Psychiatry Research. 1, 219-224 (1979)
@ Elsevier/North-Holland
Biomedical Press
Central Serotonin
Depression
Herman
Metabolism
219
and Frequency of
M. van Praag and Sietse de Haan
Received June 1.5. 1979; revised version received September 5. 1979; acceptedseptember
24.1979.
Abstract.
Central
serotonin
(5hydroxytryptamine;
5-HT) metabolism can be
disturbed in a subgroup of patients with vital (endogenous, primary) depression.
Presumably these disturbances do not result from the depression and have a
predisposing rather than a causative relationship to it. This latter statement is
based on two observations. First, in a majority of patients, the 5-HT disturbances
persist after depression has abated. Secondly, 5-hydroxytryptophan seems to have
prophylactic value, in particular in patients with persistent abnormalities in central
5-HT metabolism. In this study we approached the hypothesis that 5-HT disturbances are a predisposing factor to the occurrence of depression from still another
perspective. If this hypothesis is correct, then depressive patients with persistent
5-HT disturbances should have higher frequencies of depression than depressive
patients without demonstrable 5-HT disturbances. This was indeed demonstrated.
The same was true for family members of probands
with low levels of 5hydroxyindoleacetic acid. No cerebrospinal fluid data are available for family
members. The reported findings strongly support the predisposition hypothesis.
Key Words. Depression, depression vulnerability,
serotonin metabolism.
depression frequency, central
Post-mortem
studies of the brains of suicide victims and cerebrospinal
fluid (CSF)
studies have revealed indications of a central deficiency of serotonin (5hydroxytryptamine; 5-HT) in certain types of vital depression with a unipolar or bipolar course
(Post and Goodwin,
1978; van Praag, 19774. Vital depression
is the syndrome
referred to in Anglo-American
literature as endogenous
or primary depression (van
Praag, 1978~). This category of depression
therefore includes patients with and
without a demonstrably
disturbed 5-HT metabolism.
For this reason, it has been
suggested that depressive subgroups
can be identified using biochemical
measures
(Asberg et al., 1976; Maas, 1975; van Praag and Korf, 1971; van Scheijenet al., 1977).
Disorders of 5-HT metabolism
probably
contribute
to the pathogenesis
of the
depression instead of being a result of its occurrence. This conclusion has been drawn
from a number of observations:
5-Hydroxytryptophan
(5-HTP), a 5-HT precursor, proved to be an effective antidepressant in patients with vital (endogenous,
primary) depression (Angst et al., 1977;
van Hiele et al., in press; van Praag, 1978~; van Praag et al., 1972; Sano, 1972), and
particularly
in those with a disturbed central 5-HT metabolism
(van Praag, 19776,
l
Herman M. van Praag, M.D., Ph.D., is Professor and Head, and Sietse de Haan, Ph.D., is Statistician,
Department of Psychiatry, University Hospital Utrecht, Nicolaas Beetsstraat 24, Utrecht, The Netherlands.
(Reprint requests to Professor van Praag.)
220
1978b; van Praag et al., 1972). We have demonstrated
that patients with a disturbed
central 5-HT metabolism
are able to convert 5-HTP to 5-HT in the brain, and in fact
do so (van Praag 1977~). A 5-HTP effect, per se, is therefore unlikely.
The antidepressant
effect of 5-HTP is enhanced
antidepressant
that strongly inhibits 5-HT reuptake and
bility of 5-HT at the postsynaptic receptors) (van Praag,
Therefore,
we consider it unlikely that suppression
underlies the therapeutic effect of 5-HTP. Suppression
could occur, since 5-HTP can be transformed
to 5-HT
and could act as a false transmitter.
l
by clomipramine
(a tricyclic
therefore increases the availa19786; van Praaget al., 1974).
of catecholaminergic
activity
of catecholaminergic
activity
in catecholaminergic
neurons
In normal subjects, 5-HTP (administered
by intravenous
(Puhringe et al., 1976; Trimble et al., 1975).
l
l In patients
disinhibition,
treated with 5-HTP
has been described
drip) has a euphoric
for myoclonus, evidence of euphoria,
as well (van Woert et al., 1977).
effect
even of manic
In the majority of patients, the signs of central 5-HT deficiency persist during
symptom- and medication-free
intervals (van Praag, 1977~). This finding suggests that
the suspected central 5-HT deficiency is not so much a causal as a predisposing factor.
Corroboration
of the predisposition
hypothesis is seen in the prophylactic
effect of
5-HTP in unipolar and bipolar vital depressions, especially in patients with signs of a
central 5-HT deficiency (van Praag, 1977c, 19786). 5-HTP prophylaxis
is the first
aimed (i.e., biochemical substrate-oriented)
chemoprophylaxis
known in psychiatry.
Buchsbaum et al. (1976) had meanwhile described a second biochemical factor that
increases the risk of manifestations
of depression (and other psychiatric disorders):
diminished activity of the enzyme monoamine
oxidase (MAO) in the blood platelets.
The risk of psychiatric morbidity was increased in persons with low platelet MAO
activity and also in members of their families. We carried out a similar study to test the
hypothesis that central 5-HT deficiency increases vulnerability
to depression. In this
study, we compared the frequency of depression in patients with and without persistent disorders of central 5-HT metabolism,
and in their relatives. If our vulnerability
hypothesis was correct, these frequencies should be higher in the subgroup deficient in
5-HT.
Methods
Since 1969 we have studied 54 depressive patients who fulfilled the following criteria:
They (1) had been hospitalized
with a vital depression
and (2) had a subnormal
concentration
of 5-hydroxyindoleacetic
acid (5-HIAA) in the CSF after administration of probenecid.
In 33 of these 54 patients the 5-HIAA accumulation
remained
subnormal
after symptoms subsided and throughout
a medication-free
period of at
least 3 weeks’ duration.
These patients were studied further as the “subnormal
5HIAA group.”
Probenecid inhibits the active transport of 5-HIAA from the central nervous system
(CNS) to the blood stream. The resulting accumulation
of 5-HIAA in the CSF is an
221
indication
of the turnover of the parent substance 5-HT in the CNS. A decreased
5-HIAA accumulation
suggests a decreased 5-HT turnover. The probenecid test has
been described in detail elsewhere (van Praag, 19774. The 5-HIAA accumulation
was
considered subnormal when the value measured was below the lower limit found in the
control group (van Praag et al., 1973). 5-HIAA was determined by the autoanalyzer
method (Korf et al., 1973).
During the same period we studied 69 other patients, likewise hospitalized with a
vital depression but with a normal postprobenecid
5-HIAA accumulation
in the CSF,
both during the depressive phases and during the symptom- and medication-free
intervals. The 33 patients with the highest 5-HIAA values were studied further as the
“normal 5-HIAA group.”
Table 1 lists some biographical and diagnostic data on the patients in the subnormal
and the normal 5-HIAA groups. In both groups, we first of all determined the number
of hospitalizations
with depression, mania, or other psychiatric disorders. These data
were obtained in focused interviews with the patients and one or more relatives, and
were verified by information
requested from the relevant psychiatric
institutions.
Interviewers
were blind to the CSF 5-HIAA values. Secondly, we established how
many relatives of these patients had been hospitalized
once or several times with
depression, mania, or other psychiatric disorders. For this purpose, we interviewed the
patients and at least one relative. If possible, these data were verified by information
requested from the relevant psychiatric institutions.
The history taking was aimed at
the following relatives of the patient: parents, grandparents,
and siblings. There were
297 relatives in the subnormal
5-HIAA group and 337 relatives in the normal 5-HIAA
group.
No reliable data could be obtained on (successful) suicides, which are therefore
excluded from this discussion.
Table 1. Biographical
and diagnostic
data
Subnormal
S-HIAA group
Normal
S-HIAA group
Males
12
14
Females
21
19
Mean age
52
49
37-62
34-64
Sample characteristics
Age range
First depressive
Unipolar
Bipolar
phase
vital depression
9
18
19
10
vital depression
Mean postprobenecid
5-HIAA f SD
5
CSF
39 ? 10.3
5
139 k 36.7
Results
The number of hospitalizations
for depression
in the subnormal
5-HIAA group
significantly
exceeded that in the normal 5-HIAA group @ < 0.002; Tables 2 and 3).
Age of onset did not account for the differences in the number of admissions for
222
depression. The number of hospitalizations
for mania and other psychiatric disorders
did not differ significantly
(Table 2).
In the subnormal
5-HIAA group, the admission frequency for depression among
relatives of the patients was about twice as large as that in the normal 5-HIAA group
@ < 0.001; Table 4). The number of hospitalizations
for mania and other psychiatric
disorders did not differ significantly
(Table 4).
Table
2. Psychiatric
morbidity
Subnormal
S-HIAA group
(n = 33)
Normal
S-HIAA group
(n = 33)
For depression1
89
61
For mania
19
10
7
6
Number of admissions
For other psychiatric
conditions
1. p < 0.002.
Table
3. Frequency
of admissions
for depression
Number of admissions
per patient
1
Patient groups
Subnormal
Normal
5-HIAA
5-HIAA
1. The number
cantly exceeds
tailedl.
Table
group
group
2
3
5
9
12
9
20
4
4
5
-
Total number
of admissions
5
2
891
-
61
of hospitalizations
for depression in the subnormal 5-HIAA group signifithat in the normal 5-HIAA group (p < 0.002. Mann-Whitney
U-test; two-
4. Psychiatric
morbidity
in probands’
relatives
Number of admissions
to psychiatric institutions
Reason for admission
Subnormal
5-HIAA group
Normal
5-HIAA group
138
67
Mania
37
42
Alcoholism
26
18
Other psychiatric
conditions
24
16
Depression1
1. Relatives of low 5-HIAA probands
depression
than relatives of normal
Whitney U-test; two-tailed).
had significantly
more admissions for
5-HIAA probands
(p < 0.001, Mann-
223
Discussion
Previous investigations
led us to the conclusion
that the alleged central 5-HT deficiency in the CNS of a group of patients with vital depression is less a direct causal than
a predisposing
factor. This conclusion was based on the trait-character
of the S-HT
disturbances
and the prophylactic value of 5-HTP, in particular in the 5-HT deficient
subgroup. 5-HTP is a 5-HT precursor, readily converted to 5-HT in the brain, partly in
serotonergic
neurons.
The present investigation
was designed to explore further the predisposition
hypothesis. If a persistently subnormal
CSF 5-HIAA concentration
is associated with
increased vulnerability
to depressions,
the depression frequency in the subnormal
5-HIAA group would be expected to exceed that in the normal 5-HIAA group-as
indeed was demonstrated.
Depression frequency in the subnormal 5-HIAA group was
increased relative to that in the normal 5-HIAA group. The persistent disorders ofthe
central 5-HT metabolism seemed more or less specifically related to the development
of depressions,
and did not represent a general factor that reduces resistance to any
psychiatric disorder.
The frequency of depression was determined
by interviewing
patients and some
relatives. It is well known that reports on previous hospitalizations
are often not very
reliable, and that they tend to omit previous hospitalizations
rather than to report
hospitalizations
that did not occur. There is, however, no reason to believe that the
two groups should differ in this respect.
The data reported support the hypothesis that: (1) Central serotonergic systems are
involved in mood regulation;
(2) persistent disorders of the central 5-HT metabolism
increase vulnerability
to depression-that
is, increase the risk that an individual will
respond to threatening
stimuli from the outer and inner world with a pathological
depression of mood.
The fact that the frequency of depression is also increased in relatives of patients in
the 5-HT-deficient
subgroup of vital depression raises the question of the familial
occurrence of these metabolic disorders. We also have some indications of a familial
factor, but as yet no certainty.
It might be assumed that the decreased platelet MAO activity found by Buchsbaum
et al. (1976) manifests itself centrally as well, and that this phenomenon
is related to the
symptoms of 5-HT deficiency described here. There are at least two possible ways of
explaining this hypothesized relationship:
(1) The suspected central 5-HT deficiency is
the primary disorder, and decreased MAO activity is a compensatory
mechanism. (2)
The decreased MAO activity is the primary disorder, and the 5-HT metabolism
is
secondarily
suppressed to avoid relative overproduction.
Both possibilities
are, of
course, highly speculative. The next question to be investigated is whether persistently
subnormal
CSF 5-HIAA values and decreased MAO activity occur in combination.
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