Neuroendocrine challenge tests: Assessment of 5-HT function in anxiety and depression

Molec. Aspects Med. Vol. 13, pp. 205-220, 1992

0098 - 2997/92 $15.00 © 1992 Pergamon Press Ltd

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NEUROENDOCRINE CHALLENGE TESTS: ASSESSMENT OF 5-HT FUNCTION IN ANXIETY AND DEPRESSION A.C. Power and P.J. Cowen M.R.C. Unit of Clinical Pharmacology and University Department of Psychiatry, Littlemore Hospital, Oxford, OX4 4XN, U.K.

Introduction 5-Hydroxytryptamine (5-HT, serotonin) has been implicated in the aetiology and pathophysiology of many psychiatric disorders over the last twenty-five years. The f'mding that drugs which altered 5-HT function improved depression, together with evidence of decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF), suggested that 5-HT might play some part in the aetiology of affective disorders (Coppen, 1967). Post-mortem findings of reduced 5-HIAA and/or 5-HT, and increased numbers of 5-HT2 receptor binding sites in the brains of suicide victims have lent further support (Meltzer and Nash, 1988). However, the results from these studies remain conflicting (Deakin, 1988) and consistent evidence for the indoleamine hypothesis of depression is still lacking (Cowen and Anderson, 1991).

Neuroendocrine Challenge Studies It is wellestablished that the secretion of growth hormone (GH), prolactin (PRL), and adrenocorticotropic hormone (ACTH) from the anterior pituitary is partly controlled by 5-HT neurones (Cowen and Anderson, 1986). Neuroendocrine challenge studies can thus provide a dynamic means of assessing brain 5-HT function in various psychiatric disorders. Certain criteria need to be met: the challenge drug should act at a specified receptor site and be blocked by antagonists which act at the same receptor; drugs which selectively block other receptors should not block the hormone response and the challenge drug should cross the blood-brain barrier (Checkley, 1980). Age, weight, sex and ovarian status should also be controlled for (Checkley, 1980). Recent weight loss, in particular, may confound challenge tests with certain drugs (Goodwin et al., 1987). Neuroendocrine challenge studies in depression and anxiety have been used to complement and understand the results that have been obtained in neuropharmacological studies in animals and through direct investigation of brain tissue in post-mortem studies (Murphy et aL, 1990a). Neuroendocrine challenge studies can be divided into pre- and post-synaptic drug challenges although determination of the exact site of action of many drugs is still the subject of much research. 205

206

A.C. Power and P.J. Cowen

Neuroendocrine Challenges in Depression (A) Pre-synaptic challenges 5-Hydroxytryptophan

(5 - H T P )

5-HTP is a precursor of 5-HT that has been used as a serotonergic probe in depressive illness. It is converted to 5-HT in a one-step process by 5-HTP decarboxylase (Dickenson, 1989). Administration of 5-HTP intravenously (IV) elevates PRL, GH and cortisol but this route of administration may cause severe side effects (Cowen and Anderson, 1991). Oral administration is less reliable. The specificity of 5-HTP as a serotonergic challenge has been questioned (Meltzer and Nash, 1988) but a number of studies have employed 5-HTP with or without a peripheral decarboxylase inhibitor (see Table 1). There is some evidence to suggest that the cortisol response to oral 5-HTP is mediated by 5-HT2/1Creceptors (Lee et al., 1991). Table 1. Endocrine responses to 5-HTP in depressive illness

Study

Drug

Route Cortisol

Takahashi et al. (1973) Westenberg et al. (1982) Meltzer et al. (1984a) Koyama and Meltzer (1986) Jacobsen et al. (1987) Maes et al. (1987, 1989)

L-5-HTP L-5-HTP DL-5-HTP DL-5-H'I~ DL-5-HTP L-5-HTP

PO PO PO PO PO PO

NR O 1" T O 1"*

Responses GH PRL ,[. O NR NR O NR

NR O NR NR O 1"*

* In females only. See text for details.

