficult and poorly understood dimensions from
a neurobiological point of view) would have created
an untenable project, and we fully anticipated being
challenged around this neglect. We readily acknowledge that such heterogeneity is one of the most serious
challenges not simply to our theory, but to any theory
of depression—that is, how to accommodate the frustrating clinical heterogeneity of depression (indeed,
it is an issue for virtually every category in DSM-IV,
and perhaps for reasons that the authors nicely outline
in their commentary: that DSM-IV strives to be totally
atheoretical, to a fault.)
Rather than trying to squeeze insufficient psychological analyses into an already huge manuscript,
we thought that it might be ideal to allow our psychoanalytically oriented commentators to share their
psychodynamic perspectives without much hindrance
from our own psychological coverage. Blatt & Luyten
did that superbly, and we very much appreciate their
largely top-down perspectives where one must address
the “cognitive structural organization of meaning systems.” Although we largely agree with their analysis, an
interesting question concerns the attachment history of
individuals with the so-called introjective depressions.
This typology of “introjective versus anaclitic” depression appears to clearly imply that separation distress
in its various forms has nothing to do with the genesis
of the introjective depressive style, and we wonder
Acknowledgment: The preparation of this review was supported in part
by the Hope for Depression Research Foundation.
whether such an assumption is truly warranted. Given
that the creation of harshly self-critical traits probably
has multiple potential developmental pathways, we
wonder how much those tendencies toward excessive shame, guilt, and self-criticism still might reflect
necessary and essential contributions coming from a
systematic failure of social support at an early age. We
would still argue that self-esteem is a critical structural
residue of an attachment history and complex social
trajectory, and that low self-esteem and a poor self-image, while clearly not synonymous with depression,
function as significant predisposing long-term risk factors. We suspect that, in turn, such introjective traits
must reflect failures in attunement, empathic responsiveness, and social support and in the mitigation of
social stresses, perhaps coupled particularly with high
parental performance expectations, harsh or excessive
critical feedback, and so forth.
As we argue in the article, shame might be best conceptualized as one of the complex cognitive extensions
of separation distress, a complex affective–cognitive
structure far beyond the complexity of what a small
infant mammal could ever experience while separated
from its nest and caretakers. Shame must incorporate
such things as a self-image, a sense of exposure within
a social space, a sense of deficiency in the eyes of
others within that social space, and the sense of being
unworthy of love not because one is “bad” (that would
be more the signature of guilt) but because one is defective. We would argue that shame is an exceptionally
powerful depressogenic emotion, often seriously neglected in the clinical treatment of many depressions,
but we think it would be a mistake to conceptualize
such critical issues as shame and guilt as having no
relationship to the primary mammalian affect of separation distress. Indeed, there may be different kinds of
depression in terms of how much performance issues,
social dominance failures, and shame play a role in the
depression and its genesis versus feelings of rejection,
desertion, abandonment, etc. However, this remains an
unproven speculation about the subtyping of depression, a question we deliberately neglected (for all these
many reasons, and others!).
An additional dimension to all this not touched on
by the commentators is the manner in which depres-
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sions appear to involve a remarkable disinhibition of
shame and guilt and other negative self-images, as
though those images have somehow “escaped from the
closet” and are now “beating the person up,” whereas
previously they had been reasonably well contained
and were either mostly in the background or more actively “battled against.” Instead, in depressive states,
these negative images of self appear to be released like
a swarm of harpies to plague and torment the depressed
soul. We believe this is one of the least explained and
indeed most neglected critical features of depression.
In any case, we certainly would agree that depressive
typologies better need to account for these variables
and that the one-size-fits-all approach of DSM-IV is
not likely to be adequate to this challenge (indeed, our
review addressed some of our own concerns about
DSM-IV).
In this sense, we wonder whether both depressive
types (an anaclitic type more focused on social losses
and concerns, an introjective type more focused on
performance inadequacies) still reflect various if perhaps differential perturbations related to a fundamental failure of social support and attachment systems.
An additional question is whether introjective traits
somehow become coupled to a counterdependent and
socially avoidant coping style, where subjects suffering from introjective traits and tendencies work hard to
minimize their need for social support in the first place,
a defensive operation that we would argue “digs them
in deeper” and consolidates a long-term vulnerability
to depression, as it often ensures a virtually permanent
lack of social support. In any case, we expect that over
the long term, there will be research elucidating exactly what genotypic contributions there are to these two
phenotypes and how those genotypes interact with the
environment to create behavioral phenotypes. Unfortunately, that level of understanding is not yet available.
But we hope and expect that deeper understanding of
both endophenotypes and genotypes within the whole
spectrum of affective disorders will help clarify these
issues further.
We also consider in this brief response how such
higher order perspectives might ever link up to animal
models and basic neuroscience issues. Their psychological deconstruction of the varieties of depression
highlights a dilemma for neuroscience in general and
most especially the limits of animal models. It is much
easier for a cross-species neuroscience to identify the
primary-process emotional networks of the mammalian brain (Panksepp, 1998) than any higher order
psychodynamics that might accompany depressive
states in humans. Likewise, animal models are well
Douglas F. Watt & Jaak Panksepp
positioned to analyze the neural bases of simple forms
of emotional learning, such as classical and operant
conditioning, which we consider to be secondary processes (LeDoux, 1996). When it comes to tertiary
processes—the higher mental processes that include
thoughts and complex decision making, many of which
are unique to humans—animal models and basic neuroscience become largely impotent.
Human brain imaging might provide some revealing brain correlates, but, with as many interpretative
problems that are inherent to such indirect methodologies, they are unlikely to add that much to the complex mental analysis that Blatt & Luyten provided.
Maybe fMRI could highlight different ways in which
individuals with anaclitic and introjective depression
handle the same cognitive/emotional challenges, along
with the analysis of neural connectivity patterns, but
not much more. Functional imaging (fMRI) is unable
to highlight the critical neurochemical issues, although
PET used with neurotransmitter receptor ligands could
provide some useful insights. But only a few ligands
currently exist, and, perhaps wisely, Blatt & Luyten
suggested none. However, we are tempted to suggest
that anaclitic depression might be accompanied by
larger changes in diminished opioid-mediated socialreward dynamics, while introjective depression might
be characterized by excessive cholecystokinin (CCK)
tone in higher regions of the brain and, perhaps, diminished mesolimbic dopamine dynamics, possibly
due to dynorphin dominance. At least such preliminary
predictions could be interfaced with animals models
(see below) and could also promote relevant studies in
humans.
However, before we discuss this possibility in more
detail, we would first emphasize the limits and advantages of affective neuroscience types of animal models
and also the relative impotence of cognitive neuroscience in dealing with the kinds of psychodynamic issues
that Blatt & Luyten highlight. First, it is impossible for
animal models, especially in the more simple-minded
(i.e., less cerebrated) mammals commonly used in neuroscience research, to illuminate the intrapsychic dynamics of those higher cognitive brain processes that
provide humans a unique view of mental life. Without
any credible translations at that level, the level of “cognitive-value-meaning” analysis that Blatt & Luyten
shared so eloquently may remain intellectual territory
that will remain largely psychoanalytic/psychological
without any clear bridging toward a neurodynamic
understanding. Perhaps cognitive neuroscience will
eventually provide some strategies for studying the
underlying psychodynamics with new paradigms, but
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
we are not aware of such work, and Blatt & Luyten
provide no guidance on how such work might be pursued. It is an important area for cognitively oriented
brain scientists to cultivate, hopefully pursued in ways
that will connect up to causal clinical manipulations,
which we assume will be primarily in the neurochemical/neuropharmacological domains.
Let us provide the little guidance that we can offer:
clearly, as Blatt & Luyten highlight, our analysis was
most relevant for anaclitic forms of depression (and
because of length issues, we did restrict our coverage
to the modern neuroscience era—and we thank them
for providing a pre-neuroscientific psychodynamic
perspective, from Spitz onward). In writing the target
article, the anaclitic perspectives were foremost on
our minds, and hence we focused heavily on the social
neuropeptides, especially brain opioids and oxytocin,
as possible selective vectors through which depressive
affect emerged (e.g., leading to low social-neuropeptide tone in the anaclitically depressed brain). Let us
now entertain what animal models might add to Blatt
& Luyten’s introjective forms of depression. The models that may have the most promise here are the adult
social-competition models that attempt to simulate the
processes of psychosocial loss in adult social-dominance encounters. This has long been recognized as an
animal model of depression (for historical summary,
see Panksepp, Moskal, Panksepp, & Kroes, 2002),
and the most common, easily used model is the resident–intruder paradigm.
In common laboratory rodents, this model consists
of having a resident male–female pair that has lived
together through at least several sexual receptivity
cycles, which tends to make the male hyperdefensive
toward any perceived threat to his psychosexual resources. When an adult male intruder is placed into this
environment, the resident male makes sure that the intruder’s nose or other parts (!) do not go where they do
not belong. This is achieved by a rapid series of threats
and attacks that almost invariably throws all intruders off-kilter and into sustained submissive “despair,”
which is characterized by sustained social withdrawal.
As this type of challenge is continued, with consistent
defeat day after day, a depressive phenotype begins
to emerge. Perhaps this might begin to adequately
simulate the core affective changes accompanying introjective depressions. Whether this animal model offers a decent analog to a human who feels inadequate
more than abandoned/rejected remains, of course, to be
proven. However, on face value, as an animal model, it
does not seem to be a bad match.
What has happened in the brains of these social
89
losers? We have done considerable neurochemical
analysis on this model, and there are a variety of
neurochemical changes. The largest change we have
seen so far is an apparent elevation of CCK activity, especially in the neocortex, with smaller changes
in corticotrophin-releasing factor (CRF) restricted to
the hippocampus, and neuropeptide-Y elevations in
basal ganglia, with no observed changes in beta-endorphin, even though the sensitivity of our assay was
not optimal for seeing changes in that peptide (Panksepp, Burgdorf, Beinfeld, Kroes, & Moskal, 2007).
In more recent analyses of the same brains, we have
observed reductions in met-enkephalin, suggesting that
this model does yield some diminished opioid tone in
the brain. From this, we suspect that future psychopharmacological research could find CCK-antagonists
useful in selectively combating the introjective feature
of depression that Blatt & Luyten highlighted.
Other neurobiological aspects of depression, such
as the diminished dopamine tone that may result from
elevated dynorphin dynamics, as discussed in our target article, may be more evident in one of these two
forms of depression, but it would be premature to
offer a speculation on this in the absence of any hard
data. We simply wanted to highlight the neurochemical contributions that animal models might add to the
sophisticated psychological analysis that Blatt & Luyten provided. In general, their superb summary of the
psychological types of depression makes us wonder to
what extent the early social isolation/loss-induced, the
adult psychosocial-competition-induced, and the diversity of nonsocial stress-induced depressive phenotypes
in the many available animal models might simulate
different types of human depression. Because of the
paucity of hard data, it is surely too early to tell, but we
thank Blatt & Luyten for coaxing us to consider more
subtle psychological aspects of diverse animal models
of depression that are currently being used to try to get
at the neural infrastructure of depressive affect.
