Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder

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Metergoline Blocks the Behavioral and Neuroendocrine Effects of Orally Administered m-Chlorophenylpiperazine in Patients With Obsessive-Compulsive Disorder Teresa A. Pigett, Joseph Zohar, James L. Hill, Suzanne E. Bernstein, Gay N. Grover, Rachel C. Zohar-Kadouch, and Dennis L. Murphy

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP ), administered orally to patients with obsessive-compulsive disorder (OCD ) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPP" s behavioral effects in humans remains controversial. To ~rther study m-CPP' s actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus mCPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes, m-CPP" s ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergoline's ability to block m-CPP's effects on beh~viGr ~rd p!~m~ pr,.dactin !et,_dsjiarther support to a serotonergic mediation of mCPP's effects, including its elicitation of OCD symptoms.

Introduction Several investigators have theorized that an abnormality in serotonergic function is instrumental in the development and maintenance of obsessive-compulsive disorder (OCD) (for a review see Murphy et al 1989a). Originally, this "serotonin hypothesis" arose from

From the Section on Clinical Neuropharmacology, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD (TAP, JLH, SEB, DLM); the Beer-Sbeva Mental Health Center, Beer-Sbeva, Israel (JZ, RCZ-K); and the Clinical Center Nursing Department, National Institute of Health, Bethesda, MD (GNG). Address reprint requests to Dr. Teresa A. Pigott, Section on Clinical Neuropharmacology, Laboratory of Clinical Science, NIH Clinical Center, 10/3D41, 9000 Rockville Pike, Bethesda, MD 20892. Received February 6, 1990; revised October 4, 1990.

Published 1991 by Elsevier Science Publishing Company, Inc.

0006-1SSN/91/$O.00

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the clinical observations that the antidepressant clomipramine, a potent serotonin (5-HT) reuptake inhibitor, possessed antiobsessional ~,roperties that were lacking in tess serotoninselective agents such as nortriptyline, desipramine, amitriptyline, and imipramine. Moreover, other potent 5-HT r,~uptake inhibitors including fluoxetine (Turner et ~ ! 985; Pigott et al 1990) and fluvoxamine (Perse et al 1987; Goodman et al 1989) have shown promise as antiobsessional agents in controlled trials. In response to these clinical observations and controlled trials, there have been increasing attempts to study the neurobiology of OCD through the use of pharmacological challenges designed to assess the functional status of brain serotonin subsystems in ~ D patients, m-chlorophenylpiperazine (m-CPP), a metabolite of the antidepressant agent trazodone (Caccia et al 1981), has been shown to possess postsynaptic serotonin receptor effects in humans producing elevations in temperature, plasma prolactin, and cortisol, and behavioral changes (Mueller et al 1985, 1986; Murphy et al 1989b). Zohar et al (1987) first utilized orally administered m-CPP under double-blind, placebocontrolled conditions in OCD patients and reported that relative to normal volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after mCPP administration; most interesting was the observation that oral m-CPP caused an acute exacerbation in OCD symptoms in 11 of 12 patients. Hollander et al (1988) also reported similar behavioral effects, including OCD symptom exacerbations, after oral m-CPP, but another group (Chamey et al 1988) utilized intravenous m-CPP and did not find significant behavioral response differences between patients with OCD and controls. Metergoline, a 5-HT antagonist, has potent central effects; it has been ~ven to OCD patients in single doses without significant behavioral effects (Zohar et al 1987; Ber&elfat et al 1989). Mueller et al (1986) studied the effects of metergoline pretreatment in normal volunteers and reported that metergoline blocked m-CPP-induced elevations in plasma prolactin, cortisol, adrenocorticotropin (ACTH), and temperature; no behavioral observations were reported in this study. In the present study, OCD patients were given m-CPP, metergoline, and placebo, alone and together, to investigate whether pretreatment with oral metergoline would affect m-CPP's ability to elicit behavioral and neuroendocrine effects in this patient group. We were particularly interested in whether metergoline might attenuate m-CPP's acute exacerbation of OCD symptoms, as this would lend further support to the idea that m-CPP's behavioral effects in OCD patients are indeed serotonergically mediated. In addition to plasma prolactin and cortisol, we measured plasma m-CPP levels to insure that any effects of metergoiine pretreatment were not s;moly due to any change in m-CPP drug metabolism. Methods Twelve patients with OCD (o men, 3 women, mean age 29.4 _ 0.4 years), who were referred by local psychiatrists to the National Institute of Mental Health (NIMH) OCD outpatient program, were screened by at least 2 clinicians. All patients had a structured interview by a research psychiatrist and were diagnosed as having OCD by DSM-IH-R criteria. Additional inclusion criteria were duration of illness for at least 1 year and a minimum age of 18 years. Patients with mild secondary depression were included in this study. Mild secondary depression was defined by (1) affective symptoms beginning more than 3 months after onset of obsessional symptoms, (2) main complaint focused on OCD symptoms, and (3) a 22-item Hamilton Depression Score of <18 (Murphy et al 1982).

