the serotonin hypothesis of major depression
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The Serotonin Hypothesis of Major Depression
Michael Maes and Herbert Y. Meltzer
INTRODUCTION
The serotonin (5-HT) hypothesis of major depression has been formulated in threedistinct ways. One version of this hypothesis is that a deficit in serotonergic activity is a
proximate cause of depression. A second theory is that a deficit in serotonergic activity is
important as a vulnerability factor in major depression. A third hypothesis, now of
historical interest only, attributed increased vulnerability to major depression to enhancedserotonergic activity (51).
The last review of these hypotheses in this series (51) concluded that the available data on
the role of 5-HT in major depression favored the hypothesis that a deficiency in brainserotonergic activity increases vulnerability to major depression. This review (51)
summarized the following evidence: (a) Disorders in serotonergic activity couldcontribute to many of the symptoms of major depression, for example, mood, appetite,
sleep, activity, suicide, sexual, and cognitive dysfunction. (b) Interference with 5-HT
synthesis or storage may induce depression in some vulnerable individuals. (c)Abnormalities in serotonergic activity in depression could occur at one or more of several
levels, for example, diminished availability of L-tryptophan (L-TRP), the precursor of 5-
HT, impaired 5-HT synthesis, release, reuptake, or metabolism, or 5-HT postsynaptic
receptor abnormalities. (d) Finally, antidepressant drugs may act, in part, by enhancingcentral serotonergic activity.
Since that review, there have been numerous developments shedding further light on therole of 5-HT in depression. This chapter reviews the highlights of serotonergic research in
major depression since 1987, aiming to elucidate the role of 5-HT activity in the
pathogenesis or pathophysiology of that illness. Because of limitations on references,secondary sources were frequently cited and some sources were left out entirely (see
Serotonin and Behavior: A General Hypothesis and Indoleamines: The Role of Serotonin
in Clinical Disorders).
This chapter discusses new findings on the role of 5-HT in the pathogenesis or
pathophysiology of major depression and the mechanism of action of antidepressant
drugs. Clinical studies of 5-HT metabolism in major depression that provide evidence foran abnormality of the 5-HT system are reviewed. New evidence that the availability of L-
TRP, the rate-limiting step in the synthesis of 5-HT, is an important factor in the
pathophysiology of depression and the response of antidepressant drugs are discussed.The evidence for abnormalities in the 5-HT uptake system in major depression as well as
abnormalities in some of the numerous types of postsynaptic 5-HT receptors are
reviewed. The 5-HT1A and 5-HT2 postsynaptic receptors appear to be of particular
importance. Cooperative and competitive interactions may be important to the function of
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the 5-HT system and abnormalities in this regard are possible factors in the
pathophysiology of major depression. The function of these postsynaptic receptors in
depression has been assessed with a variety of pharmacological probes as well aspostmortem studies. The evidence that antidepressants may act via their long-term ability
to modulate pre- and postsynaptic serotonergic function is discussed. The important
relationships between serotonergic activity and the hypothalamic pituitaryadrenal(HPA) axis are reviewed. The possibility that disorders in the functional relationships
between both systems and gender differences in 5-HT function may be involved in the
pathophysiology of major depression are also discussed. Finally, the importance ofstudying interactions among 5-HT and other neurotransmitter systems in depression is
stressed. Indeed, it seems doubtful that any one neurotransmitter is entirely responsible
for the pathogenesis or pathophysiology of depression because of the extensive
interactions between neurotransmitters at the levels of cell bodies as well as terminalregions. Nevertheless, 5-HT appears to be the most important monoamine relevant to the
pathophysiology of depression and the action of antidepressant drugs (see Molecular
Biology of Serotonin Receptors: A Basis for Understanding and Addressing Brain
Function, Serotonin Receptor Subtypes and Liagands, Serotonin Receptors: SignalTransduction Pathways, Anatomy, Cell Biology, and Maturation of the Serotonergic
System: Neurotrophic Implications for the Actions of Psychotropic Drugs,Electrophysiology of Serotonin Receptor Subtypes and Signal Tranduction Pathways,
Serotonin and Behavior: A General Hypothesis, and Indoleamines: The Role of Serotonin
in Clinical Disorders, for related discussion and background).
THE AVAILABILITY OF L-TRYPTOPHAN
Total or free L-TRP and the ratio of L-TRP to the sum of competing amino acids (CAA),known to compete for the same cerebral uptake mechanism, provide measures of the
availability of L-TRP to the brain and hence for 5-HT synthesis in the brain (42). There
are several reports that plasma L-TRP availability is significantly lower in subjects withmajor depression than in normal controls or subjects with minor depression (42, 51). The
data suggest that a lower plasma L-TRP/CAA ratio in depression is related to decreased
concentrations of plasma L-TRP rather than to increases in CAA (42). Plasma L-TRPlevels following ingestion of large oral doses of L-TRP or intravenous L-TRP have been
reported to be lower in depressed patients (15, 28).
One hypothesis to explain lower plasma L-TRP concentrations and altered L-TRPpharmacokinetics in depression is enhanced catabolism of L-TRP in the liver by
induction of pyrrolase, the first rate-limiting enzyme of the kynurenine-nicotinamide
pathway (39). The activity of this pathway can be quantified by measuring 24-hr urinaryexcretion of xanthurenic acid after loading with 5 g of L-TRP (25, 39). In depression, L-
TRPinduced xanthurenic acid excretion was significantly and negatively related to
plasma L-TRP concentrations (39). The above findings lend support to the hypothesis thatincreased activity of this pathway may contribute to the lower plasma L-TRP
concentrations and increased clearance in major depression (39).