We would also emphasize that psychology-only
views of human depression, critically important as
they are, will ultimately not be as useful for guiding the
construction of the next generations of DSMs as psychobiological viewpoints that can be linked to brainbased emotional endophenotypes (Panksepp, 2006). In
closing, we would simply note that if it were to turn out
that opiates such as buprenorphine ameliorate anaclitic
and introjective forms of depression differentially (or
similarly), we would have very important neuroscientific information about the different (or shared) affective substrates of these two potentially psychologically
distinct forms of depression.
90
Response to Peter Freed’s commentary
Early attachment as one reward opportunity among
many? What are the differences between sadness
and depression?
We appreciated the thoughtful analysis and critique of
Peter Freed. Clearly there are some critical differences
between our thinking and that of Freed. Part of our disagreement may be around our making a heuristic (although qualified—see below) distinction between the
grief/sadness dimension (the acute phases of the human
separation-response) and the subsequent second phase
of separation distress, the “despair” phase, as a major
source of depression. We do not think that sadness
per se dampens all reward seeking (that would apply
more to depression), although it may dampen interest
in rewards other than those related to the lost “object”
(but even this has not yet been demonstrated, to our
knowledge). With the return of the lost object, sadness
can turn to joy very rapidly. There is no environmental
event that can achieve such a rapid reversal of true depression. That should be a telling point for Freed’s thesis. Fortunately, we both agree that sustained sadness,
and unresolved grief, is one of the major gateway variables for the depressive cascade. Thus, it should not be
controversial that some degree of chronic sadness may
be present in some sustained depressive episodes, but
sadness does not appear to be an essential ingredient
for sustaining depressive despair.
Still, we are worried that Freed wants to go back to
making sadness and depression almost synonymous,
as opposed to the complex relationship that we argued
for in our essay. Thus, we are not quite clear why
Freed has rejected our proposed theoretical framing,
in which sadness is clearly distinguished from depression. Clearly many forms of depression are not characterized by sadness. At several points in his commentary
he himself distinguishes between them, so this leaves
us a bit confused as to how he understands the relationship between these two concepts/states.
Additionally, we believe that Freed in his commentary is gravitationally attracted to his own primary theoretical question of interest—“how does the
downregulation of incentive salience occur?”—with
the hope that an answer to this question will provide
deep insights into depression. While we agree that
mechanisms for the modification of reward seeking and
withdrawal from attachment bear some intrinsic relationship to the problem of depression, we do not think
that they are the same issue, or that an explication of
the mechanism(s) by which incentive salience is downregulated neatly gives us the mechanism of depression.
Douglas F. Watt & Jaak Panksepp
We must recall that a diminution of incentive salience
(largely a theoretical, rather than an empirically wellvalidated, neuropsychological concept) presumably
always happens whenever organisms extinguish previously rewarded responses. However, to our knowledge, extinction of rewarded responses has never been
proposed to be a main vector of depression in animal
models or empirically featured as a major pathway to
clinical depression. Hence, it is just a creative conjecture. Indeed, if diminished “incentive salience” turns
out to be nothing more than an organism starting to
ignore certain stimuli in the environment—something
that occurs whenever a discriminative stimulus no
longer predicts rewards—we suspect the concept may
have less substance than is commonly believed.
In any event, Freed nominates sadness as the mechanism for “reducing incentive salience,” suggesting that
such a behavioristic scheme is a potent model for depression. He challenges our argument in these terms:
To argue that depression is the evolutionarily conserved
process by which protest is dampened is, implicitly, to
argue that it bestows some adaptive advantage that is
greater than the loss of social function it requires, relative to grief.
In a nutshell, we see this particular framing as an improbable option and one based on a key assumption
that is very questionable. Depression does not have
to have an adaptive advantage (relative to grief) in
dampening separation distress in order for it to have
been selected, simply because an infant mammal does
not have any realistic option to “grieve” the absence of
its caretaker and move on to another, better caretaker
(see later comments in this regard). If more young animals survived that went into a quiet, energy-preserving
“despair” response and then reproduced, this would
suffice for a depressive mechanism to have evolved.
But we are not dead-set on an “adaptation” but would
be just as happy if it were an “exaptation” that was a
derivative of the intricacies of the separation-distress
mechanisms of the mammalian brain.
All that aside, and more critically, we also have a
very different view from Freed as to what might be
truly constitutive for the two phases of the separationdistress process. Freed writes:
Rather than suggest that the entire despair phase performs some function with respect to the entire protest
phase, we focus on the core “positive symptom” of despair—sadness—and its relationship to the core positive symptom of protest—yearning. We hypothesize
that sadness may be a subjective correlate of neural
events in which dopaminergic yearning and seeking
mechanisms, geared toward obtaining oxytocin and
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
opioid rewards, are downregulated. We suggest that
sadness facilitates the rapid onset of what I will call
the adaptive “negative symptoms” of despair: amotivation, immobility, introversion, depressive affect,
and anhedonia. We summarize our model as follows:
When the desire for reunion with a deceased loved
one is both overpowering and maladaptive, a
mechanism that inhibits reward seeking and downregulates yearning and attentional bias [towards
the attachment] is useful. Sadness may be such a
mechanism. However, if sadness does not perform
such a function, further inquiry is needed into the
mechanisms by which bereaved persons decouple
outdated stimulus–reward associations. [emphasis
added]
We would certainly agree that sadness (mild separation distress) “facilitates . . . the ‘negative symptoms’
of despair,” an idea whose neurobiological basis has
been around since Panksepp’s initial neurobiological
work that first characterized the anatomies and neurochemistries of the separation response in a variety
of animal models (Panksepp, 1981; Panksepp, Siviy,
& Normansell, 1985; Panksepp, Yates, Ikemoto, &
Nelson, 1991). Furthermore, we would emphasize that
there are always difficulties and pitfalls in translating
from an early-infant mammal behavioral model to an
adult human one. Conceptual issues of all kinds can
readily happen whenever one has to translate from the
world of comparative animal research, where primary
processes (raw affects) and secondary processes (learning) can be studied in detail, to more complex human
clinical analogs where tertiary processes (thoughts and
the long-term appreciation of one’s lot in life) must be
considered. Human sadness cannot be thought of as
completely synonymous with the animal-model concept of separation distress, but at the same time it is
probably a complex “cognitive extension” in humans
of the original prototype mammalian state of separation distress (protest phase). However, that cognitive
extension (sadness) takes place in a system that is
vastly more complicated than the brain of any infant
mammal, the model system on which our neuroscientific understanding of separation distress is based.
These difficulties in translation potentially introduce several sources of conceptual confusion in these
two paragraphs from Freed’s commentary. First of all,
we disagree that the “core positive symptom” of the
“despair phase” following separation distress would
be any animal analog to “sadness,” as opposed to behavioral shutdown and withdrawal. Sadness is surely
much more closely related to the initial phases of a
separation response, since opioids are quite efficacious
in reducing sadness (hopefully oxytocin, too, once
91
someone actually completes an empirical test of that
straightforward idea from our understanding of PANIC
circuitry). Thus, in our view, the behavioral shutdown
of the despair phase may terminate anything that one
could consider an animal analog to sadness, since, behaviorally, the primary index here for an animal-model
analog to sadness would have to be separation cries,
which are clearly terminated by the “despair” phase
(indeed, this is how one indexes the transition!). Perhaps human sadness requires complex tertiary-process
object relations that are so well developed in humans.
We are thus genuinely puzzled as to why “sadness”
is “re-located” by Freed into the despair phase, an
animal-model analog to human clinical depression.
Even allowing for the uncertainties of translation from
an animal model to human behavior, we think this is
likely to be a mistake.
Additionally, we would argue that the “core positive
symptom” of the protest phase is not simply “yearning,”
it is active distress (in adult human terms—“grief”)
over the absence of the object and the expression of
this distress in some active motoric fashion (separation cries in the animal model, crying in the adult human—both forms of visible upset—and the seeking of
reconnection in both the animal model and the human
social situation). All of these are at least to some degree
terminated by depression (in terms of the animal model, by the despair phase). In other words, Freed places
“sadness” at the core of the “despair” phase, whereas
we believe that acute grief is largely, albeit probably
not completely, terminated (although lingering sadness
as a milder arousal of the separation-distress response
surely remains in some depressions). A major challenge
to Freed’s position becomes how he might explain the
presentation of the most severely depressed patients
who no longer express a trace of sadness and, indeed,
who are frighteningly empty, who need and want nothing except an end to their emptiness and hopelessness,
often imagined as available in death.
Equally challenging would be any empirical demonstration of what is happening in the brain during
sadness that is substantially different from what is happening during the early phase of the separation-distress
response (e.g., low opioid and oxytocin activity). We
do not see any evidence for such a substantive neurobiological difference. Freed’s suggestion that “sadness
may be a subjective correlate of neural events in which
dopaminergic yearning and seeking mechanisms,
geared toward obtaining oxytocin and opioid rewards”
being “downregulated,” strikes us as a “stretch” and
without empirical support. Whereas there are good
data confirming that human sadness is a low-opioid
state (Zubieta et al., 2003), there are no data (at least
92
Douglas F. Watt & Jaak Panksepp
that we are aware of) indicating that sadness is associated with substantive downregulation in dopaminergic
activity. Indeed, to our knowledge no one has ever
reported that pharmacological diminution of dopamine
arousal in this system provokes or amplifies sadness.
Low dopaminergic tone has been established in models
of depression (especially its more apathetic and amotivational variants) but not in sadness, underlining the
importance of the distinction between being sad versus
being depressed. Again, in our judgment, Freed’s position yields an unfortunate conflation of sadness with
depressive states that has confused and puzzled psychiatry and the DSM for quite some time, as already
commented on in the target article.
An open question admittedly raised by all this is to
what extent depressive phenotypes (and, as noted earlier, we have not tackled the challenging heterogeneity
of depression, as this is beyond the scope of our essay)
involve clearly differential degrees to which sadness
and depression might coexist. We would argue that
although sadness often coexists with lesser degrees of
depression (classically in response to recent primaryobject losses), as depression deepens subjects become
increasingly emptier, increasingly apathetic, amotivational, and, indeed, virtually incapable of sadness. In
the first author’s clinical practice, he has had many of
his more seriously depressed patients express wishes
to feel almost anything, including on many occasions
even some degree of sadness. Indeed, the most severely depressed patients no longer express wishes for anything (almost as if their SEEKING system has come to
a relative standstill). Obviously, this underlines how
depressive mechanisms can become “unhinged” from
their original adaptive/evolutionary control systems
and hypertrophied, to create the whole panoply of
depressive illness. This aspect of the process is poorly
understood, but it is instructive to remind ourselves
that virtually all illnesses reflect (at least in part) how
a regulatory or adaptive-compensatory mechanism is
stretched to the breaking point, or how its excessive
recruitment potentially causes serious perturbations in
other essential processes (e.g., the recruitment of excessive inflammatory processes, which contribute to
the diseases of aging).