Key to all tables:

$ T O NR

blunted when compared to controls enhanced when compared to controls no significant difference between controls and patients not reported

Takahashi et al. (1973) measured GH responses in patients with manic-depressive illness and patients with endogenous depression. They found inadequate GH responses in both groups of patients when currently depressed when compared to control responses from a separate study. Meltzer et al. (1984a), using oral 5-HTP, found increased cortisol responses in unmedicated depressives and manic patients when compared to controls, and hypothesised that decreased serotonergic activity in these patients was causing 5-HT receptor hypersensitivity. Interestingly, Meltzer et al. (1984b) found a positive correlation with depressive symptoms on the Schedule for Affective Disorders and Schizophrenia-Change (SADSC) and a negative correlation with psychotic symptoms; suicidal behaviour also correlated with high cortisol responses to 5-HTP.

Neuroendocrine Challenge Tests

207

Elevated cortisol and PRL responses to 5-HTP were found by Maes et al. (1987, 1989) in women with major depression. The magnitude of the cortisol response was negatively correlated with baseline cortisol levels but was not correlated with dexamethasone non-suppression (Maes et al., 1990). However, two studies have found no difference in cortisol responses in major depression (Westenberg et al., 1982) and in seasonal affective disorder (Jacobsen et aL, 1987). L-Tryptophan (LTP)

Tryptophan is converted into 5-HTP by tryptophan hydroxylase the rate limiting step in 5-HT synthesis which is not normally saturated under physiological conditions (Dickenson, 1989). Tryptophan thus increases brain 5-HT synthesis in humans. However, tryptophan competes with other amino acids for entry into the brain and may reduce brain concentrations of tyrosine the precursor of catecholamines (van Praag et aL, 1986). LTP administered IV causes a reliable increase in GH and PRL whereas oral administration is ineffective (Murphy et al., 1990a). It has been suggested that the PRL and GH responses to LTP may be mediated by 5-HT1A receptors (Cowen et al., 1990a). The PRL response is blocked by the non-selective 5-HT antagonist metergoline (McCance et al., 1987) but not by the 5-HT2/1C antagonist ritanserin (Charig et al., 1987) or the selective 5-HT3 antagonist BRL 43694 (Anderson et al., 1988). The response is, however, antagonised by the 5-HT1A antagonist pindolol which also attenuates LTP induced GH release (Smith et al., 1991). Table 2. Endocrine responses to LTP in depressive illness

Study

Heninger et al. (1984) Koyama and Meltzer (1986) Cowen and Charig (1987) Deakin et al. (1990) Price et al. (1991)

Drug

LTP LTP LTP LTP LTP

Route

IV IV IV IV IV

Responses GH

PRL

NR $ $* $ ,1,

$ ,1,? ,1,* .1,* ,1,

* In patients without significant weight loss. See text for details.

A number of studies have compared the results of intravenous LTP stimulation in depression. Most studies have found blunted PRL and/or GH responses to IV LTP (see Table 2). In the study of Koyama and Meltzer (1986) there was a blunting of the maximum PRL and GH responses in the depressed group although the significance of the PRL response disappeared when plasma tryptophan levels were taken into account. Cowen and Charig (1987) found blunted PRL and GH responses to LTP only in those depressives who had lost less than 101bs in weight; by contrast those who had lost more than 101bs had significantly increased PRL responses to LTP. Thus weight loss could be an important confounding effect in the interpretation of certain neuroendocrine challenge tests. Using IV LTP as a challenge, Goodwin et al. (1987) found marked increases in PRL and GH responses in female volunteers and increased GH responses in male volunteers who had lost weight on a 1200 kcal diet. Deakin et al. (1990) also reported blunted PRL and GH responses in depressives versus normal controls. They found that the blunted PRL responses were predicted by high basalcortisol levels in those patients who had chronic psychosocial difficulties (Deakin et al., 1990).

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A.C. Power and P.J. Cowen

Upadhyaya et al. (1991) have found considerable recovery in the blunted PRL and GH responses to LTP in depressives who had recovered and were off drug treatment suggesting that these abnormalities may be an indication of illness rather than a trait abnormality. Price et al. (1991) also found blunted PRL and GH responses to LTP in depressed patients versus normal controls. The PRL responses were increased in melancholics but this was accounted for by lower basal tryptophan levels in this group; the GH responses were blunted in all groups and there was no main effect of weight loss (Price et al., 1991) Fenfluramine

Table 3. Endocrine responses to fenfluramine challenge in depression

Study

Siever et al. (1984) Muhlbauer and Muller -Oerlinghausen (1985) Asnis et al. (1988) Weizman et al. (1988) Coccaro et aL (1989) Lopez-Ibor et al. (1989) Targum and Marshall (1989) Mitchell and Smythe (19900 O'Keane and Dinan (1991)

Drug

Route

Responses Corfisol

PRL

FEN

PO

NR

,I.