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The mean duration of OCD symptoms was 11.3 +-- 0.5 years. All patients were psychotropic drug free for at least 3 weeks prior to the test sessions. All patients had non~al physical examinations, normal routine laboratory tests (renal, hepatic, pancreatic, hematological, and thyroid function), and normal electrocardiograms prior to inclusion in the study. All patients gave voluntary written informed consent for their participation in the study. Six of the OCD patients received four separate challenges: metergoline, placebo, mCPP, and metergoline plus m-CPP. The metergoline, placebo, and m-CPP were administered in a random assignment manner, but the metergoline plus m-CPP challenge was always administered as the final challenge. The other 6 0 C D patients received two separate, random assignment challenges of metergoline alone and metergoline plus mCPP. All drug or placebo administrations were completed under double-blind conditions. Each OCD patient's OCD symptoms were measured by an experienced rater blind to the treatment condition, and blood samples, as well as behavioral ratings, were obtained from the second group of OCD patients (n = 6). Testing started at 8:30 AM Oli e~ch study day, after an overnight fast. An intravenous catheter was placed in a forearm vein of the OCD patients at approximately 8:30 AM. At 9:00 AM and at 10:00 AM all subjects received identical pink capsules containing either placebo, m-CPP (0.5 mg/kg), or metergoline (4 mg). Capsules containing m-CPP were always admiaistered at 10 AM and capsules containing metergoline were administered approximately 1 hr prior to the administration of m-CPP. Each subject was tested with a minimum of 1 week between study days. The subjects remained in bed with the head elevated throughout the 4-hr study period and were not allowed to smoke, eat, or sleep during the study time. Blood samples were obtained in a subset of the patients through an intravenous catheter at - 60, - 30, 0, + 30, + 60, + 120, + 150, + 180, + 240 min. All blood samples were placed on ice immediately and then centrifuged within 2 hr; plasma was stored at -70°C until assayed. Mood and behavior were assessed at - 6 0 , 0, 60, 120, 180, 240 min following t'le 10:00 AM capsule using a battery of scales including (1) the NIMH Self-Rating Sct,;e (Murphy et al 1989b); (2) the Comprehensive Psychiatric Rating Scale-Obsessi,-e-Compulsive-5 (CPRS-OC-5) (Thoren et al 1980); (3) the NIMH Global Scales (Murphy et al 1982), including those of OCD symptoms, anxiety, and depression, rated from 1 to 15; and (4) the NIMH Obsessive--Compulsive Rating Scale (NIMH-OC-R). All 12 OCD patients were assessed by the CPRS-OC-5, NiMH-OC-R, and the NIMH Global Scales, but only 11 OCD patients completed the NIMH Self-Rating Scale due to an unplanned omission. Plasma samples were assayed for prolactin, cortisol, and m-CPP utilizing methodology previously described (Murphy et al 1989b).

Data Analysis Data (changes from baseline following placebo, metergoline, m-CPP, or metergoline plus m-CPP) were analyzed using a repeated measures d~sign an'alysis of variance (ANOVA), accompanied by contrasts of main and interactive factors specified a priori. A p value less than 0.05 was considered statistically significant. Only the significant interactions revealed by ANOVA were examined post hoe with paired t-tests (two-tailed) for withingroup comparisons. Behavioral and neuroendoe6ne data were additionally examined by contrasting "double deltas" (i.e., subtracting the maximum change following metergoline

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Table 1. Observer Ratings after Placebo, m-CPP, Metergoline, and Metergoline + m-CPP Administration

Group Baseline scores CPRS-OC-5 Global OC NIMH-OC-R Global impairment Global depression Global anxiety Peak change from baseline CPRS-OC-5 Global OC NIMH-OC-R Global impaim'.,ent Glob:~' lepression Global Anxiety

Placebo (n = 6)

m-CPP (n = 6)

Me~ergol~ne (n = 12)

Metergoline + m-CPP (n = 12)

4.3 6.0 15.5 3.5 4.5 4.8

_ --± ± _

0 8 0.9 1.7 0.4 0.4 0.5

2.7 4.0 10.0 3.2 5.3 3.7

-*± _ ± -±

0.6 0.7 1.9 0.5 i.0 0.3

2.3 3.8 8.2 3.5 3.2 3.8

± ",± _ --

0.5 0.7 2.0 0.6 0.7 0.7

2.2 3.5 7.3 4.2 3.8 3.8

± ± ± ± -

0.4 0.5 !.5 0.2 0.4 0.4

1.0 0.2 0.2 0.8 -0.5 -0.7

-+ ± -+ +±

U.,J 0.3 2.1 0.5 0.8 0.4

4.5 7.0 lb.7 5.7 1.3 3.2

~ 0.6 b x ~).6b ± IM +_ 1.0° __ 0.8 ± l.~

1.1 0.2 2.8 1.0 0.0 0.3

+- 0.7 _+ 0.3 +- 1.9 +_ 0.4 : 0.3 ± 0.7

0.1 0.6 0.2 0.3 0.3 0.3

± ± ± ± ± ±

0.6 0.5 !.9 0.3 0.7 0.7

Op < 0.05; bp < 0.01; Cp < 0.001, differences from baseline (means ± SEM).

plus m-CPP from the maximum change following metergoline ,done), thus o b t ~ i n g an estimation of the net effect of m-CPP administration. Calculation procedures were those of the SAS Institute (Cary, N.C.). Data are reported as means -+ SEM. Results

Behavioral Measures The baseline behavioral scores and mean peak changes in observer rating scores of OCD symptoms, anxiety, impairment, and depression following placebo, metergoline, m-CPP, and metergoline plus m-CPP administration are shown in Table 1. The effects of placebo and mctergoline alone on OCD symptomalogy were negligible. However, as previously observed ~n a larger patient group (Zohar et al 1987), m-CPP elicited a significant increase in OCD symptoms. When metergoline was administered prior to m-CPP administration, there was a significant attenuation of m-CPP's ab~ty to increase OCD symptoms, such that all three OCD scales failed to exhibit a significant change from baseline. A cempadson of OCD rating responses elicited by m-CPP with and without metergoline pretreatment using "double-delta" differences revealed significant differences between the two treatments on all three OCD scales (CPRS-OC-5, t = 6.14, p < 0.005; NIMH Global O-C Scale, t = 3.78, p < 0.05; and NIMH-OC-R. t = 3.65, p < 0.05). There were no significant differences on any of the OCD scales between the metergoline alone and metergoline plus m-CPP conditions. The mean peak changes in observer ratings scores of anxiety, impairment, and depression as measured by the NIMH Global Scales revealed no significant changes from baseline after placebo or metergoline administration. After m-CPP administration, there were significant changes from baseline on the impairment and anxiety scales (Table 1). Pretreatment with metergoline prior to m-CPP administration somewhat lessened m-CPP's behavioral effects (Table l), but double delta comparisons revealed changes only at

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Table 2. Self Ratings after Placebo, m-CPP, Metergoline, and Metergoline + m-CPP Administration

Group Baseline scores Activation/Euphoria Anxiety Depression Dysphoria Altered self Functional deficit Peak change from baseline Activation/Euphoria Anxiety. Depression Dysphoria Altered self Functional deficit

Placebo (n = 6)

m-CPP (n = 6)

0.3 6.2 5.7 1.5 0.2 2.3

1.2 4.2 2.8 0.5 0.2 2.7

0.0 -1.0 1.4 0.2 0.0 1.2

- 0.2 ± 0.6 __. 0,5 ± 0.7 ± 0.2 ± 0.9 ± ± ± ± ± ±

0.0 0.7 0.5 0.2 0.0 0.60

-0.3 6.8 3.2 4.0 4.5 4.5

± ± ± ± ± ±

0.6 0.8 0.7 0.3 0.2 0.9

__. 0.3 ° ± !.8 ± lAP ± 1.1 ° ± 1.3 ° ± 1.6"

Metergoline (n = !1)

!.5 7.7 !.4 L5 1.7 4.0 0.0 0.3 2.2 -0.5 -0.2 2.4

± ± _ ±

Metergoline + m-CPP (n = 12)

I.I 2.5 0.5 !.2 ~.9 !.8

!.8 6.9 3.2 3.4 2.0 5.6

± ± ± _ ± ...

i.6 2.5 !.! 1.2 !.8 !.6

__. 0.2 ± !.7 ± !.6 ± !.5 ± 0.1 ± !.1

0.4 !.2 -0.5 -0.4 0.0 1.9

± ± ... ± --±

0.3 1.3 !.2 1.2 0.8 1.0

~p < 0.05; differences fwm baseline (means ± SEM).

statistical trend levels for differences between m-CPP alone and m-CPP plus metergoline on two scales (NIMH Global Impairment, t = 2.07, p = 0.09; NIMH Global Anxiety, t = 2.18, p = 0.08). Changes in self-ratings of mood following placebo, metergoline, m-CPP, and metergoline plus m-CPP administration are shown in Table 2. There were no significant changes from baseline on any of the NIMH Self-Rating subscales after placebo or metergoline administration. After m-CPP administration, there were significant increases in the NIMH Self-Rating subscales for anxiety, dysphoria, and feelings of altered self and functional deficit. Metergoline pretreatment abolished the changes noted with m-CPP administration alone on all of the self-report measures (Table 2). Double deltas revealed a significant difference between m-CPP alone and metergoline plus m-CPP on measures of activation/euphoria (t = 3.16, p < 0.05), dysphoria (t = 2.78, p < 0.05), and altered self (t = 2.86, p < 0.05). The anxiety subscale revealed a tendency towards significance (t = 2.33, p = 0.07). ;|-'here were no significant differences on any of the subscales between metergoline and metergoline plus m-CPP administration.

Plasma Neuroendocrine Measures There was no significant difference in baseline plasma prolactin levels on the different treatment days (baseline levels: metergoline 5.56 _+ 1.47 ng/ml, metergoline plus mCPP 4.74 _+ 1.09 ng/ml). A repeated measures ANOVA between treatment days revealed a significant day by time interaction [(F(l,6) = 7.62, p < 0.05]. This resulted because of a significant decrease from baseline in plasma prolactin levels after metergoline administration alone (peak change from baseline: metergoline - 2.46 _+ 0.90 ng/ml, metergoline plus m-CPP - 1 . 7 8 _+ 0.81 ng/ml). As oral m-CPP has been reported to significantly elevate plasma prolactin levels from baseline in both OCD patients (Zohar et al 1987) and controls (Mueller et al 1985; Zohar et al 1987; Murphy et al 1989b), this suggests

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that metergoline pretreatment results in a blockade of m-CPP's ability, to raise plasma prolactin levels. There was no significant difference between baseline cortisol concentrations on the different treatment days (baseline levels: metergoline 14.26 __. 2.89 ng/dl, metergoline plus m-CPP 13.08 _ 1.87 ng/dl). A repeated measures ANOVA revealed no significant effect on plasma cortisol levels between treatments and no significant interactions. There was no significant change in plasma cortisol from baseline after either treatment (peak change from baseline: metergoline 2. i4 __. 1.08 ng/dl, metergo!ine plus m-CPP 0.68 _+_ 1.47 ng/dl). However, ,oral m-CPP has also been reported to significantly eh. ate plasma cortisol levels from baseline in controls (Mueller et al 1985; Zohar et al 1988; Murphy et al 1999b), but not in OCD patients (Zohar et al 1987). Consequently, our results are compatable with these reports, but do not prove that metergoline pretreatment specifically blocks m-CPP's ability to elevate plasma cortisol concentrations in OCD patients.

Plasma m-CPP Levels Plasma concentrations of m-CPP given orally 1 hr after metergoline administration rose after the first 60 min, then remained at a stable plateau over the next I-2 hr, and declined slowly thereafter. The mean peak m-CPP concentration was 33.4 ± 8.9 n g / ~ . The plasma concentrations of m-CPP achieved after metergoline pretrea~ment were not substantially different by t-test from the mean peak plasma m-CPP concentrations reported in our previous studies of OCD patients [mean peak concentration (n = 9) = 26.9 ___ 3.5 ng/ml (Zohar et al 1987)1 or normal volunteers l(n = 17) = 27.5 "+- 2.7 ng/ml (Murphy et al 1989b)1 after oral m-CPP administration.

Discussion To our knowledge, this is the first report of the 5-HT agonist m-CPP administered orally concomitantly with metergoline to patients with OCD in an attempt to assess the role of serotonin in m-CPP's elicitation of OCD and mood symptoms, and m-CPP's weN-documented neuroendocrine effects, m-CPP has been proposed as a use~l probe of 5-HT receptor responsivity in man (Mueller et al 1985, 1986; Murphy et al 1989b) and, in fact, is currently being investigated as a serotonergic probe in a variety of neuropsychiatric ¢OIl~Ik.llU~l~ O;~,Zlillkll.,i~ ~..J~.,L,¢.

As previously mentioned, Charney et al (1988) utilized intravenous m-CPP (0.1 mg/kg) and tryptophan, the 5-HT precursor, in a group of OCD patients and controls and reported that the behavioral responses to m-CPP and tryptophan were similar in the patients and healthy subjects, and that neither agent had significant effects on obsessive or compulsive symptoms. Both OCD patients and controls experienced m-CPP as anxiogenic and often dysphoric. However, a recent review (Murphy et al 1989b) compared the behavioral and neuroendocrine effects of m-CPP administered orally and intravenously to healthy volunteers and suggested that the discrepancy between the findings of Zohar et al (1987) and Hollander et al (1988), in comparison with Charney et al (1988), may be related to the differing routes of m-CPP administration as well as other elements of the study design. For example, in the lauer study, OCD symptoms were only rated at baseline and 90 rnin after intravenous m-CPP administration, although maximum anxiety and other behavioral changes were observed to occur 30 min after m-CPP in both OCD patients ~ d healthy

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al

volunteers in the two reported studies that utilized intravenous m-CPP (Chamey et al 1988; Murphy et al 1989b). Zohar et al (1988) supplemented their original study of m-CPP in OCD with further investigations in which they readministered oral m-CPP to OCD patients after 4 months of treatment with clomipramine. Interestingly, the patients receiving clomipramine did not experience the previously observed increase in obsessional symptoms or anxiety after m-CPP. We postulated from this evidence that clomipramine leads to the development of subsensitivity in at least a subsystem of serotonin receptors (Zohar et al 1988; