The World Journal of Biological Psychiatry, 2009; 10: 258268
REVIEW ARTICLE
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Tryptophan as an evolutionarily conserved signal to brain serotonin:
Molecular evidence and psychiatric implications
SASCHA RUSSO1, IDO P. KEMA2, FOKKO BOSKER1, JAN HAAVIK3 & JAKOB KORF1
Departments of 1Psychiatry and, 2Laboratory Medicine University Medical Centre Groningen, Groningen, The Netherlands,
and 3Departments of Biomedicine and Psychiatry, Haukeland University Hospital and University of Bergen, Bergen, Norway
Abstract
The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of
depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the
evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific
psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in
blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This
relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral
production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated,
including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid.
Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed
social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances,
such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of
psychiatric disorders and symptoms associated with low availability of tryptophan.
Key words: Serotonin, tryptophan, depression, psychopathology, evolution, indole 2,3-diamino oxygenase
Introduction
During the last five decades, more than 25,000
reports have appeared on the possible involvement of
cerebral serotonin (5-hydroxytryptamine, 5-HT) in
a wide variety of psychiatric disorders. Dysfunctional
5-HT transmission has been associated with depression, panic, anxiety, postpartum blues and depression, obsessive-compulsive disorders, attention
deficit hyperactivity disorder, autism, eating disorders, schizophrenia and borderline personality disorders (see, e.g., Maes et al. 2001, 2002; Van Praag
2001, 2004; Jans et al. 2006; Levinson 2006; Maron
and Shlik 2006; M’Baı̈lara et al. 2006). The central
serotonergic system has also been implicated in
many physiological processes and behaviours such
as sleep (Jouvet 1999), thermoregulation (Lin et al.
1998), satiety (Leibowitz and Alexander 1998),
neurogenesis (Banasr et al. 2004), stress response
(Meijer and de Kloet 1998; Leonard 2005) and
aggression (Popova 2006). The present overview
emphasizes the non-specificity hypothesis about
brain 5-HT (and tryptophan) and psychopathology.
Accordingly, a strict (or deterministic) pathogenic
role of low 5-HT levels in most if not all the
mentioned psychiatric conditions, seems unlikely.
In far the most psychiatric disorders brain 5-HT
dysfunction and associated genes are modulating or
worsening a wide variety of psychiatric conditions,
instead (e.g. Levinson 2006; Jans et al. 2006; Maron
and Shlik 2006; Riedel 2004; Riedel et al. 2002).
We propose that low levels of brain 5-HT are not
only found in (mental) disorders, but may occur in
various physiological conditions. This idea will also
be discussed from an evolutionary point of view. The
synthesis of brain 5-HT, and therefore its function,
depends on the availability of the essential amino
acid tryptophan (Fernstrom 2000). Blood plasma
levels of tryptophan vary under a variety of conditions, such as starvation, infection and stress. Consequently, tryptophan may fulfil an important role as
a signalling molecule in the communication of the
organism with its environment. Thus, an organism
Correspondence: Jakob Korf, PhD, Department of Psychiatry, UMC Groningen, P7.16, P.O. Box 30.001, 9700 RB Groningen,
The Netherlands. Tel: 31 50 361 2100. Fax: 31 50 361 1699. E-mail: [email protected]
(Received 30 March 2007; accepted 15 June 2007)
ISSN 1562-2975 print/ISSN 1814-1412 online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.3109/15622970701513764
Tryptophan-serotonin link
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may perceive whether plasma tryptophan levels lie
outside the physiological range through cerebral
5-HT function. We speculate about the possible
survival value of this mechanism for an organism.
Some consequences of this point of view for the
clinical indications of 5-HT-potentiating drugs, such
as the antidepressants of the selective serotonin
reuptake inhibitor (SSRI)-type, will also be discussed.
Phylogenetic perspectives of 5HT neurons
Specific 5-HT-containing neurons and ascending
5-HT projections probably arose early in phylogeny
(Jacobs and Azmitia 1992; Azmitia 2001). In snails,
leeches and molluscs, specialized 5-HT-containing
neurons have been identified (Weiger 1997). In
vertebrates, 5-HT-containing cell bodies are clustered in nuclei, containing a few thousands up to
100,000 cells. Ascending serotonergic projections
almost exclusively stem from the dorsal and median
raphe nuclei clustered around the midline of the
brainstem (B7 and B9; Dahlstrom and Fuxe 1964).