FEN FEN FEN FEN FEN FEN FEN D-FEN

PO PO PO PO PO PO PO PO

0 0 $ NR 1" 0 0 1"

NR 0 $? $ $ 0 $ $

See text for details. Fenfluramine, which is used in the treatment of obesity, stimulates the release of serotonin and also blocks its re-uptake (Rowland and Carlton, 1986). It causes a dose dependent release of PRL, ACTH and cortisol (Quattrone et aL, 1983) with little or no effect on GH (Casanueva et al., 1984). The PRL response is blocked by metergoline and the cortisol response by cyproheptadine both non-selective 5HT antagonists (Murphy et al., 1990a). Our data suggest that the PRL response to fenfluramine may be mediated by post-synaptic 5-HT2/1C receptors as it is attenuated by ritanserin (Goodall et al., in preparation). Most studies using fenfluramine have used the racemic dl mixture which also stimulates noradrenergic pathways but the d enantiomer is known to be a more specific stimulus of 5-HT pathways (Rowland and Carlton, 1986). Most studies have found blunted PRL responses to fenfluramine stimulation in depressed patients when compared to normal controls although there have been some exceptions (see Table 3). Weizman et al. (1988) found that the percentage increase from baseline PRL was lower in the depressed group although they failed to find a significant difference in the maximum change from baseline (Weizman et al., 1988). The cortisol responses to fenfluramine in depression have been less consistent with one study finding enhanced cortisol responses (L6pez-lbor et al., 1989), and two studies finding blunted responses (O'Keane and Dinan, 1991; Weizman et al., 1988). Coccaro etal. (1989) found that the blunted PRL responses correlated with a history of suicidal behaviour in patients with affective disorders and they also found a correlation between blunted PRL responses and aggressive behaviour in patients with personality disorders.

NeuroendocdneChallengeTests

209

Mitchell and Smythe (1990) found that the blunted PRL responses to fenfluramine were correlated with reduced basal PRL levels in the depressed group and also suggested in a further study that PRL responses to fenfluramine might be indicative of endogenous depression (Mitchell et aL, 1990). Only one study (O'Keane and Dinan, 1991) has used the more selective d-fenfluramine as a probe. Overall the PRL responses in depression were decreased but patients with weight loss were less likely to show blunting; however there was no relation to endogenous features; in contrast, blunted PRL responses were more likely to occur in those patients with high anxiety scores on the Hamilton Depression Rating Scale (O'Keane and Dinan, 1991). Clomipramine

Clomipramine is an antidepressant which has also been used in the treatment of obsessive-compulsive disorder. When given IV it elevates plasma PRL (Laakmann et al., 1984a) and cortisol (Laakmann et aL, 1984b) probably because of its 5-HT reuptake blocking action (Golden et al., 1989). Golden et al. (1990) found blunted PRL and elevated GH responses in depressed patients when compared to controls. Anderson et al. (1992) also found blunted PRL responses which were related to melancholia, a history of suicidal behaviour and the presence of weight loss. In contrast to the findings with LTP (Goodwin et al., 1987), weight loss did not affect the PRL response to clomipramine challenge in normal volunteers (Cowen and Anderson, 1990).

(B) Post-synaptic challenges In theory, the development of selective post-synaptic 5-HT receptor ligands should enable progress to be made in locating a defect in 5-HT neurotransmission (Deakin, 1991). Until recently, selective agonists have not been available so the number of published studies is Small (see Table 4). Table 4. Post-synaptic challenges in depression

Study

Katm et al. (1988a, 1990c) Heninger et al. (1990)

Meltzer (1990) Lesch et al. (1990a)

Drug

mCPP mCPP MK 212 IPS

Route

O IV O O

Cortisol

Responses GH

PRL

0 0 0 1"

NR ,l, NR NR

0 0 0 NR

Ips- Ipsapirone. See text for details. meta-Chlorophenylpiperazine (mCPP) is a metabolite of the antidepressant drug, trazodone, with a

direct agonist action on post-synaptic 5-HT neurones and which produces dose-related increases in PRL, cortisol (Mueller et al., 1985; Kahn et al. 1990a) and possibly temperature (Mueller et al., 1985) that are blocked by pretreatment with metergoline (Mueller et al., 1986). The PRL response is also blocked by methysergide (Kahn et al., 1990b). The responses are seen after both oral and IV administration although anxiogenic and behavioural effects (dysphoria, depressive affect, derealization) are prominent only after IV administration (Murphy et aL, 1989). In humans mCPP appears to be a fairly non-selective 5-HT receptor agonist and to be ineffective at reuptake sites (Hamik and Peroutka, 1989) although animal studies have suggested that its behavioural effects are mediated via 5-HTlc receptors

210

A.C. Power and P.J, Cowen

(Curzon et al., 1991). Kahn et al. (I 988a, 1990c) did not find any difference in the cortisol response to oral mCPP in patients with major depression when compared to controls. The cortisol response was related to clinical levels of anxiety and they postulated that 5-HT mediated the cortisol and behavioural effects of mCPP (Kahn et al., 1988a). The same group also found a normal PRL response to mCPP in depressed patients (Kahn et al., 1990c). Heninger et al. (1990) obtained normal PRL and cortisol responses in depression but a blunted GH response to IV mCPP. MK-212 [6-chloro-2-( 1-piperazinyl)-pyrazine] is a post-synaptic 5-HT agonist that increases cortisol and PRL after oral administration and is thought to act via 5-HT2/1C receptors (Lowy and Meltzer, 1988). No difference was observed in the PRL and cortisol responses in controls and major depressives (Meltzer, 1990). Recent interest has focussed on the azapirones (buspirone, gepirone and ipsapirone) a group of selective 5-HT1A agonists (Cowen et al., 1990b). Buspirone has been marketed as an anxiolytic drug and may have antidepressant properties (Napoliello and Domantay, 1991; Robinson et al., 1990). Gepirone may also have antidepressant properties (Jenkins et aL, 1990). Buspirone and gepirone increase PRL, GH, and cortisol and decrease oral temperature when administered to volunteers while ipsapirone has little or no effect on PRL and GH (Cowen et al., 1990b). It is thought that the PRL, GH and cortisol responses are mediated by post-synaptic 5-HT 1Areceptors while the temperature response is mediated by 5-HT 1A autoreceptors (Cowen et al., 1990b). Lesch et al. (1990a) found blunted cortisol and ACTH responses to ipsapirone in patients with major depression and they also found an attenuation of the hypothermic response suggesting a possible defect at 5-HT1A receptors in patients with major depression (Lesch et al., 1990b). As part of an out-patient efficacy trial, Rausch et al. (1990) found that the cortisol response to gepirone correlated directly with severity of depression as measured by the Hamilton Depression Rating Scale. However, their results did not include a control group and must therefore be interpreted with caution.

Neuroendocrine Challenges in Panic Disorder That 5-HT plays a role in the development of anxiety disorders is suggested by the treatment efficacy of drugs which modulate serotonin function. Tricyclic antidepressants, 5-HTIA agonists and serotonin reuptake inhibitors have been shown to be effective treatments for generalized anxiety disorder (GAD) and panic disorder (PD) (Chamey et al., 1990; den Boer and Westenberg, 1991). The biphasic effect of serotonin enhancing drugs (initial worsening with improvement taking 2-3 weeks) and the finding that non-selective agonists such as mCPP cause acute anxiety (Kahn et al., 1988a, 1988b) have led to conflicting hypotheses for the role of 5-HT in anxiety. Kahn et al. (1988a) have suggested that hypersensitivity to serotonin occurs in anxiety disorders and that subsequent improvement is due to down-regulation of the post-synaptic receptors. Deakin (1989) has proposed that anxiety may involve excess activity of 5-HT2 receptors and that efficacy may be related to a decrease in 5-HT2 receptor sensitivity together with compensatory upregulation of 5-HTIA function. This could explain the potential efficacy of 5-HT2 antagonists such as ritanserin in anxiety (Deakin et al., 1991 ). In contrast Charney et al. (1990) propose a deficiency theory of serotonin function in anxiety and suggest that prolonged treatment with serotonergic drugs in anxiety increases rather than decreases 5-HT function.

Neuroendocrine Challenge Tests

211

All the reported studies that have used the neuroendocrine challenge protocolin anxiety have examined 5-HT function in relation to panic disorder. The lack of replicated data has made the results from these neuroendocrine challenge studies difficult to interpret. Three studies (see Table 5) have used presynaptic challenges in anxiety. Westenberg and den Boer (1989) found no difference in the cortisol response to 5-HTP challenge in PD patients and controls. A similar result was obtained by Charney and Heninger (1986) using LTP as a challenge. Targum and Marshall (1989) however, found elevated PRL and cortisol and increased levels of anxiety in response to fenfluramine. Using mCPP as a post-synaptic challenge Kahn et al. ( 1988a,b ,) found increased cortisol and behavioural responses to oral administration, and increased ACTH and PRL responses in female patients with panic disorder (Kahn et al., 1991). Chamey et al. (1987) found no differences in cortisol, PRL or GH responses after IV administration. Interestingly Charney et al. (1987) found that mCPP produced panic attacks in half of their patients and in a third of their controls. Table 5. Neuroendocrine challenges in panic disorder

Study

Charney and Heninger (1986) Westenberg and den Boer(1989) Targum and Marshall (1989) Charney et al. (1987) Kalm et al. (1988a, 1991)

Drug

Route Cortisol

Responses GH

PRL

LTP

IV

NR

NR

0

1-5-HTP FEN mCPP mCPP

IV O IV O

0 1" 0

NR NR 0 NR

NR 1" 0 1"*

$

* In females only.

Neuroendocrine Challenges in Obsessive-Compulsive Disorder That clomipramine is effective in obsessive-compulsive disorder (OCD) is now well established (Clomipramine Collaborative Study Group, 1991). This appears to be independent of its antidepressant effect as drugs which are equally effective in depression but without significant 5-HT reuptake blocking activity, do not appear to relieve the symptoms of OCD (Murphy et al., 1990b). There is also a growing body of evidence that selective serotonin reuptake inhibitors and possibly selective 5-HT1A agonists are also effective (Murphy et al., 1990b). The amelioration of OCD symptoms has been correlated with reduced CSF levels of 5-HIAA (Thortn et al., 1980) and, administering the 5-HT receptor antagonist, metergoline, to patients improved on clomipramine, exacerbates their symptoms (Benkelfat et al., 1989). Zohar and Insel (1987) found an exacerbation of OCD symptoms after acute administration of mCPP whereas metergoline produced a decrease in symptoms. In response to acute challenge the same group found that pre-treatment with metergoline blocked the behavioural and neuroendocrine effects of mCPP (Pigott et al., 1991) and that chronic treatment with clomipramine blocked the behavioural response to mCPP (Zohar et al., 1988). These results have suggested a role for 5-HT in the pathophysiology of OCD although supportive evidence from platelet and CSF studies is inconsistent (Insel, 1991). Charney et al. (1988) found lowered basal PRL levels in OCD patients when compared to controls. The hormone responses to IV LTP were similar in the patients versus controls although at a number of time points the PRL response was significantly enhanced in the patient group (Charney et al., 1988). In

212

A.C. Power and P.J. Cowen

contrast the PRL response to IV mCPP was significantly blunted in females (Charney e t a l . , 1988) (see Table 6). Fineberg et al. (in preparation) report enhanced PRL responses to LTP. Zohar et al. (1987) found normal endocrine responses to oral mCPP with a significant exacerbation of OCD symptoms. In the study of Hollander et al. (1991) the cortisol responses to mCPP were blunted in patients with OCD and there was a trend towards blunting of the PRL responses that did not reach statistical significance. Bastani et al. (1990) found blunted PRL and cortisol responses to MK212 without any change in symptoms. Two studies have found blunted PRL and cortisol responses to fenfluramine in OCD (Hollander et al., 1989 (quoted in Insel, 1991); Lucey et al., 1992) while a third has found a blunted PRL response in females (Hewlett et al., 1989 (quoted in Insel, 1991)). Lesch et al. (1991a) found no difference in the cortisol and temperature reponses to ipsapirone although the responses were attenuated in patients on chronic treatment with fluoxetine (Lesch et al., 1991b). Table 6. Neuroendocrinechallenges in OCD

Study

Charney et aL (1988) Lucey et al. (1992) Zohar et al. (1987) Charney et al. (1988) Hollander et al. (1991) Bastanl et al. (1990) Lesch et al. (1991a)

Drug

LTP d-FEN mCCP mCPP mCPP MK212 IPS

Route

IV O IV IV O O O

Cortisol

Responses GH

PRL

O ,1, O O ,1, ,L O

O NR NR O NR NR NR

1"? ,L O $* $? ,1, NR

* In females only.

Conclusions The most consistent evidence for a decrease in brain 5-HT function comes from studies in depression where, (excluding the inconsistent findings with 5-HTP), studies with LTP and fenfluramine have shown a consistent deficit in 5-HT-mediated PRL and GH release. These findings stand in contrast to the relative paucity of changes in post-synaptic 5-HT2/1C receptor function as judged by the PRL and cortisol responses to mCPP and MK-212. There is however, one report (Lesch et al., 1990a) of blunted ACTH and cortisol responses to the 5HT1A agonist, ipsapirone. Nevertheless, this abnormality could be an epiphenomenon of HPA axis dysregulation because in depressed patients the ACTH response to corticotopin releasing hormone is itself blunted (Charlton and Ferrier, 1989). Taken together, therefore, the findings in depression are most compatible with a deficit in the function of pre-synaptic 5-HT neurones which, from the LTP data, is reversible on clinical recovery. Data in OCD is less extensive but there are some clear differences in findings compared to depressed patients. For example, two studies (Charney et al., 1988; Fineberg et al. in preparation) have found either normal or increased PRL responses to LTP in contrast to the consistent reduction in this response seen in depression. Moreover, studies with MK212 and mCPP yield evidence of altered sensitivity of post-synaptic 5-HT2/lc receptors. This finding is of great interest in the light of the efficacy of selective 5-HT uptake blockers in OCD.

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213

Neuroendocrine studies in anxiety (mainly in panic disorder) yield the least convincing evidence for abnormalities in brain 5-HT function. In some measure this reflects the difficulty of separating prominent behavioural effects from altered 5-HT mediated neuroendocrine responses. For example, it is clear that patients with panic disorder may experience severe anxiety when exposed to a variety of drug challenges. In these circumstances it is difficult to conclude that exaggerated endocrine responses to 5-HT challenges necessarily reflect enhanced 5-HT neurotransmission rather than non-specific stress effects. Much, therefore, remains to be done to clarify the undoubted role of 5-HT pathways in affective and anxiety disorders. It seems likely that the most effective progress will be made by the development and investigation of more selective 5-HT receptor ligands. Such drugs may well enable us to understand the role that the different 5-HT receptor subtypes play in diverse pathological disorders and may in addition lead to the long-awaited development of more effective therapies. References Anderson, I.M., Cowen, P.J. and Grahame-Smith, D.G. (1988). The effect of BRL 43694 on the neuroendocrine responses to L-tryptophan infusion. J. Psychopharmac. 2, 2. Anderson, I.M., Ware, C.J., Da Roza Davis, J.M. and Cowen, P.J. (1992). Decreased 5-HT mediated prolactin release in major depression. Br. J. Psychiat. 160, 372-378. Asnis, G.M., Eisenberg, J., van Praag, H.M., Lemus, C.Z., Harkavy Friedman, J.M. and Miller, A.H. (1988). The neuroendocrine response to fenfluramine in depressives and normal controls. Biol. Psychiat. 24, 117-120. Bastani, B., Nash, J.F. and Meltzer, H.Y. (1990). Prolactin and cortisol responses to MK-212, a serotonin agonist in obsessive-compulsive disorder. Archs Gen. Psychiat. 47, 833-839. Benkelfat, C., Murphy, D.L., Zohar, J., Hill, J.L., Grover, G. and Insel, T.R. (1989). Clomipramine in obsessive-compulsive disorder: further evidence for a serotonergic mechanism of action. Archs Gen. Psychiat. 46, 23-28. Casanueva, F.F., Villanueva, L., Pefialva, A. and Cabezas-Cerrato, J. (1984). Depending on the stimulus central serotonergic activation by fenfluramine blocks or does not alter growth hormone secretion in man. Neuroendocrinology 38, 302-308. Charig, E.M., Anderson, I.M., Robinson, J.M., Nutt, D.J. and Cowen, P.J. (1987). L-tryptophan and prolactin release: evidence for interaction between 5-HT 1 and 5-HT2 receptors. Hum. Psychopharmac. 1, 91-97. Charlton, B.G. and Ferrier, N. (1989). Hypothalamo-pituitary-adrenalaxis abnormalities in depression: a review and a model. Psychol. Med. 19, 331-336. Charney, D.S., Goodman, W.K., Price, L.H., Woods, S.W., Rasmussen, S.A. and Heninger, G.R. (1988). Serotonin in obsessive-compulsive disorder: a comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Archs Gen. Psychiat. 45, 177185.