Recent studies suggest that a reduction of dietary L-TRP can induce depressive
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symptomatology under some circumstances. In normal men, lowering of plasma L-TRP
by dietary means has been reported to cause an acute lowering of mood, which was
inversely related to postingestion plasma L-TRP levels (75). In recently remitteddepressed patients receiving selective 5-HT reuptake inhibitors (SSRIs), acute L-TRP
depletion coupled with ingestion of large concentrations of CAA led to a rapid clinically
significant return of depressive symptoms, such as depressed mood, terminal insomnia,decreased appetite, loss of energy, loss of interest, anhedonia, decreased concentration,
ruminative thinking, and a sense of worthlessness (16, 23). Remitted depressed patients
maintained with tricyclic antidepressants, however, were less prone to a depressiverelapse following L-TRP depletion. Because SSRIs enhance central presynaptic 5-HT
activity (see the section below on neuroendocrine probes and antidepressive treatments),
the findings strongly suggest that the synthesis of 5-HT from plasma L-TRP is necessary
for the maintenance of remission induced by those drugs. Decreased plasma L-TRPconcentrations are most likely related to lower central presynaptic 5-HT activity, because
diets causing a decrease in plasma L-TRP availability also reduce cerebrospinal fluid
(CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA) in humans. Therefore, the
behavioral and cognitive changes observed may be due to a deficiency in centralpresynaptic 5-HT elements, which may result from lower plasma L-TRP availability. The
above results are consistent with the findings that anorexia, anergy, sleep disorders,cognitive disturbances, and depressed mood are psychopathological correlates of lowered
L-TRP availability in depression (43). However, it is noteworthy that unmedicated
depressed patients do not worsen following L-TRP depletion. The lack of worsening byfurther interference with 5-HT synthesis may suggest that decreased serotonergic activity
is not the limiting factor in the severity of depression in untreated major depression. This
is consistent with the hypothesis of diminished serotonergic activity as a vulnerability
factor in depression.
Mller et al. (56) reported that the plasma ratio of L-TRP/CAA was inversely related to
the response to antidepressive treatment, such as L-TRP, imipramine, amitryptiline, andlithium + L-TRP, and that major depressed subjects with lower L-TRP availability
responded preferentially to treatment with SSRIs, such as citalopram and paroxetine.
These results suggest that (a) plasma L-TRP availability may influence the therapeuticresponse to antidepressive treatment and may predict a favorable response to SSRIs; (b)
lower plasma L-TRP availability may be related to lower central 5-HT activity; and (c)
that antidepressive treatment with serotonergic drugs (L-TRP, L-TRP + lithium, SSRIs)
may compensate for this deficit.
INDICES OF PRESYNAPTIC SEROTONERGIC NEURON FUNCTION
Blood Platelets
Blood platelets are able to take up, store, and release 5-HT by mechanisms that aresufficiently similar to those of central 5-HT neurons to render platelets a model for the 5-
HT neuron (50). Several dozen studies of platelet 5-HT uptake in major depression have
been published between 1971 and 1992; approximately 65% to 75% have reported
significantly lower Vmax values in patients with major depression than in normal
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controls (50). However, studies on platelet 5-HT uptake lack specificity and sensitivity
for clinical use on their own. The question of whether lower platelet 5-HT uptake
indicates lower 5-HT uptake in the brain remains elusive.
There are now several reports on lower imipramine binding (Bmax) in platelets of
depressed patients compared to normal controls (50). However, 3[H]imipramine bindingis rather heterogeneous since this substance labels two separate binding sites: one high-
affinity binding site that corresponds to the 5-HT uptake site and one low-affinity site that
is unrelated to the 5-HT transporter (49). Paroxetine is a potent and selective inhibitor of5-HT uptake in platelets and brain. Paroxetine is a superior ligand for labeling the 5-HT
transporter in both platelets and brain compared to imipramine, because 3[H]paroxetine
labels the 5-HT transporter more selectively than does 3[H]imipramine, while exhibiting
a higher affinity (49). Several groups were unable to find significant differences inplatelet paroxetine binding between depressed patients and controls (31).
5-Hydroxyindoleacetic Acid in Cerebrospinal Fluid
Concentrations of 5-HIAA, the major 5-HT metabolite, in CSF have been extensively
studied in depressed subjects, both in basal conditions and after blockade of itsreabsorption by probenecid treatment (51). Meltzer and Lowy (51) concluded that it is
very difficult to draw any valid conclusions on 5-HT turnover in depression on the basis
of CSF 5-HIAA data. Several papers published after their 1987 review were also unableto find significant differences in CSF 5-HIAA between major depressed subjects and
normal controls (63). In fact, there is more evidence that low CSF 5-HIAA levels are
related to (violent) suicidal behavior and to violence-impulsivity rather than to depression
per se (17).
Plasma or Platelet Serotonin Contents
The possibility that peripheral abnormalities in 5-HT metabolism occur in melancholic
patients has been further investigated by the study of the 5-HT content of plasma and
platelets. Platelet 5-HT is considered to represent a reserve pool of peripheral 5-HT (64).Plasma 5-HT has a turnover rate considerably higher than the platelet pool and represents
the equilibrium between 5-HT secretion, 5-HT catabolism (by monoamine oxidase
enzyme activity in liver and lung), and platelet uptake mechanisms (64). Lowered plasma
and platelet 5-HT contents in depression have been reported by several groups (64).Celada et al. (7) reported that chronic treatment with fluvoxamine decreased platelet 5-
HT content and that responders had significantly lower platelet 5-HT content
pretreatment. These authors suggest that SSRIs may be most useful in patients with lowplatelet 5-HT. The significance of the above findings for central serotonergic activity is
unknown.