Additionally, we probably would raise questions
about the framing of one other aspect of Freed’s argument already briefly alluded to above:
In our model, the opportunity cost of protest is its
most serious downside. While a period of heightened
incentive salience may adaptively promote reunion
with a missing object, attention/yearning/seeking/crying comes at the expense of pursuing other strategies
toward adaptive fitness. At a certain break-point the
opportunity cost of protest becomes too high relative
to other avenues toward regaining function, and for
adaptive fitness to be maximized, it must be downregulated.
This paragraph involves a potentially excessive behavioristic, as opposed to a neuropsychoanalytic, framing
(and we doubt if Freed is a true behaviorist) that lost
objects constitute “reward opportunities” and that the
pursuit of these lost opportunities involves “costs”
regarding other reward possibilities. While social attachments are surely places for “reward” (as we have
emphasized: Panksepp, 1998; Watt, 2007)—a mutuality of play and smiling responses, as well as comforting/empathic responses when one party in the dyad is
distressed—early attachment for the infant mammal
should not be conceptualized as simply “one reward
opportunity among many.” Instead, we believe that one
has to assume that early attachment must function as a
“linchpin” system in the brain, simply because the loss
of a caretaker for a helpless infant mammal would be
invariably fatal. In other words, evolution would have
selected against early bonding in this context being
simply “one reward opportunity among many” (analogous to having to choose between pizza, cheeseburgers, or tofu!). In this important sense, we would argue
that Freed’s formulation of an “opportunity cost” for
protracted attachment for an infant mammal is untenable. Without a supportive social bond, every infant
mammal is likely to lose its life. While Freed emphasizes the “opportunity cost” of protest and continued
“cathexis” in terms of an infant mammal, the loss of
this primary caretaking attachment in a literal and real
biological sense has to be understood as involving the
potential termination of virtually all life opportunities.
Rene Spitz demonstrated this relational disaster
overcoming human infants who were well fed and
watered as involving some kind of poorly understood
homeostatic/physiologic collapse. Indeed, given how
similarly deprived monkeys survive in Harry Harlow’s
classic experiments (Harlow, 1962), one is forced to
the conclusion that humans are possibly even more
dependent on primary social bonding in a profound
biological sense than even other mammals, again underlining the likelihood that attachment must function
as a massive regulatory-linchpin system in the human
brain. For this reason, we do not think that behaviorist metaphors about reward, reward opportunities, and
disordered “incentive salience” are adequate, because
they imply a kind of unrealistic equipotentiality to various “rewards” and reward opportunities/incentives. It
is also worth reminding ourselves that for a long period of time behaviorism had a very dismissive view
of early attachment and bonding, regarding “excessive
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
attachment” between mother and child as very undesirable and something to be avoided (Watson, 1928).
Although such an extreme degree of vulnerability
to object loss may not exist for many adult humans,
for all our outward appearance of independence, we
remain deeply dependent on a matrix of social connections. There can be little question that group cohesion
and social bonding must have been strongly selected
early in mammalian evolution and perhaps even amplified further in hominid evolution, as a single human
being, even as an adult, had very little chance of survival, except in unusually rich and “easy” nutritional
environments, and, of course, absolutely no chance
at procreation. In this sense, we would suggest that
early social attachment cannot be thought of as simply
“one reward opportunity competing among many” but
as a massive regulatory system (probably consisting
of several interacting prototype emotional systems as
outlined by Panksepp, 1998) sitting over homeostasis
proper (hunger, thirst, pain, temperature regulation,
etc.). In this sense, it would have to have a primary
influence over motivational systems. Shutting down
attachment in this context would be costly, but again,
in the original prototype situation, animals tend to
“thaw out” quickly when placed back in the original social supportive context of the nest, underlining
how this mechanism was probably originally hinged
to intrinsically prosocial (“reactivating”) mechanisms
that would rapidly terminate depressive cascades on
reunion, a critical issue that remains empirically poorly
mapped, but we can be reasonably certain that opioid
release figures heavily in these reunion “rewards.” It is
safe to assume that serious depressive illnesses reflect
the failure of these “reactivating” mechanisms on depressive shutdown, again something that is still poorly
understood and a neglected question in the molecular
and bottom-up view of depression in psychiatry.
The problem of separation distress is again not
simply that an infant mammal continues to waste opportunities for other things (there are precious few
opportunities available in the internal world-model of
a helpless infant mammal without its caretakers). We
argued that the cost of protest is not a “lost opportunity for other rewarding things” but, rather, the more
dangerous prospect of metabolic exhaustion and the
manner in which protracted distress (if unsuccessful at
achieving reunion relatively quickly) could only function as a beacon for predators. In this sense, it is easy to
see how evolution would have carved a comparatively
short time frame for a period of active separation distress, protest, and agitation, by virtue of its adaptive
necessity. Such a period of protest would need to be
long enough to alert caretakers in the immediate envi-
93
ronment but, additionally, short enough not to totally
exhaust and deplete infant mammals who have just
lost their primary source of metabolic supply and also
not long enough to alert every predator in the immediate region. One suspects that the fine tuning of this
evolutionary equation would have to be different for
different species emerging from different evolutionary
niches (yielding relatively longer vs. relatively shorter
periods of protest before a putative shutdown mechanism would have to be activated). For instance, laboratory rats and mice show an incredibly short separation
response (several minutes at best) suggesting that they
have a vestigial protest system (Panksepp, 2003a) and
would be less likely to cascade into depression following social isolation than would more deeply bonded
animals.
Indeed, if social bonding-attachment arises from a
massive emotion regulatory system sitting over homeostasis and consisting of multiple prototype emotional systems, it makes perfect sense that depression
would have to turn down motivation of all kinds by
somehow getting at the base of generalized motivational arousal, what the second author has conceptualized as a SEEKING system, anchored in the ventral
tegmental mesolimbic/mesocortical dopamine systems
and their extended connectivities. Anything less than
a shutdown of this system would not achieve the goal
of behavioral inhibition and termination of futile efforts at seeking reconnection and reestablishment of
proximity to a caretaker. It is this cost–benefit problem
in depression that Freed also is seeking to address (and
which he captures in his metaphor of “turning off one
bulb by blowing every fuse in the house”), but we
would argue that the cost–benefit equation hinges on
the trade-offs between what are two differential lifethreatening scenarios (loss of the primary caretaker
vs. metabolic exhaustion and predation). Given that
evolution appears to drive prediction algorithms about
life contingencies eventually into the brain structure
(the brain functioning as a vast prediction engine), we
argue that evolution carved social bonding and separation distress as well as a mechanism for terminating
separation distress probably in a coincident fashion.
In this context it is noteworthy that antidepressants
such as imipramine actually elevate separation distress
when vocalizations have diminished as animals enter
the despair phase (Panksepp et al., 1991), supporting
how the despair phase, which downregulates separation protest, is likely to have substantial mechanistic
overlap with human clinical depression. These findings
also suggest the importance of preserving a careful
distinction between these two phases of the separationdistress architecture.
94
Although the shutdown phase of the separation-distress response may seem like a bad trade-off in terms of
“lost reward opportunity”—and certainly the generalized motivational deficit and behavioral shutdown of
protracted depression are potentially very costly—evolution (at least in our judgment) apparently “decided”
that a capacity for depression would become the most
primitive readily available solution to protracted separation distress, built in to the complex multidimensional and interactive “tool-kits” of an intensely social
brain. In our analysis of more “bottom-up” mechanisms, we argue that this shutdown emerges from multiple interacting factors (our notion of a “depressive
matrix”), but particularly from how protracted stress
cascades (potentially dysregulated by proinflammatory
cytokines and potentiated by crashing opioid and oxytocin systems) could upregulate inhibitory dynorphin
feedback on the ventral tegmental system. Proof of this
working hypothesis would require establishing a clear
temporal correlation between transition from protest to
shutdown and measures of separation-distress-related
upregulation of dynorphin (or other modulators of DA
function including cytokines: Ye, Tao, & Zalcman,
2001) and downregulated dopaminergic activity. To
our knowledge this has not yet been fully achieved.
But because this transition is so critical (at least
in our judgment) to understanding the evolutionary
genesis of depression, we do not agree that it would be
better simply to “throw out” the phases of the separation-distress response, as Freed suggests, and substitute some version of an “adaptive task framework.”
We believe that Freed is seduced into this position
by virtue of an assumption that understanding the
mechanisms by which “incentive salience” is altered
is superordinate to the problem of depression, because
this mechanism appears (at least implicitly in his judgment) more critical to adaptive success than does the
maintenance of early social bonds, an assumption that
Freed does not explicitly defend but one that would,
in our opinion, be questionable. We argue instead that
this transition from protest to shutdown is the loudest
and most consistent clue as to the nature of a phenomenon as complex and multidimensional as human
adult clinical depression. If we ignore this transition
because it is not, in Freed’s judgment, focused enough
on “adaptation,” we miss the most critical source of
biological data on what depression really is. This problem is different, however, from the main problem that
Freed wants to address—namely, the issue of how
we achieve decathexis from an absent figure and also
how we “downregulate” (a now-unrealistic) “incentive
salience.” We agree that human adult grieving must
Douglas F. Watt & Jaak Panksepp
play a central role in detachment, although its neural
mechanisms remain to be clearly elucidated. We agree
that sadness must relate to those mechanisms of “decathexis,” but we do not anticipate that answers to those
questions will give us a deep or complete understanding of depression. Our overall view is that a fuller understanding of the dynamics and vicissitudes of social
bonding—of how protracted separation distress might
affect other systems, including prototype emotional
systems for playfulness and seeking urges—will be the
primary processes upon which we must focus our clinical and research attention.
Response to Paul E. Holtzheimer’s commentary
A natural history of depression in mammals?
Continuing confusions between sadness and
depression?
We appreciated Paul Holtzheimer’s supportive and at
the same time incisive comments on our review of depression, and he poses three major questions for us that
provide opportunities to both test as well as sharpen
our argument and thinking about the problem of depression and its relationship to separation distress.
Question #1: Does the natural history of separation
distress in humans and other mammals support
such an explanatory model for human depression?
Conversely, if adult human depression represents an
evolutionarily conserved process, what is its analog and
prevalence in other adult mammals?
This is an excellent question about the natural history of separation-distress reactions in humans and in
other mammals, particularly adult mammals. There has
been virtually no substantive study or detailed review
of this question, but we believe that what little work
exists does support our position (for some relevant
overviews, see Carter, 1998; Carter, Lederhendler, &
Kirkpatrick, 1999). We could not find, however, either
a long-term longitudinal or population study of depressive reactions in adult mammals. We suspect that sustained depressive reactions in adult mammals are quite
rare in the wild, probably because they would often
be associated with major premature mortality (possibly for both prey and predator species). Additionally,
such reactions would be potentially inhibited by virtue
of social groups, consistent with our hypothesis that
briefer depressive reactions in mammals are normally
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
attenuated by re-establishment of social bonds and
social support within a larger social context. Mammals cut out from their normal social groups for one
reason or another might be exposed to more substantial
depressive reactions, but this has received almost no
formal study to our knowledge, and obviously our
suspicion would be that sustained depressive reactions
in the wild might have major associated morbidity, as
would the potential precipitating stress of extrusion
from social groups. Obviously, any adult mammal
extruded from its group by definition would have no
chance at procreation and, for that matter, significantly
reduced chances of survival. Unfortunately, it would
probably be impossible to study this naturalistically
with any degree of neurobiological monitoring because
simply capturing animals who might be dealing with
potential depressive states would severely stress them
and presumably exacerbate any depressive reaction.
We suspect, therefore, that a true naturalistic study of
this question in any mammalian natural grouping that
might combine both behavioral and neural measures
would be virtually impossible.
All those difficulties aside, we believe that intruder
stress and dominance paradigms studied in the laboratory are excellent models for understanding adult mammalian depressions, and these certainly show deeply
homologous neurobiology to the human clinical situation and with separation-distress neurobiology also
(Panksepp et al., 2002). As we noted in our review of
previous evolutionary thinking on depression, several
previous thinkers and theorists have hypothesized conservation of somewhat different depressive reactions
in relationships to social losses versus social failures
(Keller & Nesse, 2006). These dimensions may also
link up to work on anaclitic (social loss) versus introjective (social failure) differences in major depression
emphasized in Blatt & Luyten’s commentary. Keller
and Nesse asked 445 participants to identify depressive symptoms that followed a recent adverse situation.
They found that descriptions of guilt, rumination, fatigue, and pessimism were prominent following failed
efforts, while crying, sadness, and desire for social
support were prominent following social losses.
As for the question of the natural incidence of depressive reactions in adult mammals, we cannot find
any data on this question. However, as we questioned
in the review, we do not believe that the lifetime incidence of depression is likely to be the 7%–15% in humans that Holtzheimer references, as we consider most
epidemiological estimates of depression to be a significant underestimation due to intrinsic and potentially
severe reporting bias. We would argue that the vulner-
95
ability of humans to depression may be greater than
that of other mammals because of our apparently even
greater dependence on social bonds than are monkeys
(hospitalism in humans vs. the survival of Harlow’s
monkeys) and, additionally, that modern technological
societies are perhaps intrinsically isolating, subjecting
humans to multiple forms of classic depressogenic
stress. In this sense, the incidence of depression in a
natural mammalian group would not have to even remotely reflect the incidence in Western technological
societies for our hypothesis to be supported (indeed,
identical incidence in a natural mammalian social
group vs. what we suspect is a more isolated cultural
group of humans would be quite problematic for our
hypothesis). We think better support would come from
demonstrations of homologous neurobiology (such as
elevated HPA axis and proinflammatory cytokines, reduced seeking and self-stimulation, reduced opioids
and oxytocin, etc.) across multiple species that show
early social bonding and a solid separation-distress response system (which, for example, might raise serious
questions about using rats as a model species).
However, supporting our argument in a general way
is, for example, the finding that depression has similar
comorbidities in other mammals to those in humans.
Shively, Musselman, and Willard (2009) found that
depressed female monkeys (subjected to social-status
stressors and subordinate positions within social hierarchies) become socially withdrawn and have changes
in body fat, low levels of activity, high heart rates
(implying catecholamine overdrive), and disruptions
in various hormone levels along with accelerated atherosclerosis, all paralleling findings in humans. They
found alterations in HPA axis, ovarian function, lipid metabolism, and autonomic changes, particularly
heart-rate variability, suggesting that depression in female monkeys has many of the same “comorbid companions” as it carries in the human clinical situation.
Regarding Holtzheimer’s comment on human clinical depression and the uniqueness of the prefrontal
systems in humans, and how this might affect both
the incidence and manifestations of depression in humans versus other mammals, this is also an excellent
question, but again one with little substantive empirical exploration, to our knowledge. Given the primary
“supervisory” role of prefrontal systems in relation to
emotion, and how different prefrontal systems (orbital,
medial, and dorsolateral) differentially “gate” (both activating and inhibiting) numerous subcortical systems
involved in prototype emotion, it is perhaps not surprising that changes in prefrontal function are associated both with the induction of depression and with its
96
possible long-term effects. We suspect that a primary
issue here would be the disruption of various higher
and more cognitive executive functions that cannot be
readily measured in animal models, although, perhaps,
with some ingenious behavioral measures one might
construct plausible homologies, which has already been
done for some aspects of executive function (such as
animal models for working memory based on delayed
nonmatching to sample). Additionally, animal models cannot at the present time capture the depressive
cognitive space of humans, with its tendency toward
rumination, negative prediction, and the darkening of
virtually every complex cognitive perspective. However, we do not believe that our greater executive or
cognitive complexity means that animal models cannot
provide excellent testing grounds for virtually every
other aspect of depression, especially the all-important
affective substrates. We have yet to find a significant
disjunction between animal and human models in relationship to many monoamine systems, the stress axis,
multiple neuropeptide systems, and multiple aspects of
hormonal, immune, and homeostatic regulation. In this
sense, perhaps the cognitive “icing on the cake” might
be pretty different, but underneath that it certainly
looks like deeply shared mechanisms in the subneocortical affective networks! We doubt that animals
ruminate, and clearly many other cognitive aspects of
depression cannot be studied, but animal models have
provided an exceptionally rich and fertile ground for
understanding in every other way.
Question #2: If depression fundamentally results from
brain mechanisms related to social-loss separation
distress, how are nonstress-related depressive episodes
explained?
Some of what we discussed in relationship to Question
#1 helps to address this question, and there was also
some discussion of this in the target article, although
not in detail. An easy evolutionary argument would
be that a mechanism that can be instantiated early in
development in relationship to social loss can be easily recruited later in relationship to different kinds of
social stresses, particularly those related to dominance
hierarchies and social-subordination stress. In any situation involving chronic helplessness in the face of
virtually any severe stressor, depressive shutdown can
potentially be elicited. This can include not simply
attachment-related losses, of course, and not simply
classic dominance issues, but almost any serious and
sustained unpleasantness that one can imagine. Chronic pain is an excellent example of a depressogenic
Douglas F. Watt & Jaak Panksepp
stress. It becomes harder to see what the evolutionary
advantage of a depressive response might be in relationship to chronic pain (perhaps relative immobility
might lessen pain), but as Keller and Nesse (2006)
have emphasized, depressive conservation/withdrawal
mechanisms are clearly adaptive in dominance conflicts, where continuing in the dominance conflicts
would result in imminent risk of severe injury and
death. Perhaps another dimension to the depressogenic
nature of pain could be its close intrinsic relationship
with separation distress (Panksepp, 1998).
Question #3: Does human depression (from a
neurobiological perspective) correspond to the state
of physiological shutdown associated with separation
distress or with the abnormal regulation of this process?
That is, is depression “sadness” or “the inability to
regulate sadness”?
Holtzheimer also notes:
What appears to distinguish the clinical disorder of
depression is not sadness itself, but (1) the presence
of sadness in the absence of a known trigger; (2) a
degree of sadness and associated emotions/cognitions
(e.g., guilt, anxiety, hopelessness, suicidal ideation)
more extreme than would be expected given a known
trigger; and/or (3) the persistence of sadness beyond
presumably normal limits.
Some of these same difficult issues are addressed in our
response to Peter Freed’s commentary, and we would
refer Holtzheimer to those comments also. Sadness is
clearly a component of mild depression. However, we
think that severe depression operates, for the most part,
to shut down sadness, which would be the closest adult
human homologue to the protest phase of separation
distress in infant animals. We are somewhat skeptical
that the three criteria proposed by Holtzheimer are
heuristic or clinically useful, particularly about sadness
“beyond normal limits,” more than expected, or “without any apparent trigger.” How does one clarify what
is the normal limit of sadness in relationship to the
loss of a spouse or child? Clearly these are profoundly
distressing (indeed if they weren’t profoundly distressing, that would raise major questions itself), and the
more hurtful and distressing the loss, the greater the
potential for induction of a depression. Indeed, to the
extent that anyone has “all their eggs in one basket” in
an attachment sense, the loss of that attachment is more
likely to be intrinsically “depressogenic.” We see this
perspective as having more heuristic value clinically
than any attempt to spell out whether a person’s sad-
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
ness is “excessive.” As we emphasized in the article,
the problem of a seriously depressed mood is not that
the person is truly “sad” in a primary sense; it is more
that they are losing a more hopeful orientation toward
rewards and social opportunities in the world. This is
the essence, at least in our judgment, of a depressed
mood—not simple sadness. The loss of a more hopeful
orientation and the collapse of other reward-seeking
and attachment behaviors, especially the collapse of
baseline positive emotional responses such as playful
and smiling responses to others, might be a better metric of depression than simple sadness. In other words, a
key feature of depression is the inability to experience
positive affective feelings. Sadness that can be rapidly
alleviated by positive social intercourse is not depression. Of course, in patients with schizoid features,
where there is a chronic shortage of such responses to
others, this criterion becomes harder to apply.
Again, as we emphasized in the response to Freed,
we do not see depression in a strict sense as a “sadness disorder,” simply because subjects certainly can
be quite sad without being depressed at all, and quite
depressed without being sad at all. We don’t think
that sadness in the absence of a known or expressly
articulated “trigger” is necessarily pathognomonic of
depression, because clearly there are many instances
of people having trouble acknowledging a loss of one
kind or another without necessarily becoming clinically depressed. Part of the problem again is simply the
excessive conflation of being sad with being depressed,
a conflation that psychiatry has been guilty of for a
long time. While in a simple animal model the temporal disjunction between a “sad mood” (protest phase)
and a “depressed mood” (despair phase) is relatively
clear-cut and measurable (the animal simply stops protesting in the despair phase), we suspect that the massive overlay of cortex—especially prefrontal system
cortex—in humans changes this simple equation to a
more complex one. Presumably this happens in some
“Jacksonian fashion” (later arriving cortical systems
modulate what were originally relatively inflexible
routines) to yield varying admixtures of sadness and
depression. In other words, the initial and beginning
recruitment of a depressive shutdown mechanism does
not completely terminate all sadness and separation
distress, and the transition from sadness to depression
loses perhaps some of the clear-cut disjunction evident
in the simpler animal models. Certainly as depressions
deepen, the evidence is fairly compelling (at least in
terms of clinical descriptions) that sadness is ablated,
and, indeed, virtually all emotion and motivation are
gradually emptied out.
Holtzheimer poses one final challenging question:
97
it would be instructive if . . . [the authors] . . . could
comment on whether they view depression, from a
neurobiological standpoint, as referring to the state
of shutdown itself or the disrupted regulation of the
shutdown process.
This difficult question gets at the critical difference
between intrinsic mammalian endowment versus the
potential epigenetic effects of less-than-optimal development on those same endowments. Although our current understanding is surely preliminary, the evidence
suggests that early histories of loss, neglect, isolation, or abuse potentiate the recruitment of depressive
mechanisms and/or inhibit and compromise their termination. Those early environmental factors obviously
interact with what are in all probability many genetic
polymorphisms, barely mapped, which further amplify
or reduce subsequent vulnerability to depression.
Holtzheimer’s question also points to one very critical issue that has been generally neglected. Depression, in the sense of a mammalian endowment for a
protective shutdown mechanism, clearly must have
intrinsic naturalistic and inhibitory controls on it, perhaps largely mediated by the effects of reunion and
re-immersion in a social matrix. Depressive illness in
humans suggests the possibility that those controls,
which adaptively terminate depressive cascades on
reunion and the reestablishment of social support, are
somehow disrupted. This important question has received almost no substantive attention from clinical
neuroscience, perhaps again because the conceptualization of depression has been mostly ripped off its
basic emotional moorings in psychiatry, especially its
close and intrinsic relationship to the vicissitudes of attachment. It is too often conceptualized as a bottom-up
molecular problem that will eventually be solved by a
brute-force reductionist molecular approach, without
any substantive psychological thinking being necessary. Obviously, this is the approach to depression that
we most take issue with. We would suggest that the
termination of depressive shutdown in animals that
are reunited would be an extremely productive way of
deepening our understanding of how those essential
regulatory mechanisms might fail in clinical depressive illness. To our knowledge, there has never been
any substantive empirical investigation of this question, because the current dominant molecular approach
in psychiatry has become largely blind to depression’s
true naturalistic context.
In any case, we concede that the complexities of
an adult human brain cannot be completely reduced
in a Procrustean fashion to the comparatively simple
concepts derived from animal models. However, we do
think the animal models can give us deep and funda-
98
mental clues about the deep primary-process emotional
nature of the clinical disorder. We chose the animal
social separation-distress model because among the
many existing animal models for depression, we feel
that one has the best overall congruity with the clinical realities, in which various flavors of loss form the
most common precipitating stressors for depression.
Of course, no “univalent” or single-dimensional theory
is ever going to explain virtually anything going on in
an adult human brain, especially in its full cognitive
complexities, but we do think that the animal models
advocated for in our article provide fundamental clues
about how one might understand and heuristically integrate the confusing thicket of correlations in the
depression literature, with a clearer vision of possible
neurochemical controls, hopefully clearing a path toward a more integrated understanding of this increasingly widespread human problem.
Response to Ilia Karatsoreos & Bruce S.
McEwen’s commentary
A more bottom-up (homeostatic) view of
depression than ours
Ilia Karatsoreos and Bruce McEwen generally agreed
that the types of emotional dysregulations we discuss
are likely contributors to depression, and they proceeded to highlight how other bodily dysregulations,
especially disruptions in the circadian systems, may
be an especially prominent vector in amplifying “allostatic overload” that may promote depression. Such
alternative, synergistic, views are useful for establishing research programs that may help better distinguish
the bodily and brain imbalances that are, in fact, most
influential in the genesis of depression. However, until
empirically demonstrated otherwise, we would still
argue that the current “state of the art” more clearly
supports a brain affective–emotional–motivational
source of depression than simply a circadian–homeostatic one.
Although Karatsoreos & McEwen focused largely
on their own alternative conceptual viewpoint, one that
we believe is not yet as well empirically supported as
the disrupted emotional–affective view we advocated,
we would take this opportunity to highlight a few
concerns that one must have about such an alternative
view. So far their proposal is largely a “plausibility
argument,” and we would share some perspectives that
may help sharpen their analysis.
First, “allostasis” is a general conceptual concept,
such as “drive” and “incentive,” for organizing a di-
Douglas F. Watt & Jaak Panksepp
verse set of distinct bodily processes. In other words,
there are a host of endophenotypes (real entities of
brain and body physiology) under such broad concepts, and Karatsoreos & McEwen primarily focus on
the role of disrupted circadian oscillators and bodily
homeostasis in the genesis of depression. Within that
broad conceptual view, one might make a first-pass
hypothesis that lesions of the suprachiasmatic nucleus
(SCN) or continual darkness or illumination would all
potentially promote depression in experimental animals. To our knowledge, no robust lines of data affirming those predictions yet exist. Indeed, one might even
imagine that forcing animals to eat food just during the
half day that animals normally do not eat much (i.e.,
light phase in rats) might promote depression. Such
manipulations should clearly shift many associated behavioral rhythms and presumably circadian oscillators,
but so far there are no data that such manipulations are
depressogenic. Although a disrupted circadian oscillator is certainly one of the consequences of depression,
to our knowledge there is currently no robust database
indicating that it is a major source of depression. Still,
we look forward to a full evaluation and testing of this
hypothesis from the McEwen lab.
We suspect that this line of argument could be made
more robust if it were restricted to endophenotypes of
circadian processes, such as the role of the pituitary
adrenal axis in depression. Everyone would surely
agree that a sustained HPA stress response is important
in the genesis of depression; indeed, negative emotions
such as separation distress are very effective in recruiting this response, and it will be interesting to evaluate
whether certain paths to imbalances in this general
homeostatic system, such as social-emotional challenges, are more likely to promote depression than the
bodily-homeostatic regulatory challenges that would
fall more directly under their concept of allostatic overload. From their perspective, one might predict that
sustained stressors such as hunger and thirst would be
as influential, or even more influential, than social loss
in the genesis of depression. To our knowledge there
has been no head-to-head comparison of such body
regulatory and brain emotional stressors in the genesis
of depression. One data point unfortunately against
this argument is the literature on calorie restriction,
where animals and also humans are chronically hungry
(but not malnourished), and yet, despite this, calorie
restriction appears to provide a kind of stress inoculation that may protect against depression and, indeed,
against many other biological stresses (Anderson et al.,
2008). In fact, calorie restriction is the gold standard
in reducing the diseases of aging and even aging itself.
This suggests that simple homeostatic energy chal-
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
lenge cannot be equipotent with severe social loss or,
for that matter, pain and physical injury/disability as
inducers of a depressive response.
One homeostatic threat that has at least clinically
been extensively linked with the genesis of depression
is, of course, the common phenomena of pain. Chronic
pain syndromes have enormous comorbidity with depression (Williams et al., 2003). Indeed, the clinical
incidence of depression in patients with chronic pain
who also have classic psychosocial stressors such as
serious degrees of social isolation, other severe social
stress, and/or recent major losses approaches 100%. A
completely unexplored question in this association between chronic pain and depression is whether chronic
pain is effective in eliciting depressive shutdown in
part by virtue of potentially close evolutionary connections between pain and separation distress.
All of these questions underline the vast unmapped
territories in the intimate interregulation between
emotion and homeostasis, a vast borderland no better
mapped and perhaps more systematically neglected in
neuroscience than the other great borderland—namely,
emotion–cognition interactions. These three large domains of homeostasis, emotion, and cognition are surely seamlessly integrated in a fashion that remains to be
well detailed by neuroscience. Science is very poor at
tackling the massive challenge of system-wide integration, but this clearly is a target we must better appreciate if we seek to understand emotion and its profound
interdigitations with “higher” cognitive operations and
“lower” homeostatic processes. Although we are certainly open to the possibility that homeostatic challenges promote and might even provoke depressive
mechanisms, in general we would regard homeostatic
challenges as mostly activating SEEKING and other
basic arousal mechanisms, because homeostatic challenges of various kinds promote the emission of conserved behavioral routines. Protracted homeostatic
challenges, particularly when they are life-threatening,
obviously provoke behavioral agitation in virtually any
conscious organism, but depressive shutdown in this
context does not appear to be adaptive either. In other
words, depressive shutdown appears more optimally
aimed at stresses for which an organism cannot easily recruit adaptive responses and, even more specifically, may be aimed at a developmentally early stage of
separation distress where protracted agitation may be
fatal for several possible reasons (metabolic depletion,
attraction of predation). Along these lines, we might
wish to consider that the most common homeostatic
mechanisms in the animal kingdom most intimately
hinged to depression might be those involved in hibernation. Many available antidepressant therapies appear
99
to inhibit the ability of organisms to hibernate (Tsiouris,
2005). Given the intimate relationship between the
onset of hibernation and other homeostatic and circadian sensing mechanisms (shortening of daylight) and
lessened availability of nutrition, reduced temperature,
and so forth, it is certainly possible that mechanisms
for behavioral shutdown and depressive withdrawal
could be directly hinged to a single circadian oscillator,
although frankly we doubt that it would work this way.
However, that question remains to be established, and
the likelihood of a “master control” for depression that
“low” in the overall system seems intuitively unlikely
to us. But it is admittedly an open question.
Thus, Karatsoreos & McEwen’s thesis will be easier
to test when it is framed in specific endophenotypic
variables that fall under the allostatic overload concept
rather than simply relying on the general allostatic
concept, which is a way for semantically organizing a
diverse set of influences important for bodily health.
For instance, we are tempted to suggest that the disruption of the bodily and brain plasticity and repair that
may emerge from disruption of a stable sleep rhythm
may be such a variable (Cho et al., 2008; Krueger et
al., 2008). From this vantage, it is very useful that
Karatsoreos & McEwen focus their discussion primarily on the brain circuits and genes that control circadian oscillators. This hypothesis would clearly have
to dynamically link circadian oscillators with the large
interconnected set of processes that we have outlined
in our article (our hypothesis of a “depressive matrix”),
including a relative downregulation of the mesolimbic
VTA dopamine system, the promotion of proinflammatory cytokines, the downregulation of oxytocin and
opioid tone, the promotion of the stress axis, etc. Most
if not all of those connections clearly remain to be
elucidated. It is also important to emphasize that if
they are on the right track, then the body regulatory
stressors, especially discrete brain manipulations like
SCN lesions, would generally be more influential than
the emotional stressors we favor.
In this context, we also wish to note that terms such
as emotions and affects are also very broad conceptual
entities, like allostasis and homeostasis, and that is one
reason we favor moving directly to the endophenotypic
level of specific emotional systems (Panksepp, 2006),
prioritizing those systems that are most likely to contribute most clearly to social bonding (SEEKING, PANIC,
CARE, and PLAY) and focusing most intensely on the
system that may be the largest contributor to “psychic
pain”—namely, the sequential unfolding of the separation-distress/PANIC response toward depressive despair, along the conceptual lines originally outlined by
Bowlby (1980). What modern affective neuroscience
100
has been able to add is a more precise understanding of
specific brain systems that undergird the concepts that
Bowlby brought to the forefront. Likewise, our emerging understanding of the timing genes and circuits
of the SCN have provided similar endophenotypic
mechanisms for understanding circadian regulation,
but so far such knowledge links up empirically only to
a general concept of stress and bodily homeostasis but
not to the affective–emotional balances of organisms.
Hopefully this will change as behavioral neuroscience
investigators begin to utilize more discrete and refined
emotional system concepts (Panksepp, 1998) rather
than the outdated “fight–flight” conflations and “brain
reward system” misnomers.
In our view, the SEEKING system mediates the acquisition of all varieties of external incentives (Alacro,
Huber & Panksepp, 2007; Ikemoto & Panksepp, 1999;
Panksepp, 1981, 1986, 1998; Panksepp & Moskal,
2008; Panksepp, Nocjar, Burgdorf, Panksepp, & Huber, 2004) and is not just “the brain reward system” as
most investigators have been trained to believe. This
system mediates all forms of exploration, foraging, and
the pursuit of rewards. In its ability to support survival
in such a general way, SEEKING arousal promotes
feelings of affectively positive euphoria and eager
anticipation (Panksepp & Moskal, 2008; Volkow & Li,
2004). Thus, we were perplexed by the way Karatsoreos & McEwen interpreted our viewpoint to mean that
“the system for reducing separation distress is rooted in
mesolimbic regulatory regions.” That is definitely not
our view. Rather, we highlighted that the diminution
of activity in this SEEKING system, whether it be by
frustrative nonreward, addictive-drug withdrawal, or
the loss of important relationships, is a central vector in
the genesis of depressive affect when there is a severe
disruption in the flow of expected rewards. In our view,
arousal of the SEEKING system surely helps “protect
homeostasis” (as well as the organism’s pursuit of virtually every other potential goal; Panksepp, 1998) and
hence, when well operating, would help reduce the potential for induction of depression. Indeed, our article
emphasized how a critical role in this process is played
by kappa opioids, promoted by chronic stress and acting in an inhibitory fashion on the SEEKING system.
Buprenorphine is a special drug in part because it
is the only commercially available kappa antagonist,
and this relatively unique neuromodulatory property
is combined with partial mu agonism in a fashion that
would counter the changes associated with separation
distress itself and also promote a generalized feeling of
positive affect.
We do agree with the proposal by Karatsoreos &
McEwen that protection of bodily homeostasis and
Douglas F. Watt & Jaak Panksepp
the reduction of allostatic load are very beneficial to
bodily health and hence are bound to reduce depressive
cascades, because they minimize overall bodily allostatic overload (i.e., stress). Still, we think it is unlikely
that the massive levels of depression in our society
will be primarily explained by such bodily factors. It
will surely be a contributory factor, but until demonstrated otherwise, we suspect a focus on imbalances in
social-emotional systems and overall biogenic amine
brain-arousal regulatory factors and changes in certain
positive affective chemistries (especially opioids) will
be more germane for understanding the sources of depression in modern societies.
Future research should attempt to pit these hypotheses directly against each other. We, of course, agree
that it is important to envision depression as a multidimensional process in both affective and neuroscientific
terms. Thus, we completely agree with Karatsoreos &
McEwen’s advocacy that therapies need to take multidimensional “holistic” approaches to the treatment of
depression, which include a clear focus on genetic predispositions and emotional endophenotypic changes, as
well as bodily stress and circadian factors, in attempts
to promote concurrently the return of within-brain affective as well as bodily homeostasis.
Response to Otto Kernberg’s commentary
A metapsychological view of depression: where
work needs to go from a realistic psychological
perspective
We were pleased that Otto Kernberg, one of the most
prominent psychoanalysts of our era, viewed our contribution as fitting “harmoniously with contemporary
psychodynamic thinking regarding depression,” and
we appreciate his complementary, albeit psychologically more subtle, views on the developmental vectors
that promote depression. Rather than critiquing our
heavily neuroscientific approach, he provided a synopsis of his own psychoanalytic perspectives on this topic
of mutual interest. As a result, we were not coaxed to
provide any further clarifications of our own points
of view, but to consider how his views might supplement our own. Thus, his commentary provides us an
opportunity, as did the previous one by Karatsoreos &
McEwen, to consider markedly different views of the
genesis of depression than our own.
Our initial impression was that Kernberg’s set of
concepts about depression was not as easily scientifically testable as our own, largely because he highlights
metapsychological concepts that remain far more
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
difficult to integrate with available neuroscientific
advances. Virtually any single psychoanalytic metapsychological statement can be unpacked into multiple
behavioral and phenomenological outcomes, and the
lack of adequate operational definitions makes empirical testing of psychoanalytic hypotheses at best challenging, perhaps at worst impractical to impossible.
We might now want to consider the challenge of how
such a more metapsychological/psychoanalytic view
may be neurologized and operationalized. Indeed, this
is where the rub is currently in many neuropsychoanalytic attempts to bridge between two cultures—one
that is strongly neuroscientific and positivistic in its
empirical outlook, accepting only traditional third-person scientific evidence as being relevant, while the
other is deeply psychological and theoretical, where
first-person introspective analysis of the mental apparatus is de rigeur. To try to link Kernberg’s intriguing
position to neuroscientific evidence, we regrettably do
not have as rich a database as we did for constructing
our own theoretical synthesis.
The core issue on which we agree is the central importance of mother–infant bonding and the vicissitudes
of emotional storms that arise from the traumatic severance of such bonds or from situations in which the
infant is simply left in a highly distressed state without
adequate comforting from a parent. We focused, in our
analysis, almost exclusively on the dynamics of separation distress, and depressive sequelae; Kernberg took
a more nuanced approach to the subtle dynamics of
mother–infant interactions, where not only is the distress of being lost or abandoned a main concern, but so
too is the quality of mother–infant interactions where
there is abundant opportunity for “libidinal” frustrations and resulting rage. We did not even bring up the
issue of anger that can arise from unfulfilled expectations and a multitude of attachment-related frustrations, whereas Kernberg’s metapsychological analysis
emphasizes the internal management of aggression as
a core psychological dynamic, but one that remains
much harder to model in neuroscientific terms.
To our knowledge, animal models have never noted
rage as being a prominent component of the separation response. Kernberg repeatedly suggests that such
rageful feelings may be critically antecedent to depression. Thus, while Kernberg suggests that “prolonged
separation of the infant from its mother powerfully
activates the affects of rage first, despair later, and
under extreme circumstances, despondency and reduction of the capacity for object-relatedness,” we would
suggest that the appropriate sequence is separation
distress/PANIC and despair, and rage only if there is an
opportunity for such instrumental actions in the midst
101
of an insecurely attached parent–infant dynamic. However, the absence of any animal-model data suggests
that rage does not appear to be a primary response to
separation and requires higher mental representations
that are hard to study in animal models. This, of course,
does not mean that rage is not a factor that needs to be
considered in the depressive cascade. Accordingly, we
think separation distress/PANIC is the primal response
to separation in helpless infants and is a key evolutionary determinant of the depressive cascade; we consider
that rage may loom larger among the tertiary processes
of childhood, as well as in adult human precipitants of
depression.
Certainly in adulthood, anger is a gateway to loneliness. No one can tolerate another’s rage for too long,
as chronic rage is inherently toxic. Persistent anger at
another is a sure recipe for life companions to seek
separation, but one key question is whether such anger
is only a gateway to the ensuing separation distress or
whether it alone is a primary pathway to depression.
We suspect the former is the correct view. However,
both rage and separation distress may be linked to the
experience of a primary helplessness. Until shown otherwise, we would suggest that the cascade of primary
affects arising directly from separation may be the
more influential in depression than those arising from
the secondary, strategic emotional responses such as
anger. During early development, such anger displays
may promote insecure attachments both in parents and
in children and hence more abundant opportunities for
separation distress, a condition that could easily promote depression throughout the lifespan.
In adulthood, persistent anger and blame are surely
major paths for the loss of social support, thereby
widening the gateway to depression. But this may be
a secondary process. The leaving of angry persons
in the throes of their own discontents maximizes the
likelihood of separation in adult relationships. Animal
models are so far not of much use in evaluating such
issues, not because of absence of models of aggression, but largely for absence of relevant affect-focused
discussions in behavioral neuroscience. Certainly, the
resident–intruder model of social loss (e.g., Panksepp
et al., 2002) is a relevant model for addressing such
questions. Indeed, various depressogenic neuropeptide changes have been documented in the brains of
male social intruders, who always lose in the almost
obligatory aggressive encounters that arise when intruders are placed into the domestic territory of other
rats (Panksepp et al., 2007). But presumably this is not
because of their own anger, but only because of the
hyperdefensive, fearful posture they are forced into.
However, such work has rarely addressed the brain and
102
psychological changes that transpire in the more rageful, resident animals. But that is the issue that may need
to be evaluated. If such encounters adversely influence
the stable social relationships of the resident animals,
a relevant model might be developed to evaluate the
consequences of rage on the emergence of depressive
phenotypes.
The pharmacological work may be a bit more of
a help in resolving this issue. The RAGE system of
the brain is enriched with the anger-facilitating neuropeptide substance P at all relevant levels of the
primary-process RAGE circuitry—in medial amygdala, medial hypothalamus, and dorsal periaqueductal
gray. Substance-P receptor blockade does reduce rage
displays (Gregg & Siegel, 2001). In this context, it is
noteworthy that Pfizer originally developed Aprepitant
as a potential antidepressant, and even though it failed
to exhibit any greater potency than SSRIs, ensuing
work has confirmed that such agents do, in fact, have
significant antidepressant properties (Alvaro & Di Fabio, 2007; Kramer et al., 2004). Might this be partially
due to the moderation of angry behaviors in established
relationships, which might promote warmer, more accepting attitudes? If so, a relevant neuropsychoanalytic
database for considering how rage figures in the genesis of depression could be constructed. This intriguing
idea, concordant with Kernberg’s hypothesis, is that
if one were able to pharmacologically diminish anger
with such agents in adult relationships, the likelihood
of separation would diminish, which would secondarily be prophylactic for the depressive cascade that
emerges from the many social separations that arise
from dysregulated anger in relationships.
Since this kind of analysis is robustly linked to
brain emotional systems that can be analyzed in some
detail both in animal models and in human relationships, with unique neuropsychoanalytic implications,
we would provisionally conclude that Kernberg’s hypothesis may be on the right track. Still, we should
emphasize, as did Kernberg, how difficult it is to
translate the affective dynamics arising in human relationships onto our emerging understanding of mammalian-brain emotional network functions. Thus, his
commentary implicitly highlights a central dilemma
for a neuropsychoanalytic enterprise. We hope that
at some future time, Kernberg will share his clinical
wisdom on how such linkages between brain and mind
can be objectively enhanced, with enough operationalization of concepts that scientific observation can lead
the empirical analyses. Although he may be right that
at “this time psychoanalysis and neurobiology are still
too far apart in their focus and methodology to permit
any satisfactory integration,” we hope that our own
Douglas F. Watt & Jaak Panksepp
article has highlighted how that is possible in certain
areas of thought, because affective neuroscience has illuminated the nature of certain universal primary-process affective mechanisms of the human/mammalian
brain. Although Kernberg feels that such linkages are
close to impossible, because complex mental processes
have no one-to-one correspondence to specific neuralcircuit activities, in fact at the primary-process level
there appear to be remarkable correspondences that
can enhance neuropsychoanalytic analyses of phenomena as complex as romantic love (Yovell, 2008), empathy (Watt, 2007), and the pleasure principle (Johnson,
2008).
In any event, we agree that most of Kernberg’s
analysis is at a level of intersubjective psychological
subtlety that cannot as readily be neurologized and
has more immediately discernible psychotherapeutic
implications than neuroscientific ones. At present, the
current state of the art in the interdisciplinary endeavor
known as “neuropsychoanalysis” is confronted by a
host of human problems that cannot be readily neurologized. However, what affective neuroscience has
offered is a reasonable strategy to finally analyze,
with all the power of modern neuroscience, the linkages between primary emotional processes and the
raw affective states in which Freud was so intensely
interested. Using a dual-aspect monism strategy (Panksepp, 2005; Solms & Turnbull, 2002), we can, with
considerable assurance, conclude that certain basic affective states arise from the same genetically provided
neural circuits that control emotional instinctual action
sequences (Panksepp, 2005, 2008). This was the level
of analysis that constrained much of our own thought
in the target article.
However, Kernberg’s analysis coaxes us all to go to
higher psychological levels (to deal with “psychological experiences that further augment the threat of social loss or psychological abandonment and constitute
the psychodynamic disposition to depression,” where
unique developmental and epigenetic landscapes of
complex interpersonal interactions rule the day. These
higher mind functions may lead to “pathological internalization of early object relations and their role in dysfunctional regulation of self-esteem.” It will be a great
challenge for future neuropsychoanalysts to cultivate
the neuroscientific as opposed to the metapsychological dimensions of such an important problem. To do
that with any real efficacy, we will need a clearer image
of scientific results already harvested from parent–infant interactions, especially studies that have accepted
the complexity of the infant mind as being much more
than the simplified reflex-learning machine that many
have traditionally envisioned it to be. (A target article
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
along those lines could be profitably sought for this
journal.)
We would only briefly note that a growing number
of such objective analyses are emerging from modern developmentalism, especially the more psychologically sensitive ones that Colwyn Trevarthen (2005)
and his students (Trevarthen, Aitken, Vandekerckhove,
Delafield-Butt, & Nagy, 2006; Trevarthen & Reddy,
2007) have revolutionized across the past few decades.
For instance, remarkable treatises on such issues, such
as the one just published by one of Trevarthen’s most
revolutionary students, Vasu Reddy (2008), set a new
standard for scientifically understanding the infant
mind from a second-person, interactive perspective.
New insights into better child-rearing practices have
emerged from our understanding of the power of basic
emotional systems and the intersubjective stance of
the human infant (Sunderland, 2006). Regrettably, we
do not have space here to adequately delve into such
works, but neuropsychoanalysis will be well served
to cultivate strong relationships with such emerging
research traditions and the potential interfaces with
animal models where the underlying brain networks
can be studied in some detail.
Response to Harold W. Koenigsberg’s
commentary
Early therapeutic strategies and options in
relationship to separation-distress cascades—can
we stop depression before it starts?
We appreciate Harold Koenigsberg’s insightful analysis on how to push the evolutionary ideas we shared
toward novel forms of evaluation and treatment. We
agree, that this type of approach is of most importance
whenever new theoretical syntheses are proposed. To
some extent the idea has been already evaluated pharmacologically, since it has been known for some time
that during prolonged separation, antidepressants such
as imipramine keep animals in the protest phase longer
(Panksepp et al., 1991), but so far this has only been
evaluated in acute rather than chronic studies.
Koenigsberg’s ideas on how to intervene early following social loss so as to prevent the onset of the
separation-distress shutdown (SDS) mechanism is
especially intriguing and appreciated. We strongly
suspect that this could be achieved in part pharmacologically and in part psychotherapeutically, with
appropriate synergisms between these two types of
interventions. In this context, we would note that there
are two distinct types of separation-distress shutdown
103
mechanisms—in other words, mechanisms that terminate the protest phase of separation distress. One
mechanism appears to be clearly depression itself,
while another, less appreciated one is based on the
return of the objects (and associated neurochemistries)
of affection, so that positive emotional homeostasis is
re-established rapidly after the initial separation experience, preventing the affectively negative shutdown
mechanism from having room to prevail. Here there
is abundant room for new medicinal agents such as
safe opioids like buprenorphine (Bodkin, Zornberg,
Lukas, & Cole, 1995) and perhaps oxytocinergics, both
of which dramatically soothe separation distress, to
prevent the cascade of depression in a sense before it
really gets started. One might also expect that the same
agents could have efficacy in the chronic shutdown
phase by directly promoting psychologically healing
positive affect. Indeed, that is why we focused on the
evidence that buprenorphine, at very low sublingual
doses, looks as though it would be a rapid antidepressant. One might expect the same for oxytocin, but in
a recent study that did not prove to be the case (Kose
et al., 2008). Indeed, depressed males tended to be
resistant to the prosocial effects of oxytocin that were
evident in controls, which suggests that their depressive condition may have been accompanied by oxytocin receptor insensitivity. This is outwardly consistent
with previous work indicating that young men who had
lost parents when young exhibited diminished effects
of intranasal oxytocin on plasma cortisol measures
(Meinlschmidt & Heim, 2007). However, epigenetic
mechanisms underpinning this have yet to be fully
clarified, to our knowledge. Perhaps this kind of insensitivity is somehow part of the shutdown process
itself, where active depressive affect (perhaps reflected
in a dynorphin mediated shutdown of the seeking system) prevails in the mental apparatus. If so, it is still
possible, as Koenigsberg notes, that oxytocin could
have major benefits during the acute grief/mourning
phase, especially in a therapeutic context. From our
perspective the primary-process changes produced by
oxytocin would be a reduction of separation distress
(Panksepp, 1988, 1992), a decrease in various forms of
aggression (McCarthy, Low, & Pfaff, 1992; Riters &
Panksepp, 1997), and increased confidence (Panksepp,
2009a). All of these emotional changes could easily
provide positive vectors for psychotherapeutic change
especially in the context of clinical interventions that
were attuned to the possibility of an SDS cascade.
Indeed, the possibility that oxytocin might facilitate
the psychotherapeutic enterprises is currently on many
minds, but no relevant data yet exist.
Lasting effects could be achieved by recontextualiz-
104
ing, and if one is burdened by painful social memories,
might oxytocin mellow the ache and provide opportunities for reframing and recontextualizing those memories within a framework of greater social warmth and
social connection? Might the memory-reconsolidation
process, which can now be facilitated pharmacologically (Norberg, Krystal, & Tolin, 2008), be best achieved
if one promotes oxytocinergic warmth and confidence,
so that when past memories are reconsolidated one
takes the edge off the distressing affective mixture that
might otherwise lead to the SDS cascade? Very similar
scenarios could be generated for endogenous opioids,
perhaps even more so since opioids are fundamentally
more powerful in promoting unconditional positive
affect than are oxytocin. Panksepp’s lab repeatedly
tried to obtain conditioned place preference (CPP)
with oxytocin, but with no success (but see Liberszon,
Trujillo, Akil, & Young, 1997) until they used a socially induced place-preference paradigm (Panksepp,
Nelson, & Bekkedal, 1997) and found that oxytocin
could facilitate the ongoing social-reward process. It is
known that oxytocin can sustain opioid reward in the
brain (Kovács, Sarnyai, & Szabó, 1998), and it remains
possible that many of the positive hedonic effects of
oxytocin are indirectly mediated by opioid amplification. Several subcortical sites are known to mediate
opioid reward (Olmstead & Franklin, 1997) as well
as opioid alleviation of separation distress (Herman &
Panksepp, 1981). These considerations suggest a mix
of possible poorly understood synergisms between opioids and oxytocin as well as some independent effects
on critical separation-distress and bonding dynamics.
The ability of oxytocin to reduce aggressiveness and
increase social confidence is generally less well appreciated than the many other prosocial effects of oxytocin (increased maternal behavior, facilitation of social
bonding, etc.: for summary see Nelson & Panksepp,
1998), so let us focus briefly on the relevant findings. It
has long been known that male rodents exhibit less infanticide when treated with oxytocin (McCarthy, Low,
& Pfaff, 1992). In a study of quail we saw provocative
results suggesting vasotocin (the avian oxytocinergic)
made quail more peaceful. Male quail are quite ready
to peck each other’s heads in vying for dominance. If
one male of a combatant pair was given intraventricular vasotocin, it showed very little aggression, taking
each nasty peck in its stride (Riters & Panksepp, 1997).
Usually those animals should become submissive, but
remarkably when the male that had exhibited a peaceful attitude under vasotocin was given the control
(placebo) solution, it promptly started to peck the other
bird, making the other now assume a submissive posture. Very strange! It appears that all the earlier pecking
Douglas F. Watt & Jaak Panksepp
had had very little effect on the put-upon quail’s sense
of dominance. Maybe the confidence those birds felt
while under oxytocin, along with the anti-aggressive
attitude, was sufficient to prevent the trauma received
on previous sessions from consolidating a sustained
submissive attitude.
To directly evaluated oxytocin’s ability to promote
confidence, Panksepp (unpublished data, 1988) contrasted groups of eight young chicks given intracerebral oxytocin or control solution, and they were placed
under a bucket for a minute. When the bucket was
lifted, the degree of interanimal dispersion was monitored as chickens exhibited their normal flock-linked
foraging-exploratory patterns. Clearly, oxytocin animals seemed more confident, as those oxytocin-treated
flocks gradually became more widely dispersed than
controls. Clearly something like “confidence” seemed
to be elevated by oxytocin. Might this be the underlying affective construct for the increased “trust” that has
been seen in human investment studies after intranasal
oxytocin (Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008)?
These kinds of primary-process psychological effects should be very beneficial to manipulate early in
grief/trauma psychotherapy so as to recontextualize
and reconsolidate memories that will tend to retard the
SDS cascade toward depression. Indeed, we would not
be surprised that if clinicians also took oxytocin, they
might be more consistently in a better psychological
frame of mind to really facilitate the psychotherapeutic
process. In any event, the bottom line to this analysis, to which we appreciate Koenigsberg focusing our
attention, is the possibility of using direct affective
manipulations, early enough in the separation-distress
cascade so as to forestall and possibly reverse the despair shutdown phase before it has consolidated into a
more sustained and refractory psychological state.
Response to Georg Northoff’s commentary
Transitions from intersubjective relational coding to
self-referential coding in depression
Georg Northoff raises a critical conceptual issue and
devilishly complex empirical issue in his inquiry about
the relationship between psychoneurological integration between the brain coding of external stimuli and
internal network dynamics—between cognitive inputs
from the world and, in our terms, the degree to which
affective consciousness rules the mental apparatus.
As Northoff knows as well as anyone, we are here in
the domain of high theory—hopefully with empirical
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
implications—rather than the land of mundane data
harvesting. His own discovery of high resting-state
activity in cortical midline structures (CMS) in the
depressed state is one of the most important discoveries of what happens within the depressed brain when it
falls under the dominion of internal negative feelings
as opposed to sustaining a balance of well-regulated,
mental-health-promoting intersubjective domains of
social interchange. Unfortunately, except for select areas such as fear conditioning in animal models, we do
not yet know empirically how inputs from our external
senses control the evolved affective powers of our
minds. For fearfulness, there does seem to be a cascade
from higher deliberative regions of the frontal lobes,
especially medial frontal regions, when danger is far,
to a rapid arousal of lower brain regions, such as the
periaqueductal gray, when threat is imminent (Mobbs
et al., 2007). How does healthy social interchange,
anchored in a cognitive locus of control (preciously
patched together by early developmental landscapes),
regulate deeper affective domains where the intensity
of negative affect is most intense? Northoff has provided one vision of such interactions, and we would share
a complementary view based on how we envision raw
affects to be organized within the deeper, subcortical
regions of the brain.
What does it mean to have an emotional affect? In
our view, this surely has to reflect a large-scale network dynamic, with a primordial subcortical locus of
control/activation. We do not have good neuroscientific techniques yet to study such network properties
of the brain. Perhaps modern brain imaging currently
gives us the best estimates of the cognitive variants,
but those impressive tools are not quite as effective
for envisioning subcortical affective variants where
the frequencies of action potentials are low, and often
systems can release neurotransmitters (e.g., dopamine)
largely by changes in the patterning rather than the
overall frequency of action potentials. Since modern
brain imaging techniques sense metabolic changes provoked largely by energy consumption from changing
frequencies of action potentials and associated glial
metabolic support systems, those techniques are often
“blind” to envisioning the more ancient affective brain
mechanisms where the power of neuromodulators such
as neuropeptides are more important than changes
in the fast transmission properties of glutamatergic,
GABAergic and related rapidly firing cortico-cognitive
brain systems.
Without additional fine neuroscience techniques,
similar to those that allowed the “neuron doctrine” to
rule neuroscientific thinking, it is difficult to craft an
objective neuroscientific database for understanding
105
the large-scale network dynamics that apparently control the endogenous subcortical functions of the affective brain/mind. Currently the best metaphors we have
for these large-scale network dynamics that we cannot
yet measure objectively are “attractor landscapes” and
other concepts from nonlinear dynamics (Freeman,
2003; Lewis, 2005; Panksepp, 2000). Unfortunately,
no one has yet cashed out such metaphors with robust
and understanding-illuminating research programs, as
least with respect to emotion (Freeman, 1991, has done
so with respect to olfaction).
Until tools to monitor such ancient affective network dynamics are developed, the very best measures
of the brain’s own internal processes (the evolved
tools for living) that we have are the instinctual emotional behaviors (distinct action patterns) upon which
the affective neuroscience approach for decoding the
primary-process affective mind is based (Panksepp,
2005). This blessing—the correspondence between internal affective brain network dynamics we cannot yet
directly observe and the emotional action patterns that
we can—has allowed rapid scientific progress in decoding the neural nature of the raw affects (Panksepp,
1982, 1998, 2008). There is no better tool than a good
“proxy,” both in affective neuroscience as well as in
many kinds of biochemical research (e.g., measuring
chemicals via their absorbance and emission spectra).
In other words, one does not have to understand a
whole brain/mind network before one can begin to
make substantial progress in understanding what various functional networks do.
Furthermore, behavioral neuroscience has had one
robust tool for looking at the interface of cognitive
sensory inputs and complex evolutionarily provided
internal networks dynamics for some time through
the highly reliable procedures of Pavlovian classical
conditioning. The regrettable aspect of this analysis is
that the majority of investigators have devoted most
of their time to evaluating how conditional stimuli
(cognitive inputs from the world) modulate the development of conditioned responses (e.g., LeDoux, 1996)
while ignoring the critical nature of the large-scale
unconditioned responses (UCRs) that “motivate” the
conditioning. UCRs are typically simply accepted as
“givens,” which they are, but the whole terrain of affective internal structures is hidden within this internal
domain that behaviorism largely ignored. One goal of
affective neuroscience was to rectify that flaw, and now
instead of a variety of unconditioned and conditioned
“outputs” of fear conditioning, we have a vision of
an integrated unconditional FEAR system, and other
basic emotional networks (Panksepp, 1998). Regrettably, a more complete answer to Northoff’s question
106
has been delayed because the neurobehaviorists avoid
conceptualizing and studying the nature of their UCRs
and, thereby, avoid any talk about the real, evolved
emotional processes of the mammalian brain.
In any event, classical conditioning provides an
effective empirical model for addressing the central
question that Northoff poses, and it provides a robust
way to study systematically how conditioned triggers
can control the large-scale neurodynamics of emotional primes within the brain, just as flicks of a light
switch can illuminate vast spaces of our external environments. There is insufficient space here to detail
the extensive and highly relevant literature, but for
simplicity we can now envision how in the emergence
of “normal-healthy” minds, various cognitive trigger
points can guide emotional dynamics almost like a
modest cognitive touch on the steering wheel of your
car can guide the many horses of your automotive engine. It is when massive stressful learning experiences,
or the disconnection of the affective engines from
cognitive controls, emerge that psychopathologies like
depression move into a ruling position within the mental apparatus, and one begins to drown in unbearable
affect. Because neurobehaviorism was so fascinated
by learning rather than the internal organization of the
brain, we now know a great deal about how such nodes
of learning emerge from the biochemical changes shaping the formation of “Hebbian synapses.”
As Georg Northoff knows as well as anyone, some
kind of self-referential information processing, where
core-self structures situated at the midline of the brain
evaluate external stimulus inputs, presently provides
a coherent vision for how the external world, through
sensory portals, interacts with the internal world of
affective dynamics (Northoff & Panksepp, 2008; Northoff et al., 2006; Panksepp & Northoff, 2009).
Once we can develop good and synergistic human
and animal models to study such brain dynamics, will
we have good answers to the critically important questions Northoff has posed? His own provisional answer
to his question is quite similar to our own, except he
may still be envisioning emotions in more traditional
cognitive-neuroscience types of information-processing terms than do we. For us, the internal network
dynamics of emotional affects have little resemblance
to the “information-processing modules” so popular in
cognitive neuroscience (Panksepp, 2003b). However,
it is now well known that under normal psychological
circumstances, high-cognitive information-processing
activities are quite effective in suppressing ancient limbic–affective network functions (Liotti & Panksepp,
2004; Northoff et al., 2004). This may help explain
Douglas F. Watt & Jaak Panksepp
how diminished higher control of affective energies
may often be effectively restored by therapies that focus on mindfulness and various cognitive-behavioural
interventions.
So let us extend our brief response to Northoff’s
seminal question one additional step into the realm of
psychotherapeutics and affect management, topics we
have discussed at some length elsewhere (Panksepp,
2009b; Watt, 2007). Various novel psychotherapeutic
practices may emerge from a better understanding of
the core affects and other UCRs in guiding the formation, framing, and retrieval of memories that may be of
use for the development of new variants of “affective
balance therapies” (Panksepp, 2009b). This may arise
from our new scientific understanding of how flexible
past memories—both ordinary and traumatic—are to
reconsolidation, especially after they have been retrieved into active memory stores (Norberg, Krystal, &
Tolin, 2008). One goal of posttraumatic-stress disorder
management—in addition to the softening of other
horrendous memories that promote garden-variety
anxieties and depressions—might be the psychotherapeutic (1) recontextualization, (2) affective reframing,
and (3) subsequent reconsolidation of memories into a
softened, more positive, affective surround.
For instance, if we envision cognitions to be “dimples” (small wavelets) on the large-scale attractor landscapes of emotional-affective network dynamics, might
it be useful, in the safety of supportive psychotherapeutic environments, to reactivate traumatic memories
promptly after which one generates positive emotional
states that can provide a reconsolidated recontextualization of those horrendous, joy-sapping, memories?
For instance, we envision that if the spontaneous or
therapist-facilitated retrieval of a traumatic memory is
fully accepted in a warm and supportive environment,
and the therapist were to actively seek to activate a
powerful countervailing affect, such as a joyful-PLAYful state, promptly after the power of the traumatic
memory had run its course, then the traumatic memory
might be reconsolidated in a more gentle, life-affirming way. The affective valence of the memory will not
have fundamentally changed (one does not, generally
speaking, turn a traumatic memory into a positive one),
but its power to activate unrestrained negative emotion
is fundamentally modulated and inhibited, and disconnected islands of affective trauma are turned into a coherent narrative now told with an empathy for the self
that was previously lacking, leaving the knowledge of
one’s lot in life embedded in a gentler nest of affective
acceptance and understanding. In this way, the client
may be saved from being immersed in oceanic and
Depression: An Evolutionarily Conserved Mechanism? • Response to Commentaries
extremely painful affects and drawn back to the safety
of a positive, cognitively reframed shoreline. This kind
of work could clearly be modeled in animals, using
creative methodologies, if investigators could be less
impressed by our obvious cognitive differences with
our mammalian cousins and more impressed by our
deeper affective similarities.
In sum
We deeply appreciate the participation of all the commentators in this discussion, as well as their many
thoughtful comments and challenges. Clearly, depression is a multidimensional disorder that is reflected at
all levels of mind/brain organization. Future progress
in the field will need better integration among all
the levels, from the basic neuroscience of emotional
processes to the many regulatory influences of higher
mental processes as well as the physiological wisdom
of the body.
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