From these nuclei, ascending axons project to many
regions in the brain and spinal cord, including the
hippocampus, hypothalamus, amygdala, basal ganglia and the neocortex. According to the common
anatomical features in vertebrates, 5-HT must have
widespread effects on the state of the central nervous
system and may secondarily influence a wide variety
of behaviours in the organism.
Blockade of the 5-HT transporter with an SSRI
during early development in mice resulted in
abnormal adult behaviour (Ansorge et al. 2004), and
5-HT-depletion of the pregnant mother (lacking
TPH-1) limited normal development of the cerebral
5-HT in the offspring (Cote et al. 2007). These
findings suggest that 5-HT may also function as a
morphogen during early development of neural
wiring (Fukumoto et al. 2005; Nakamura et al.
2006). Such function may also be maintained in the
adult, as 5-HT affects brain plasticity via the induction of neurotrophins (Mattson et al. 2004). It
should however be mentioned here that the morphogen-like signalling function of 5-HT may in particular depend on the synthesis of 5-HT through
tryptophan 5-hydroxylase (TPH, subtype 1).
Tryptophan and 5-HT synthesis
Tryptophan is an essential amino acid in higher
organisms, but its abundance in proteins is relatively
low (Bender 1983). It is conceivable that the
availability of tryptophan is a limiting factor in the
synthesis of several compounds such as proteins,
nicotine amide and 5-HT. The cerebral influx of
tryptophan is determined by the ratio of plasma
tryptophan and other large neutral amino acids with
which it competes for transport over the bloodbrain
barrier (Fernstrom 2000). Figure 1 shows an overview of the here discussed metabolic pathways.
In both mammalian and non-mammalian species,
a direct relation between tryptophan levels, cerebral
synthesis and metabolism of 5-HT has been observed. For instance, tryptophan loading increases
the formation of brain 5-HT and its main metabolite
Tryptophan hydroxylase
type 2
Serotonin
5-HT
Indole diamino
oxydase IDO
Brain
tryptophan
Protein
synthesis
259
Decarboxylation
Serotonin
5-HT
Tryptophan
hydroxylase type 1
Blood–brain
barrier
5-Hydroxy
indole acetic
acid
5HIAA
Kynurenine
pathway
TO/IDO
Circulation
tryptophan
Ingestion
Tryptophan is an
essential amino acid
Figure 1. Overview of the metabolic fate of tryptophan en serotonin (5HT). The emphasis is on the differential dependence of the cerebral
5HT formation via TRP type 1 and 2 and on the tryptophan influx from the circulation. Transport is indicated with gray arrows. Metabolic
conversions are indicated with black arrows. Broken arrow indicates that 5HT synthesis is dependent from free (cerebral) tryptophan.
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260
S. Russo et al.
5-hydroxyindole acetic acid (5-HIAA) in fish
(Koutoku et al. 2003) and it reduces cortisol
secretion during stress in a dose-dependent manner
(Lepage et al. 2002), features strikingly similar to
those seen in mammals. The consequences of
tryptophan loading on the cerebral synthesis and
metabolism of 5-HT have, however, best been
documented in mammals. In various species, administration of tryptophan leads to acute increases of
cerebral 5-HT and/or 5-HIAA (Bender 1983). Conversely, rapid tryptophan depletion, through the
ingestion of food or beverages devoid of tryptophan,
resulted in impaired cerebral 5-HT formation in all
mammals studied, including humans. In humans,
plasma levels of tryptophan can thus be reduced to
approximately 10% of baseline levels a few hours
after ingestion of such a beverage (Delgado et al.
1994; Jans et al. 2006). In the vervet monkey, CSF
levels of 5-HIAA are diminished following dietary
tryptophan depletion (Young et al. 1989). Microdialysis studies on rats demonstrated that dietary
depletion of tryptophan diminishes cerebral 5-HT
release in both acute and chronic designs (Fadda
et al. 2000).
These observations together, point to a direct
relationship between the availability of tryptophan,
neuronal release and metabolism of 5-HT. Apparently, this relationship is evolutionarily conserved.
Regulation of 5-HT synthesis
The rate-limiting step for the cerebral biosynthesis of
5-HT is the enzyme tryptophan 5-hydroxylase
(TPH). Recently, two different forms of TPH have
been identified. TPH1 is expressed in peripheral
tissues, the pineal gland, and in many brain regions.
TPH2 is expressed in virtually all brain areas and is
responsible for the majority of the cerebral 5-HT
production (Walther et al. 2003; Zill et al. 2004,
2007). In vitro the human brain isoform TPH2 has a
significantly lower affinity for tryptophan than
TPH1 (McKinney et al. 2005). The in vitro Km
value for tryptophan of the TPH2 enzyme is in the
range of the free concentration of tryptophan of the
intact organism (McKinney et al. 2001, 2005). This
implies that the production of cerebral 5-HT is
directly dependent on the non-protein-bound concentrations of tryptophan in blood and brain. In
contrast, the closely related TPH1 isoform has a
lower Km value, so within physiological ranges the
production of 5-HT by this isoform is maximal.
From an evolutionary perspective one can envision
that if such substrate-dependence were harmful to
the organism, ‘‘evolutionary pressure’’ should have
led to the formation of a tryptophan hydroxylase
with high substrate affinity. On the contrary, in the
brain the low affinity TPH subtype (TPH2) is the
most abundant isoform present. We propose therefore that variations in blood levels of tryptophan are
perceived via the rate limiting enzyme TPH2, which
is confined to cerebral 5-HT neurons, and that the
relatively low affinity of TPH2 for tryptophan has
been conserved throughout evolution.
Inducible tryptophan degradation
In mammals less than 1% of dietary tryptophan is
converted to 5-HT and only 10% of that conversion
takes place in the brain. The quantitatively most
important catabolic pathway of tryptophan is the
so-called oxidative or kynurenine pathway, metabolizing about 99% of dietary tryptophan (Bender
1983). End products such as nicotinamide adenine
dinucleotide and H2O2 are formed via tryptophan
oxygenase (TO) which is found mainly in the liver.
This pathway is most prominent under non-challenged
conditions. However, oxidative catabolism of tryptophan is susceptible for various internal and external
stimuli, such as hormones, stress and immuneactivation.
The human liver TO is induced by the administration of large amounts of tryptophan and following
high levels of adrenal stress hormones, including
cortisol (Bender 1983; Renkawitz et al. 1996). In
volunteers, administration of cortisol results in a
reduction of plasma tryptophan levels (Maes et al.
1990). In rats undergoing immobilization stress, a
decrease in plasma tryptophan levels of 20% was
observed (Martin et al. 2000). In most organisms,
low levels of brain 5-HT enhance corticoid release,
thus rendering the animal more responsive to stress
(Lucki 1998). But, increased excretion of cortisol or
corticosterone is also induced by 5-HT-releasing
drugs, such as fenfluramine, and by anxiolytic drugs
(summarized in Bechtholt et al. 2007). In summary,
there is a complex mutual interaction between
glucocorticoid levels and cerebral 5-HT function.
Although it is clear that long-term exposure to high
corticosteroid levels induces enhanced tryptophan
catabolism, the ultimate effect of increased circulating glucocorticoids on the release of 5-HT is difficult
to predict. Transient depletions may therefore have
different effects than lasting depletion of tryptophan
and subsequently on cerebral serotonin.
Extra-hepatic catabolism of tryptophan along the
oxidative pathway occurs via the enzyme indoleamine 2,3-dioxygenase (IDO). Under normal conditions IDO activity is minimal, but the enzyme
becomes induced through pro-inflammatory cytokines such as interferon (Stark et al. 1999) and in the
placenta (Kudo and Boyd 2000). High IDO activity
has been observed in activated macrophages of the
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Tryptophan-serotonin link
peripheral immune system and in activated microglia
of the brain. Induction of IDO has been observed in
human, rodents and a few other species (Cannazza
et al. 2001). Catabolism of tryptophan by IDO
causes accumulation of the NMDA receptor antagonist kynurenine in the brain. This might cause a
dysbalance of glutamatergic neurotransmission, thus
contributing to the development of disorders such as
depression and schizophrenia (Muller and Schwarz
2006). In diseases such as AIDS and cancer, high
formation of endogenous interferon-g is concomitant with low plasma levels of tryptophan (Iwagaki
et al. 1997). In inflammatory brain diseases including Alzheimer’s dementia, microglia concomitant
with IDO will become activated, leading to an
increased degradation of tryptophan, thereby reducing local synthesis of 5-HT (Versijpt et al. 2005).
Therapeutic intervention with pro-inflammatory
interferons in patients suffering from hepatitis-C or
cancer leads to increased excretion of tryptophan
catabolytes and consequently to low blood levels of
tryptophan (Russo et al. 2005). A function of the
induction of IDO in the immune cells is to deplete
tryptophan locally, so protein synthesis of pathogens
(bacteria, viruses) and tumours will be decreased.
Placental IDO protects the foetus from pathogens
and the immune rejection by the mother (Munn
et al. 1998). During or just after delivery low
tryptophan may evoke emotional instability, such
as postpartum blues.
The organism may thus perceive activation of
immune activity or sustained exposure to glucocorticoids through cerebral 5-HT neurons, as the result
of induction of tryptophan catabolism by immune
cells or in the liver, respectively. Considering the
balanced ingestion and catabolism of tryptophan,
the in vivo availability of tryptophan is in a pseudosteady state, implicating that any (physiological)
change has direct or indirect consequences for
cerebral 5-HT function.
Receptor regulation of 5-HT neuronal activity
The multitude of functions of the cerebral serotonin
system is consistent with the large number of brain
areas innervated by serotonin and the varying
distribution patterns of the multiple serotonin receptor subtypes within the brain.
Serotonergic neurons display spontaneous firing
activity (0.21.0 Hz; Vandermaelen and Aghajanian
1983), which is regulated by both homo- and heteroreceptors. In the raphe area 5-HT1A receptors are
located on the soma and dendrites of serotonergic
neurons (but not exclusively, see Kirby et al. 2003)
where they are involved in feedback regulation of
neuronal firing (Sprouse and Aghajanian 1987),
261
5-HT release (Sharp et al. 1989; Bosker et al.
1994, 1996) and synthesis (Hutson et al. 1989). In
axon terminal areas 5-HT release and synthesis is
also controlled via 5-HT1B receptors (Engel et al.
1986; Middlemiss et al. 1988; Limberger et al. 1991;
Hjorth et al. 1995). Other 5-HT receptors subtypes
have been implicated in 5-HT neural activity, but
their role as auto-receptor is not very well established. Feedback inhibition likely serves to limit
excessive firing of 5-HT neurons, but its precise
physiological role is not well established. It is
conceivable, however, that a decrease of 5-HT
release will lead to an increased firing rate of 5-HT
neurons, leading to a faster exhaustion of the
transmitter pools, in particular when the synthesis
becomes limited.
Hetero-receptor regulation is achieved by converging projections to 5-HT neurons. Several pathways
have been identified, including projections from
prefrontal cortex, central amygdala and hypothalamic nuclei (e.g., Bosker et al. 2001a,b). Most of
these projections are excitatory, presumably glutamatergic acting through NMDA, kainate and AMPA
receptors (see, e.g., Liu et al. 2002). Noradrenaline
and dopamine also play a role, through a1,2-adrenoceptors (Hopwood and Stamford 2001) and D2
receptors (Ferre et al. 1994), respectively. Moreover,
serotonergic neurons are a minority in the raphe
nuclei. Inter-neurons of the dorsal and median raphe
nucleus are predominantly inhibitory (GABA), acting via both GABAA and GABAB receptors (Judge
et al. 2004). Finally, a considerable number of cells
in the dorsal raphe that express NK1 receptors also
contain glutamate (Commons and Valentino 2002).
The endogenous NK1 receptor agonist substance P
increases the firing rate of dorsal raphe glutamatergic
neurons that activate serotonergic neurons (Liu et al.
2002). This suggests that NK1 agonists make use of
a glutamatergic mechanism to control the activity of
5-HT neurons in the dorsal raphe. Valentino and
Commons (2005) also suggest that 5-HT neuronal
activity in dorsal raphe nucleus is controlled by
CRH1 and CRH2 receptors via opposite actions on
GABA. According to these authors, the abundant
expression in dorsal raphe nucleus of NK1 receptors
in the vicinity of neurons that co-localize 5-HT and
CRH suggests that the dorsal raphe nucleus is an
important locus for 5-HT-CRH-NK interactions.
The regulatory effects of the various 5-HT-receptors, together with the converging neuronal innervation, indicate that the activity of the serotonergic
raphe neurons depends both on auto-inhibition,
local inhibition and on excitatory input from brain
regions involved in higher functions and from
‘‘lower’’ cerebral neurons. A decrease in circulating tryptophan and 5-HT synthesis results in less
262
S. Russo et al.
auto-inhibition. At low tryptophan levels the average
release of cerebral 5-HT over time may at least in
part be compensated initially by an increased 5-HT
cell firing, but the 5-HT pool may become exhausted soon thereafter.
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Behavioural aspects of tryptophan
Delineation of a specific function of the 5-HT
system in behaviour is mainly based on mammalian
research, but there are also reports on non-mammalian species, including fish and reptiles (Weiger
1997). Modulation by 5-HT has been shown in
feeding, sleep, and sexual and aggressive behaviour
(Winberg et al. 1993). In rats, mice, monkeys and
humans the behavioural consequences of low brain
5-HT content have been studied extensively. Increased feeding behaviour of rodents has been
observed after depletion of 5-HT, whereas drugs
that enhance the release of 5-HT (e.g., fenfluramine) or block the uptake of the amine (e.g.,
sertraline) reduce food intake (McGuire and Troisi
1998). In general, tryptophan loading or feeding in
animals results in a reduction of aggressive behaviour, drowsiness, sleepiness and satiety (Fernstrom
2000; Luciana et al. 2001). In pigs subjected to
social stress, the resulting cortisol peak was unaltered after tryptophan loading, but plasma levels
returned faster to pre-stress levels (Koopmans et al.
2005). In all mammalian species studied, aggressive
behaviour was negatively correlated to brain 5-HIAA
and 5-HT content. This relation is also present in
non-mammalians such as the rainbow trout (Winberg
et al. 1993). In rats, depletion of hippocampus 5-HT
induces an increased killing behaviour towards mice,
that was dose-dependently decreased by 5-HT
agonists and 5-HT reuptake blocking agents (Molina
et al. 1987). Depletion of 5-HT also increases conspecific and predatory behaviour in rodents. 5-HTdepleted rats show increased frequency and duration
of offensive behaviours with an intruder rat in the
cage. In the vervet monkey increased 5-HT (induced
by tryptophan or fenfluramine) suppresses aggressive behaviour and promotes dominant behaviour
(Fairbanks et al. 2001). In other monkey species
there was an inverse relationship between aggression
and CSF 5-HIAA as well (McGuire and Troisi
1998). This trait was not only significant at an
inter-individual level but also at an inter-species level
(Westergaard et al. 1999). Furthermore, 5-HIAA in
CSF has positively been correlated to social rank
(McGuire and Troisi 1998). These data together
suggest that in animals aggressive behaviour becomes often facilitated when the central 5-HT tone
is reduced. Moreover an organism may strive to a
maximally active cerebral 5-HT transmission for
wellbeing.
In humans the behavioural consequences of low
5-HT have systematically been assessed through the
effects of the acute transient tryptophan depletion
paradigm (e.g., Young and Leyton 2002; Booij et al.
2002, 2003; Jans et al. 2006). Most emphasize the
effects on mood in depressive patients and depression vulnerable subjects. Initially, it was reported
that patients and healthy human subjects showed
mild deteriorating effects on mood, hostility and
irritability (for review, see Young and Leyton 2002).
Meta-analysis showed that the effects on mood were
seen in particular in patients with pre-existing
psychopathology, recurrent depressive episodes, female gender, prior exposure to SSRI treatment and
previous suicidal thoughts/attempts, all being independent predictors. Also, chronicity of depression
and familiar and genetic vulnerability were powerful
predictors (Booij et al. 2002; Jans et al. 2006). A
recent study in healthy volunteers demonstrated that
tryptophan depletion induced a shift away from
cooperative behaviour associated with more longterm gain in favour of short-term profit (Wood et al.
2006). Support for non-specificity of transient
tryptophan depletion was demonstrated in patients
suffering from bulimic, depressive and anxiety disorders (e.g., Goddard et al. 1994; Kent et al. 1996;
Weltzin et al. 1995; Smith et al. 1998). Interestingly,
acute depletion of tryptophan improves focused
attention (Riedel 2004Riedel 2002). Others have
observed improvements in simple motor speed/
attention tests and decision making following tryptophan depletion (Hughes et al. 2003; Talbot et al.
2006).
These and many other examples (see, e.g., the
recent comprehensive review of Jans et al. 2006)
suggest that low 5-HT alone is insufficient to cause
psychopathology. Accordingly, emerging behavioural and psychopathological responses during a
transient decrease of circulating tryptophan depend
on (existing) subject characteristics and propensities.
In humans, the consequences of long-term depletion of tryptophan cannot be systematically studied
with a tryptophan-deficient diet, because of ethical
restrictions. However, some somatic diseases and
also pregnancy allow the assessment of behavioural
effects following persistently reduced tryptophan
levels. For instance, low tryptophan can be the result
of an inflammatory response or a peripheral tumour
consuming tryptophan. We studied patients with
hepatitis-C, during a treatment with interferon-a, or
with carcinoid tumours. The latter are slowly
progressive intestinal tryptophan-consuming tumours. In only a few cases depression was noted;
in far the majority (80%), lack of impulse control
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Tryptophan-serotonin link
and irritability was the main feature (Russo et al.
2004, 2005). The latter symptoms did indeed
correlate with lowered plasma tryptophan levels. In
the carcinoid patients there were no serious cognitive
impairments, but an increased ability to rapidly shift
attention was observed (Russo et al. 2003a). The
reviewed studies illustrate that low brain 5-HT
resulting from acute and the long-term tryptophan
depletion, does not lead to major cognitive and
functional impairments.
In psychiatric patients low cerebral 5-HT levels
have been associated with aggressive suicide attempts, impulsive arsonism, and outwardly directed
hostility in personality disorders (Asberg et al. 1976;
van Praag 2001, 2004), rather than with depressive
symptoms. In a double-blind cross-over design study
in 100 volunteers, consumption of 1 g of tryptophan
after each meal for 12 days increased dominant
behaviours. Furthermore, quarrelsome behaviours
significantly decreased (Moskowitz et al. 2003). In
another study, high stress prone subjects showed
attenuation of post stress cortisol peak after a meal
that increased brain tryptophan levels (Markus et al.
2000). Recent genetic studies have demonstrated an
association between several psychiatric diagnostic
categories and certain polymorphisms of genes
associated with serotonin functions, including those
of TPH1, TPH2, 5-HT receptors, and the 5-HT
transporter (Zhang et al. 2005). These polymorphisms, however, seem to account for a small proportion of patients with these diagnoses. In somatic
patients we observed that the change (decrease)
rather than baseline plasma levels of tryptophan
triggered aggressive and impulsive behaviour (Russo
et al. 2005). Low tryptophan during pregnancy or
following delivery are seen in far the most women,
but only a fraction of the subjects appeared to
experience a ‘‘postpartum blues’’ (Maes et al.
2001, 2002; M’Baı̈lara et al. 2006), possibly because
of protection by the high levels of progesterone and
oestradiol during pregnancy. Evidence for a genetic
association between genes of the 5-HT pathway and
aggressive behaviour has recently been summarized
(Popova 2006). These observations together tend to
support the idea that regardless of psychiatric
diagnosis (van Praag 2001) symptoms such as the
lack of impulse control and (auto) aggression are
associated with persistent low tryptophan and consequently low cerebral 5-HT.
Such a conclusion, however, is in apparent contrast with some recent studies showing an association
of trait aggressive behaviour (reviewed by Olivier
2004) or of a decreased dominant behaviour in male
subjects (aan het Rot et al. 2006) on a tryptophan
supplementation diet. Another recent study emphasized gender differences in the (positive) relationship
263
between plasma free tryptophan levels and hostility
(Suarez et al. 2006).
All these behavioural observations together suggest that there is no simple relationship between
tryptophan levels and related behavioural consequences: such behaviour may depend also on the
history and inclinations of the subject. In addition,
in long-term studies 5-HT receptor regulation may
also influence the emerging behaviour during high or
low availability of tryptophan. We suggest, therefore,
that additional parameters, including characteristics
of subjects or patients have to be taken into account
to understand the relationship between low tryptophan and psychopathology.
Comments
Tryptophan as signal
The levels, biosynthesis and neuronal release of
5-HT are highly dependent on the blood levels of
the essential amino acid tryptophan and this dependence is maintained during the evolution of animal
species. If this mechanism was harmful to the
organism, it would have disappeared during evolution. Under physiological circumstances, over 90%
of ingested tryptophan is degraded. By increasing its
rate of degradation, tryptophan in the circulation
can rapidly be depleted. Enhanced catabolism of
tryptophan and consequently lowered levels of
cerebral serotonin occur by the induction of tryptophan-degrading enzymes in the liver (i.e. by glucocortiocoids), the placenta and in the immune system
(i.e. by cytokines). These inductive processes are
found in many animal species. These issues together
lead us to the suggestion that tryptophan has a
signalling function to inform the organism via its
influence on cerebral 5-HT synthesis (Table I).
Figure 2 gives a schematic overview of the various
functional aspects described in this report.
Table I. Arguments supporting that tryptophan has signalling
capacity.
In all animal species the cerebral formation and release of
serotonin depends on influx tryptophan in physiological ranges.
The tryptophan dependent synthesis of serotonin is mediated by
only one of two isoforms of tryptophan hydroxylase (TPH2)
present in the brain.
The low functional affinity of TPH2 for tryptophan hydroxylation
is conserved during evolution and thus unlikely to be harmful,
but must be beneficial for an organism.
Tryptophan is an essential and the least abundant of amino acids,
so its levels are highly susceptible for changes in catabolism.
There are several inducible metabolic routes for tryptophan that
once activated, lead to changes in cerebral 5HT release.
Low tryptophan and low serotonin affect inter-subject
interactions and may thus have survival value, e.g., to limit
con-species distributions of pathogens.
264
S. Russo et al.
Organism
Diet + tryptophan
IDO in
inflammatory cells
Catabolism of
tryptophan
Tryptophan
Blood
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INPUT
BEHAVIOUR
Higher
brain
structures
Neuronal projections
Converging to the
raphe nucleus
Raphe 5HT neurones
5HT projections
diverging to several
brain areas
Figure 2. Schematic representation of the functional relationship between serotonin production, neuronal release and the availability of
tryptophan ( ). The tryptophan flux is indicated as the result of intake and degradation. The figure emphasizes that final emergent
behaviour is the consequence of both input and stored information, whereas serotonin modulates intended behaviour, but does not cause it.
Functional aspects
The next question is what could be the survival value
of a signalling function of tryptophan for an organism. We have already emphasized that there was no
clear deficiency in human functioning following
transient or persistently low tryptophan levels: in
fact some neuropsychological tasks were performed
better. The emergent behaviour in psychiatric patients following low tryptophan may better be
considered as the result of pre-existing and latent
pathology and other motivations of the subject. The
activity of 5-HT neurons and associated release of 5HT is the consequence of precursor availability,
auto-regulation and neuronal input from several
higher brain centres. So it is conceivable that
external factors or challenges in combination with
existing information (stored in the brain) determine
emergent behaviour and that the magnitude of
response to external stimuli depends on the state
5-HT- neurotransmission. In short: cerebral 5-HT
modulates, rather than induces, intended behaviour.
We illustrate this idea with differential social
behaviour observed during low tryptophan levels.
Humans and animals become often more responsive
to external stimuli and there is the tendency towards
aggression. Since animals do not possess senses to
detect an infectious environment, they cannot actively avoid contact with infected littermates. During
serious and chronic infections, tryptophan levels
decrease, because of the induction of IDO, and the
affected subjects become irritated and social interaction will be avoided actively, passively, or both.
Accordingly, tryptophan depletion may reduce the
con-specific spreading of an infectious agent. Humans treated with a pro-inflammatory interferon
also become more irritable, showing diminished
impulse control and symptoms of depression. Interferon treatment isof coursea non-natural condition, but is nevertheless similar to the infectious
state.
The possibility that low tryptophan and 5-HT
affects non-specificity various psychiatric conditions
may also be seen in the light of recent genetic
reports. For instance, Caspi and co-workers reported an association between a genetic polymorphism of the promoter gene of the 5-HT transporter
and the precipitation of depression following severe
life events (Caspi et al. 2003). The specific allele
was, however, not associated with the prevalence of
depressive disorder. Low 5-HT may aggravate
various underlying or existing psychopathologies.
We speculate that the psychopathology associated
with somatic disease is a remnant of the natural
reaction of an organism to immune activation, as
affected subjects avoid close inter-individual contact.
Thus, a consequence of alterations in cerebral 5-HT
transmission is a change of social behaviour.
Psychopharmacological implications
SSRIs have particularly been developed to modify
the cerebral 5-HT transmission and are among the
most prescribed drugs in depression. It may be
questioned what is the best indication for SSRIs.
Meta-analyses point to the modest efficacy of SSRIs
in depression (e.g., Moncrief and Kirsch, 2005)
suggesting that there is no firm aetiological relation
between 5-HT (deficiency) and depression. In
addition, antidepressants, including the SSRIs, are
used in a wide variety of psychiatric disorders and
conditions, including anxiety, phobia and pain (see
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Tryptophan-serotonin link
Introduction). Moreover, low 5-HT has been associated with apparently unrelated neuro-psychiatric
disorders. The conventional rationale for SSRIs is
that they are prescribed in disorders characterized by
low brain 5-HT. Taking into account the studies
reviewed, one indication for SSRIs should be disorders associated with low cerebral 5-HT and low
tryptophan availability. Psychiatric disorders due to
low tryptophan and/or responding to antidepressant
medication do not necessarily match present diagnostic systems. The consequence of our suggestion is
that if the indications of SSRIs were be limited to
conditions with low levels of brain 5-HT, it would
predict a better therapeutic response. Certain subgroups may be identified, in which SSRI treatment is
appropriate. For instance patients marked by tryptophan depletion, which has been observed, for
instance, in diseases accompanied by inflammatory
responses. Also in genetically susceptible individuals
5-HT-ergic drugs may be prescribed. Such patients
could be identified by tracing polymorphisms of the
5-HT transporter and TPH2. Furthermore, SSRIs
or tryptophan could be administered to improve
social interaction of for instance aggressive subjects.
This could help these subjects to implement new
coping strategies in their behavioural repertoire.
Indeed, tryptophan supplementation proved to be
useful in treating aggressive inpatients (Young and
Leyton 2002). In somatic patients suffering from the
behavioural consequences of increased tryptophan
catabolism, serotonergic medication may be appropriate (Musselman et al. 2001). It was recently
proposed to administer tryptophan to these patients
(Turner and Blackwell 2005). However, some caution has to be taken into account. Induction of the
tryptophan catabolic pathway releases several neurotoxic compounds such as quinolinic acid. In
rodents, brain quinolinic acid production is demonstrated after IDO induction but not under physiological circumstances (Saito and Heyes 1996).
Tryptophan supplementation might not be beneficial in circumstances of induced IDO activity. We
have, for instance, circumvented such risk by successfully applying mirtazepine to treat psychopathology of interferon-treated patients (Russo et al.
2003b). Finally, prescription of SSRI had positive
effects on social function in volunteers (Knutson
et al. 1998). Therefore, psychiatric patients could
benefit from these drugs, regardless of their diagnosis, because social functioning is an important
treatment issue in many patients. More emphasis on
the role of SSRIs in social functioning might also
contribute to the integration of pharmacological and
non-pharmacological treatment.
265
Final comments
The presently described evolutionarily conserved
tryptophan-5-HT link could have a function in
shaping adaptive behaviour. We have emphasized
that low brain serotonin levels per se do not
necessarily lead to a single psychiatric diagnostic
entity, as illustrated in Figure 2. The emergent
pathology may for instance depend on the duration
of low tryptophan levels. The behavioural effects of
acute low tryptophan levels, as studied with the
acute tryptophan depletion test, are likely to be
associated with current and/or underlying psychopathology. Lasting low tryptophan levels may ultimately evoke behaviour aimed at survival of
the organism. Such a hypothesis dissociates an often assumed deterministic relationship between
low serotonin and certain diagnostic categories, such
as anxiety and depression. We realize that the
present hypothesis does not take into account the
rich pharmacology of the cerebral 5-HT system,
considering the high number of 5-HT receptors, as
summarized in part here. So, specific receptor
blocking or activating agents could in addition refine pharmacological interventions. Central in
these considerations is the notion that cerebral 5HT neurons are regulated by a multitude of processes acting in parallel: there are the neuronal
inputs of higher centres, such as the cerebral cortex
and limbic areas, and, in addition, the here emphasized biosynthetic regulatory mechanisms. The
consequences of low serotonin depend in our
view primarily on the neuronal input and from
the information thus generated in these brain
centres, which intensity may-in addition be modulated by the composition of the diet.
Acknowledgements
We thank the following colleagues for their continuous support and contribution to the development
of our ideas J.C. Boon, MD, J.A. den Boer, MD,
PhD, E.G.E. de Vries, MD, PhD, P.H.B. Willemse,
MD, PhD and E.B. Haagsma, MD, PhD.
Statement of interest
The authors have no conflict of interest with any
commercial or other associations in connection with
the submitted article.
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