Indices of Serotonin Presynaptic Function Obtained from Postmortem Samples
Reports of 5-HT and 5-HIAA concentrations in the brain of suicide victims have yielded
conflicting results: some found decreased levels or no changes in 5-HIAA concentrations
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in the brain of depressed suicides, whereas others reported increased 5-HIAA levels in the
hippocampus or amygdala of (depressed) suicide victims (10). Taken together, the above
results offer little support that 5-HT turnover is reduced in depressed subjects who havecommitted suicide. Moreover, the effect of drug treatments, substance abuse,
glucocorticoid elevations, and receptor sensitivity alterations make it difficult to interpret
the results.
Brain Serotonin Uptake Transporter
Some, but not all, groups described a reduction in imipramine binding in the frontal
cortex of suicides (20). The latter group also found an increase in imipramine binding
sites in the hippocampus of suicide victims. No significant differences in paroxetine
binding sites of several brain areas could be detected between normal controls and suicidevictims in whom a diagnosis of depression was made (30). Leake et al. (32) found lower
3[H]citalopram binding in the brains from depressed subjects.
POSTSYNAPTIC SEROTONIN RECEPTORS
5-HT2 Receptors
Three studies of 5-HT2 binding in the blood platelets of depressed patients and normal
controls, found increased 5-HT2 binding (Bmax) in the former, but one study did not (2).Increased 5-HT2 binding (Bmax) in depressed patients is also supported by the increased
5-HT2 receptor functional response as measured by phosphoinositide turnover and 5-HT
induced platelet aggregation (55). Mikuni et al. (55) reported that the effects of 5-HT to
increase intracellular calcium in platelets was greater in depressed patients than incontrols, which is consistent with the hypothesis of 5-HT2 receptor up-regulation in
depression.
A new and original method to assess central 5-HT2 function is the assessment of slow-
wave sleep (SWS) after challenge with 5-HT2 receptor antagonists. Blockade of 5-HT2
receptors is normally accompanied by an increase in SWS (69). Sharpley et al. (67) foundthat the normal increase in SWS following treatment with cyproheptadine, a nonspecific
5-HT receptor antagonist, was absent in major depressed patients maintained on tricyclic
antidepressants. Staner et al. (69) found that ritanserin enhanced SWS stage 3 in normal
controls and depressed subjects, but the latter group showed significantly lower SWS instage 4. These findings are consistent with 5-HT2 receptor up-regulation in patients with
major depression (69).
There are now several reports of increased 5-HT2 receptor-binding sites in the frontal
cortex of (depressed) suicide victims or depressed subjects who died from natural causes
(1, 2). Other laboratories found a trend toward or a significant decline in 5-HT2 bindingin membrane homogenates from the prefrontal cortex of suicide victims (11). However,
differences among the above studies may be due to drug effects (treatment with
antidepressants and antipsychotic agents reducing 5-HT2 binding), use of different
ligands, the postmortem interval, or the heterogeneity of psychiatric illnesses (e.g.,
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schizophrenia, alcoholism) and personality (e.g., borderline and antisocial) disorders
associated with suicide.
5-HT1 Receptors
Increased 5-HT1A binding in the prefrontal cortex of nonviolent suicides compared toviolent suicides and controls has been reported (48). Several other studies reported no
significant differences in the number or affinity of 5-HT1 binding sites in the frontal or
temporal cortex between drug-free depressed suicide victims and controls (12). Thenumber of 5-HT1 binding sites was significantly lower in hippocampus, whereas the
affinity of 5-HT1 binding sites was significantly lower in the amygdala (12). These
results may provide some evidence of increased cortical 5-HT1 receptors in (depressed)
suicides, and decreased density of 5-HT1 receptors in the hippocampus and amygdala ofdepressed subjects. These findings need to be further explored using more specific
ligands, autoradiography, and with attention to variables such as type and severity of
depression, concomitant alcoholism or other drug abuse, the effects of suicide per se, and
so on.
THE NEUROENDOCRINE STRATEGY
One strategy to assess central serotonergic neurotransmission in vivo is the measurement
of HPA-axis hormone, prolactin, growth hormone, and other responses following theadministration of 5-HT precursors and direct or indirect 5-HT agonists (38, 54). Secretion
of these hormones is, in part, regulated by 5-HT inputs, and their responses to the acute
administration of 5-HT agents are mediated at least in part by 5-HT mechanisms (54).
There is strong evidence suggesting that 5-HT1A, 5-HT1C, and 5-HT2 receptors may
stimulate cortisol and prolactin secretion in man (52). Various neuroendocrine (behavioral
and electrophysiological) studies with 5-HT agonists and antagonists have providedevidence for important interactions between 5-HT1A and 5-HT2/1C receptors (52). In
rats, there is some evidence that 5-HT2/ 5-HT1C receptors may modulate 5-HT1A-
related behaviors. 5-HT1A receptors may provide inhibitory effects on 5-HT2 receptor-mediated functions. These findings suggest the possibility of a signal transduction from
5-HT1C/5-HT2 to 5-HT1A receptors in the expression of 5-HT1A-mediated behaviors,
together with an inhibitory effect of 5-HT1A receptors on 5-HT2-mediated functions.
Cooperation among those receptors has important implications for the interpretation ofneuroendocrine challenge studies with serotonergic agents (52). In particular, our
laboratory has provided some evidence that blunted prolactin responses to challenge with
5-HT precursors or agonists may be due to diminished 5-HT1A or 5-HT1C/5-HT2receptor sensitivity, whereas enhanced cortisol responses might be from increased
sensitivity of 5-HT1C/2 receptors which would be unaffected by 5-HT1A receptor
subsensitivity (52).
5-HT1A Agonists
Ipsapirone administration significantly increases HPA-axis hormone secretion in normal
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men and rodents (34). Major depressed subjects show blunted HPA-axis hormone
[adrenocorticotropic hormone (ACTH) or cortisol] responses following ipsapirone
challenge compared to normal controls (34; also Meltzer and Maes, unpublished).Therefore, these attenuated responses may be interpreted to indicate that major
depression is characterized by a down-regulation or hyporesponsivity of postsynaptic 5-
HT1A receptors.