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Charney, D.S. and Heninger, G.R. (1986). Serotonin function in panic disorders: the effect of intravenous tryptophan in healthy subjects and patients with panic disorder before and during alprazolam treatment. Archs Gen. Psychiat. 43, 1059-1065. Charney, D.S., Woods, S.W., Goodman, W.K. and Heninger, G.R.(1987). Serotonin function in anxiety: I/. Effects of the serotonin agonist mCPP in panic disorder patients and healthy subjects. Psychopharmacology 92, 14-24. Charney, D.S., Woods, S.W.H., Krystal, J. and Heninger, G.R. (1990). Serotonin function and human anxiety disorders. Ann. NYAcad. Sci. 600, 558-573. Checkley, S.A. (1980). Neuroendocrine tests of monoamine function in man: a review of basic theory and its application to the study of depressive illness. Psychol. Med. 10, 35-53. Clomipramine Collaborative Study Group (1991). Clomipramine in the treatment of patients with obsessive-compulsive disorder. Archs Gen. Psychiat. 48, 730-738. Coccaro, E.F., Siever, L.J., Klar, H.M., Maurer, G., Cochrane, K., Cooper, T.B., Mohs, R.C. and Davis, K. (1989). Serotonergic studies in patients with affective and personality disorders: correlates with suicidal and impulsive aggressive behaviour. Archs Gen. Psychiat. 46, 587-599. Coppen, A. (1967). The biochemistry of affective disorders. Br. J. Psychiat. 113, 1237-1264. Cowen, P.J. and Anderson, I.M. (1986). 5-HT neuroendocrinology: changes during depressive illness and antidepressant treatment. In: The Biology of Depression, pp. 71-89, Deakin, J.F.W. (ed.) Gaskell, London. Cowen, P.J. and Anderson, I.M. (1990). Investigations of 5-HT neuroendocrine function in depression. In: Serotonin: from Cell Biology to Pharmacology and Therapeutics, pp. 493-497, Paoletti, R., Vanhoutte, P.M., Brunello, N. and Maggi, F.M. (eds) Kluwer Academic, Dordrecht. Cowen, P.J. and Anderson, I.M. (1991). Abnormal 5-HT neuroendocrine function in depression: association or artefact? In: 5-Hydroxytryptamine in Psychiatry: a Spectrum ofldeas, pp. 124-142, Sandier, M., Coppen, A. and Harnett, S. (eds) Oxford University Press, Oxford. Cowen, P.J., Anderson, I.M. and Gartside, S.E. (1990a). Endocrinological responses to 5-HT. Ann. NY Acad. Sci. 600, 250-259. Cowen, P.J., Anderson, I.M. and Grahame-Smith, D.G. (1990b). Neuroendocrine effects of azapirones. J. Clin. Psychopharmac. 11) (Suppl. 3), 21s-25s. Cowen, P.J., and Charig, E.M. (1987). Neuroendocrine responses to intravenous tryptophan in major depression. Archs Gen. Psychiat. 44, 958-966. Curzon, G., Kennett, G.A. and Whitton, P. (1991). Anxiogenic effects of the 5HT1c agonist mchlorophenylpiperazine. In: 5-Hydroxytryptamine in Psychiatry: a Spectrum of Ideas, pp. 198206, Sandier, M., Coppen, A. and Harnett, S.(eds) Oxford University Press, Oxford. Deakin, J.F.W. (1988). 5HT2 receptors, depression and anxiety. Pharmac. Biochem. 29, 819-820.

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