Buspirone is another azapirone which is a partial agonist at 5-HT1A receptors; its acute
administration evokes dose-related HPA-axis and prolactin responses (53). The prolactinresponse is blocked by pindolol, suggesting it is 5-HT1A-mediated. Our laboratory found
no significant differences in buspirone-induced cortisol or prolactin responses between
major depressed subjects and normal controls. The reason for the discrepancy between
the cortisol responses to ipsapirone and buspirone in major depression requires furtherstudy. It is possible that differences in the intrinsic activity as partial 5-HT1A agonist may
be relevant. It is likely that the prolactin response to buspirone is mediated by DA2-
receptor blockade rather than 5-HT1A agonism. Further efforts to employ buspirone-
induced cortisol or prolactin responses as probes of 5-HT1A function in depressionappear to be of limited value.
Precursors of Serotonin
Intraperitoneal or oral administration of high doses of 5-HT precursor (5-HTP) causes amarked increase in corticosterone secretion in rodents, whereas the effects of oral 5-HTP
on HPA-axis hormone secretion in humans are somewhat more variable in studies using
lower doses of the racemic mixture (D, L) and/or enteric coated tablets (52). There is now
evidence that 200 mg L-5-HTP, in nonenteric coated tablets, reliably stimulates HPA-axishormones and prolactin secretion in normal humans, and that 5-HTP-induced activation
of both HPA-axis and prolactin secretion are probably related to 5-HT mechanisms (52).
Significantly higher 5-HTP (D, L: 200 mg; L: 125 to 200 mg) -induced cortisol responseswere observed in major depressed subjects than in normal controls or minor depressed
subjects (38, 54). The use of 5-HTP as a 5-HT probe was challenged, because
administration of very high doses of 5-HTP in rodents may lead to 5-HT synthesis incentral catecholaminergic neurons and may increase synthesis of catecholamines (73).
The dose of L-5-HTP used in human studies, however, is much lower than that needed to
increase catecholamine turnover in animal studies. Because 5-HT1A postsynaptic
receptors are probably down-regulated in major depression, the above findings may beexplained either by supersensitive 5-HT2 or 5-HT1C receptors. Since several types of
studies (reviewed here) indicate increased 5-HT2 receptor binding or disorders in 5-HT2
related behaviors in major depression or suicide, whereas there is no specific evidence asyet for 5-HT1C receptor supersensitivity in depression, it may be suggested that the
results of the studies with 5-HTP as challenger are compatible with up-regulation or
supersensitivity of 5-HT2 postsynaptic receptors (52).
Administration of L-TRP reliably increases prolactin secretion (58). Several papers
reported blunted prolactin responses to intravenous L-TRP in depression (15, 28). The
blunted prolactin responses to L-TRP may reflect abnormalities in the synthesis of 5-HT
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from L-TRP, its release or reuptake, or decreased responsivity of postsynaptic 5-HT
receptors that may mediate the serotonergic influence on prolactin secretion (e.g., 5-
HT1A postsynaptic receptors). There is as yet no evidence from studies with direct-acting5-HT agonists for a blunted prolactin response in depression.
Higher doses of L-TRP also increase corticosterone secretion in rodents (18). Ourlaboratory has reported significantly increased 24-hr urinary free cortisol (UFC) secretion
in melancholic subjects than in normal controls or minor depressed patients after loading
with L-TRP (2 or 5 g orally) (46). This finding is consistent with hyperresponsivity of 5-HT2 postsynaptic receptors.
However, the use of L-TRP as a 5-HT probe was challenged: (a) One study found that,
after controlling for differences in L-TRP plasma concentrations, the differences inprolactin responses between depressed subjects and normal controls disappeared (28).
Thus, blunted TRP-induced prolactin responses, in fact, may result from disorders in L-
TRP disposition in major depression. (b) L-Tryptophan may be acting nonspecifically,
that is, not via 5-HT (73). Indeed, administration of 2 to 5 g of L-TRP significantlydecreased various indices of catecholaminergic turnover (26, 46, 73). This may be
explained by the capacity of L-TRP to decrease L-tyrosine availability to the brain andthe transport of tyrosine through the bloodbrain barrier, which may cause a decrease in
brain noradrenergic turnover (46). (c) Finally, administration of L-TRP produces only
small increases in 5-HT formation but very important increments in metabolites of thenicotinamide pathway, which may exert pharmacological actions (26, 27).
Indirect and Direct Serotonin Agonists
D,L-Fenfluramine promotes a rapid release of 5-HT, inhibits its reuptake, and may
function as an indirect 5-HT receptor agonist. In rats and humans, D,L-fenfluramine
produces a dose-dependent increase in prolactin secretion. Most but not all laboratories(36, 41) have reported significantly blunted D,L-fenfluramine-induced prolactin
responses in major depressed subjects compared with controls. However, because the L-
isomer may block striatal DA receptors and increase DA turnover, a combination ofserotonergic and dopaminergic effects could account for blunted D,L-fenfluramine
induced prolactin responses in major depression (58).
D-Fenfluramine stimulates the serotonergic system more specifically than the racemicmixture; D-fenfluramineinduced prolactin secretion may be mediated via 5-HT1A
receptors as well as 5-HT2/5-HT1C receptors. Maes et al. (41) were unable to detect any
significant differences in postD-fenfluramine (45 mg orally) prolactin responsesbetween healthy controls and major depressed subjects. O'Keane and Dinan (60), on the
other hand, found that plasma prolactin responses after D-fenfluramine (30 mg orally)
were significantly lower in major depressed patients than in control groups. Inconclusion, there is some agreement that prolactin responses to D,L- and D-fenfluramine
administration may be blunted in major depressed subjects compared to normal controls.
These findings could be explained by a combination of decreased availability of 5-HT,
increased inactivation or diminished 5-HT1A postsynaptic receptor sensitivity.
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The clomipramine probe assesses central 5-HT activity through the assay of prolactin
responses following acute, intravenous challenge with clomipramine. There are nowseveral publications reporting blunted clomipramine-induced prolactin responses in major
depressed subjects compared to healthy controls (19). Blunted prolactin responses to
clomipramine are not attributable to diminished prolactin secretory capacity in anteriorpituitary, because prolactin responses to thyrotropin-releasing hormone, which acts
directly on the pituitary to release prolactin, were normal in those patients. In conclusion,
the clomipramine-challenge findings are in agreement with the blunted prolactinresponses after challenge with L-TRP, D,L-fenfluramine, or D-fenfluramine.
SEROTONIN AND ANTIDEPRESSIVE TREATMENTS
Neuroendocrine Probes in Relation to Antidepressive Treatments
Enhanced prolactin responsivity to TRP challenge has been found following various
antidepressive treatments, for example, amitriptyline, desipramine, fluvoxamine,clomipramine, tranylcypromine, and tricyclics with lithium (9). Fenfluramine-induced
prolactin responses were significantly increased following therapy with imipramine,clomipramine, and amitryptiline or fluoxetine (61). Electroconvulsive therapy may or
may not (61) enhance the prolactin responses to fenfluramine. Prolactin responses to
clomipramine were significantly enhanced by short-term lithium treatment. Shapira et al.(66) and Upadhyaya et al. (72) provided some evidence that this enhancement of
serotonergic function by antidepressive treatments represents a true correction of an
underlying serotonergic deficit and not a continued effect of antidepressant treatment or a
manifestation of medication withdrawal. In conclusion, it appears that variousantidepressive treatments share the capacity to enhance central pre- or postsynaptic 5-HT
activity.
Effects of Antidepressive Treatments at 5-HT2 Receptors
Several studies have shown that long-term treatment with tricyclic antidepressants ormonoamine oxidase inhibitors leads to down-regulation in the number of 5-HT2 receptor
binding sites in the brains of rodents (13). A further observation is that the time course of
this 5-HT2 receptor down-regulation following antidepressive treatment is similar to that
of clinical response in depressed patients. Some, but not all (e.g., citalopram) SSRIsproduce adaptive changes that manifest themselves by a decreased responsiveness of 5-
HT2 receptors (35). Chronic treatment with 5-HT1A agonists also may induce 5-HT2
receptor down-regulation (35). Electroconvulsive therapy, on the other hand, has beenshown to increase the number of 5-HT2 binding sites in the brain (33). Most
antidepressive drugs reduce 5-HT2 receptor mediated behaviors in the rodent (e.g., head-
twitch response), whereas electroconvulsive therapy may increase 5-HT2-relatedbehavior (13). One study has shown that increased 5-HTPinduced cortisol responses in
depressed patients were normalized after chronic antidepressive treatment (54). It may be
argued that the above effects of antidepressives on 5-HT2 receptors are probably due to
rapid desensitization or down-regulation following agonist stimulation or to the 5-HT2
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receptor-blocking properties of some antidepressive drugs (35).
Effects of Antidepressive Treatments at 5-HT1A Receptors
Effects of antidepressive treatments on 5-HT1receptor binding or functioning are rather
conflicting. Chronic treatment with some monoamine oxidase inhibitors, SSRIs, typicalantidepressants or electroconvulsive therapy may decrease 5-HT1 binding sites,
responsiveness of 5-HT1A presynaptic receptors, or 5-HT1A postsynaptic receptor-
mediated behaviors (47, 70). Hayakawa et al. (22) found that repeated treatment withelectroconvulsive therapy causes an upregulation of postsynaptic 5-HT1A receptors in the
hippocampus. Chronic treatment with desipramine or amitryptiline resulted in a
functional up-regulation of 5-HT1A-receptor-mediated behaviors in rats or increased
postsynaptic 5-HT1A receptor binding in the hippocampus (37, 74).
Electrophysiological Changes in the 5-HT System Induced by Antidepressive Treatments
Blier and colleagues (3) have thoroughly investigated the effects of short- and long-termtreatment with various antidepressants on pre- and postsynaptic electrophysiological
properties of 5-HT neurons. Long-term treatment with tricyclic antidepressants andelectroconvulsive therapy appears to increase the sensitivity of postsynaptic 5-HT
receptors, although no long-term effects on basal firing rate or autoreceptor-induced
inhibition of 5-HT turnover are observed. Postsynaptic sensitization to 5-HT occursprobably in the hippocampus, suprachiasmatic nucleus, and somatosensory cortex (3).
Blier et al. (3) have provided some evidence that this postsynaptic sensitization to 5-HT
is, at least in part, attributable to the increased number of 5-HT1A binding sites in the
hippocampus, cerebral cortex, and septum. Moreover, the time course for developingsensitization to 5-HT is consistent with the delayed activity of tricyclic drugs in relieving
the symptoms of depression (3). Administration of monoamine oxidases and SSRIs
appear to enhance 5-HT release per impulse from desensitization of the terminalautoreceptor (probably the 5-HT1B in rodents or the 5-HT1D receptor in humans). In
conclusion, rodent studies indicate that various antidepressive treatments induce a gradual
development of increased 5-HT activity; the mechanisms by which this enhancement isachieved may be different for these treatments.
RELATIONSHIPS BETWEEN SEROTONIN AND HYPOTHALAMICPITUITARY
ADRENAL AXIS FUNCTION IN MAJOR DEPRESSION
HypothalamicPituitaryAdrenal Axis Hyperactivity in Major Depression
Increased activity of the HPA-axis has been consistently reported in severe depression.
There is converging evidence from various studies that major depression is characterized
by a moderately increased spontaneous HPA-axis function and by a failure to suppressplasma intact ACTH (the 139 sequence) and cortisol with the 1 mg dexamethasone
suppression test (DST) (45). It is assumed that the above disorders are related to (a)
central corticotropin releasing hormone (CRH) hypersecretion; (b) potentiating effects of
increased arginine vasopressin (AVP) secretion on CRH-induced ACTH secretion; and (c)
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subsensitivity in negative feedback by glucocorticoids, which may be related to down-
regulation of glucocorticoid receptors (GR) or mineralocorticoid receptors (MR) in the
hippocampus, which, in turn, may be induced by sustained exposure to highconcentrations of glucocorticoids.
Glucocorticoids and Plasma L-Tryptophan Levels
One major hypothesis to relate the HPA axis to serotonergic dysfunction in depression is
that lowered plasma L-TRP availability may be related to activation of the kynurenine-nicotinamide pathway in the liver due to induction of liver pyrrolase by glucocorticoids
(42). This hypothesis is supported by the following findings: in depression there is a
significant inverse relationship between plasma L-TRP or L-TRP/CAA values and post-
DST cortisol values (44); in rats, administration of a cortisol suppression dose ofdexamethasone results in significantly augmented liver pyrrolase activity and a decreased
availability of L-TRP to the brain (57); dexamethasone (1 mg, orally) administration also
significantly reduces L-TRP plasma levels in normal controls and minor and major
depressed subjects (42).
Glucocorticoids and Serotonin Turnover
The hippocampus has been demonstrated to be a site of serotonergic innervation
associated with CNS control of the HPA-axis. A good correlation exists between theconcentrations of cellular receptors for 5-HT and glucocorticoids. There is now
compelling evidence that glucocorticoids may accelerate 5-HT synthesis and turnover in
the brain of rodents (8). Increased central 5-HT turnover is, in part, caused by
glucocorticoid or CRH-mediated induction of tryptophan hydroxylase (68). In humans,glucocorticoids may also augment central 5-HT turnover; some groups found that TRP-
induced prolactin responses were significantly higher after dexamethasone administration
and found increased levels of CSF 5-HIAA after administration of dexamethasone in agroup of psychiatric patients (71).
Glucocorticoids and 5-HT1A Receptors
It has been suggested that glucocorticosteroid hypersecretion in major depressed subjects
may down-regulate the sensitivity of postsynaptic 5-HT1A receptor signal transduction or
of the 5-HT1A receptor itself (15, 34, Meltzer and Maes, unpublished). Increasedbaseline cortisol secretion was shown to be related to diminished ipsapirone-induced
cortisol responses (34, Meltzer and Maes, unpublished). Hypercortisolemia may also
explain the impaired D,L-fenfluramine and L-TRPinduced prolactin responses (15, 61).This hypothesis is supported by experimental data showing that chronic exposure to
glucocorticoids may alter 5-HT1A receptor-mediated functions or behaviors in rodents
and that adrenalectomy may increase the number of 5-HT1A binding sites (8).
Glucocorticoids and 5-HT2 Receptors
It has been shown that both ACTH and corticosterone administration may increase the
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number of 5-HT2 receptors in the neocortex of forebrain and 5-HT2mediated behavioral
responses in rodents (29, 62). These findings suggest that HPA-axis hyperactivity in
depression may contribute to upregulated 5-HT2 receptor density in the prefrontal cortex(29).
Effects of Serotonin on HypothalamusPituitaryAdrenal Axis Function
The role of 5-HT in stimulating the HPA axis encompasses effects on CRH by activation
of 5-HT1A and 5-HT2/5-HT1C receptors and on AVP by activation of 5-HT2 receptors(5, 18). Recently, it has been demonstrated that serotonergic structures may modify
glucocorticoid negative-feedback effects on HPA-axis function. Seckl and Fink (65)
found that depletion of 5-HT in hippocampal structures may attenuate the negative-
feedback effects of glucocorticoids on the HPA axis through reduced expression of GR orMR. In depression, a significant negative correlation between plasma L-TRP availability
and baseline cortisol-adjusted post-DST cortisol values was found, suggesting that lower
presynaptic 5-HT activity is related to escape of negative-feedback inhibition (44). This
suggests the possibility that a diminished central 5-HT neurotransmission in majordepression may attenuate the hippocampal negative-feedback control over the HPA axis,
thus inducing excessive corticosteroid secretion. Treatment with L-TRP (3.5 to 7 g/day)for 1 to 2 weeks has been shown to improve DST nonsuppression in depressed subjects
(59). Therefore, it may be hypothesized that TRP treatment may have restored the
serotonergic deficit in the hippocampus, thus increasing the negative feedback over theHPA axis. Treatment with fluoxetine and imipramine may also increase the level of MR
messenger ribonucleic acid (mRNA), thus increasing the efficacy of the negative
feedback on hypothalamic CRH mRNA (4). Other results may indicate that upregulation
of postsynaptic 5-HT2 receptors in major depression is related to escape ofACTH/cortisol secretion from negative-feedback effects; compared with patients who
had minor depression, those with a diagnosis of major depression exhibited a significant
enhancing effect of L-5-HTP (125 to 200 mg) on post-DST ACTH or cortisol values,although L-5-HTP converted DST cortisol or ACTH suppression into nonsuppression in
some major depressed subjects (40).
GENDER DIFFERENCES IN PERIPHERAL AND CENTRAL SEROTONIN
ACTIVITY
There are several reports suggesting that there are gender differences in peripheral andcentral 5-HT metabolism. Preclinical data suggest that female rats have a higher activity
of 5-HT synthesizing enzymes, a greater storage capacity for 5-HT in brain 5-HT
neurons, a more pronounced 5-HT behavioral syndrome in response to 5-HT agonists,and higher brain and CSF levels of TRP, 5-HT, and 5-HIAA compared to males (6).
Animal data show that female rats exhibit a larger prolactin response to 5-HT1A receptor
agonists than male rats (21).
Significantly lower fasting plasma L-TRP levels are found in female control subjects
(42). Delgado et al. (16) found that males maintained their plasma free and total TRP
levels closer to baseline values in response to TRP depletion. Our laboratory found that
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buspirone evoked a significantly greater prolactin response in women than in men (53).
Delgado et al. (16) found that males demonstrated smaller prolactin responses to L-TRP
infusion than did female subjects.
In depression, plasma total L-TRP levels tend to be more reduced in female than in male
patients (42). In female major depressed subjects, but not in males, there is a significantnegative correlation between self-rated depression and plasma levels of total L-TRP (42).
Depressed females show significantly higher xanthurenic acid excretion following L-TRP
loading than depressed males (39). Major depressed females exhibit significantly higherL-5-HTP-induced cortisol responses than male major depressed subjects (38).
Some of these gender related differences in 5-HT metabolism may perhaps be explained
by the fact that liver pyrrolase activity is greater in women and that 5-HT receptorsappear to be estrogen sensitive. Curzon's group (14) found that female rats, as opposed to
male rats, failed to adapt to repeated restraint stress. Maladaption in female rats was
associated with greater corticosterone response and defects in 5-HT1A receptor-mediated
behavior.
THE SEROTONIN HYPOTHESIS OF MAJOR DEPRESSION
The above review has provided some evidence that among the biological factors
predisposing a person to major depression, alterations in presynaptic 5-HT activity,alterations in postsynaptic 5-HT2 and 5-HT1A receptors in the brain, and reciprocal
relationships between dysfunctions in these systems and the HPA axis may be of special
importance. Table 1 summarizes the various findings on peripheral and central and pre-
and postsynaptic 5-HT activity in major depression.
There are several arguments to support a deficient 5-HT presynaptic activity: lower
availability of plasma L-TRP to the brain; induction of depressive symptomatology by L-TRP depletion techniques; the relationship between lower L-TRP levels and positive
response to serotonergic antidepressive treatments; lower L-TRP, 5-HT, and 5-HIAA in
postmortem tissues of some depressed suicide victims; blunted L-TRP, D,L-fenfluramine,D-fenfluramine, or clomipramine-induced prolactin responses; antidepressive-treatment
induced increases in L-TRP-, D,L-fenfluramine-, or electroconvulsive-therapystimulated
prolactin responses; and antidepressivetreatmentinduced increments in presynaptic 5-
HT activity.
Major depression is characterized by an increased number, affinity, or responsivity of
central postsynaptic 5-HT2 receptors. This evidence comes from higher 5-HT2 receptorbinding in platelets of major depressed subjects and in the prefrontal cortex of depressed
suicide victims; lower 5-HT2 antagonist-induced SWS; increased HPA-axis responses to
L-TRP and (L)-5-HTP; and antidepressivetreatmentinduced decrements in 5-HT2binding and 5-HT2-related behavioral or hormonal responses.
Major depression is accompanied by down-regulated or desensitized postsynaptic 5-
HT1A receptors. This hypothesis is corroborated by attenuated ipsapirone-induced HPA-
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axis hormone responses; lower hippocampal 5-HT1 receptor binding in postmortem
brain; blunted prolactin responses to L-TRP, fenfluramine, or clomipramine; and
sensitization or up-regulation of 5-HT1A postsynaptic receptors by chronic antidepressivetreatment with tricyclic antidepressants and electroconvulsive therapy.
At present, it is difficult to conclude whether presynaptic 5-HT hypoactivity and changesin 5-HT2 or 5-HT1A postsynaptic receptor function are causally related. First, lesioning
of serotonergic neurons has been reported to enhance, not decrease, certain responses of
5-HT1A receptors (24). Second, there are now several data that suggest that an increasein 5-HT2 binding does not represent a compensatory up-regulation of postsynaptic
elements in response to deficiencies in the presynaptic neurons innervating cortical
targets (29, 35). It may be hypothesized that desensitized postsynaptic 5-HT1A receptors
could diminish the 5-HT1Amediated inhibition of 5-HT2 receptor responsivity, leadingto an augmentation of 5-HT2 receptor responsivity. In addition, the decrease in
presynaptic 5-HT activity may be a factor preventing the restoration of normal 5-HT2
receptor responsivity.
Disorders in both peripheral and central 5-HT metabolism and HPA-axis hyperactivity
may be interrelated phenomena, which participate in the pathophysiology of majordepression. Diminished central hippocampal serotonergic activity may result in elevated
central and peripheral HPA-axis activity due to lowered hippocampal negative feedback
by GR or MR on hypothalamic CRH. Increased CRH secretion may stimulate HPA-axisactivity and increased glucocorticoid levels may be involved in further down-regulation
of GR or MR, defective 5-HT1A postsynaptic receptor signaling pathways and maybe up-
regulation of 5-HT2 receptors. Supersensitive 5-HT2 receptors in limbic structures or in
the hypothalamus may sustain 5-HTrelated HPA-axis hyperactivity, through stimulatoryeffects on CRH and AVP secretion and an enhanced negative-feedback breakthrough
secretion of pituitary ACTH. Increased cortisol secretion may further compromise central
serotonergic activity, by lowering L-TRP availability through induction of the liver-pyrrolase pathway. Other putative effects of HPA-axis hormones may be regarded as
compensatory mechanisms that try to restore a lowered central presynaptic 5-HT activity,
for example, increased 5-HT turnover. The latter could also explain the more conflictingresults on central presynaptic 5-HT activity in major depression.
The gender-related differences in peripheral and central 5-HT metabolism, together with
the greater susceptibility of 5-HT and HPA-axis systems to environmental stressors infemales, could contribute to the higher incidence of major depression in females.
FUTURE RESEARCH
Although much has been learned about serotonergic dysfunction in major depression
since 1987, it is clear that there is no simple answer to the question of whether altered 5-HT activity is directly related to the pathogenesis or pathophysiology of major depression
or whether it acts as a vulnerability factor in that illness. Future research on serotonergic
activity in depression might focus on the following issues.
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The availability of L-TRP to the brain, which may be the rate-limiting factor in the
synthesis of 5-HT in patients with major depression remains an important issue. Further
study is needed of the conversion of a TRP load to 5-HT versus the products of thekynurenine-nicotinamide pathway. The transport of L-TRP into the brain needs to be
studied. The findings of Mller (56) of a low-plasma L-TRP to CAA ratio predicting
clinical response to serotonergic antidepressive drugs needs confirmation. The basis forthe failure of L-TRP depletion to exacerbate major depression in untreated patients
should be clarified.
Further studies are needed of postmortem indices of 5-HT function, such as brain 5-HT
and 5-HIAA concentrations; 5-HT1A, 5-HT1C, and 5-HT2 receptor binding; and second
messenger systems in depressed patients who died of natural as well as suicide causes.
They must control for gender, age, drug treatment, substance use or abuse, seasonality in5-HT function, comorbidity with, for example, anxiety, personality, or impulse control
disorders, and glucocorticoid elevation.
There are only a few studies using single photon emission computed tomography(SPECT) or positron emission tomography (PET) with serotonergic markers in
depression (e.g., 125I-ketanserin). The results of these studies are difficult to interpret fora variety of reasons. More SPECT or PET scan studies with ligands that are relatively
specific for 5-HT2/5-HT1C or 5-HT1A sites and the 5-HT transporter in depressed
patients prior to and after remission are needed.
Until now, there have been few neuroendocrine studies using direct agonists at 5-HT2/5-
HT1C sites (e.g., MK-212, mCPP) in major depression. The finding of
hyporesponsiveness of cortisol to the 5-HT1A agonist ipsapirone needs furtherreplication. More research should be focused on the possible cooperation between 5-
HT2/5-HT1C and 5-HT1A receptors. One strategy to investigate this cooperation
between 5-HT receptors in major depression is neuroendocrine challenge (HPA-axishormone and prolactin assays) after administration of L-5-HTP in depressed patients and
normal controls pretreated with pindolol or ritanserin.
The relationships between HPA-axis hyperactivity and peripheral and central 5-HT
turnover in major depression await further elucidation. More information on the
following topics is needed to fully delineate the 5-HT/HPA-axis hypothesis: effects of
glucocorticoids on L-TRP transport through the bloodbrain barrier, and the uptake of 5-HT, and imipramine and paroxetine binding to blood platelets. Additionally, the effects of
glucocorticoids at 5-HT1A and 5-HT2/5-HT1C receptor sites need further exploration
through neuroendocrine or imaging studies.
Finally, comprehensive studies of the relevant monoamine systems, such as
norepinephrine and dopamine, and g-aminobutyric acid which may interact with 5-HTand each other to cause depression, must be studied using the techniques described above.
Because multiple variables must be measured, large sample sizes and multiple
cooperating laboratories will be needed. This could be the goal of a national or
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international collaboration.
Serotonin adalah neurotransmitter monoamina yang terutama ditemukan pada
gastrointestinal (GI) saluran dan sistem saraf pusat (SSP).
Sekitar 80 persen dari total serotonin tubuh manusia terletak dalam sel-selenterochromaffin di usus, di mana ia digunakan untuk mengatur gerakan usus.
Sisanya disintesis di neuron serotonergik di SSP di mana ia memiliki berbagai fungsi,termasuk regulasi suasana hati, selera makan, tidur, kontraksi otot, dan beberapa fungsi
kognitif, termasuk memori dan belajar, dan dalam trombosit darah di mana ia membantu
untuk mengatur hemostasis dan darah pembekuan.
Selain manusia dan hewan, serotonin juga ditemukan pada jamur dan tanaman.
Serotonin adalah digunakan oleh berbagai organisme sel tunggal untuk berbagai tujuan.
Selektif serotonin re-uptake inhibitor (SSRI) telah ditemukan untuk menjadi racun bagiganggang. Parasit gastrointestinal''''Entamoeba histolytica mengeluarkan serotonin,
menyebabkan diare sekretorik berkelanjutan pada beberapa pasien.
Pasien yang terinfeksi Entamoeba histolytica''''telah ditemukan memiliki kadar serotoninyang sangat tinggi dalam serum yang kembali ke resolusi berikut normal infeksi.
''''Entamoeba histolytica juga menanggapi kehadiran serotonin dengan menjadi lebih
ganas.
Serotonin pada awalnya ditemukan oleh Vittorio Erspamer Italia di Roma pada 1935 dan
para ilmuwan Amerika di akhir 1940-an. Terisolasi dan dinamai pada tahun 1948 olehMaurice M. Rapport, Arda Hijau, dan Page Irvine dari Klinik Cleveland, nama''''serotonin
adalah sesuatu yang keliru dan mencerminkan keadaan penemuan senyawa. Itu awalnya
diidentifikasi sebagai zat vasokonstriktor dalam serum darah - maka''''serotonin, agen
serum mempengaruhi tonus vaskuler. Agen ini kemudian kimia diidentifikasi sebagai 5-hidroksitriptamin (5-HT) oleh Rapport, dan, sebagai berbagai peran fisiologis yang
dijelaskan, 5-HT menjadi nama yang lebih disukai di bidang farmakologi.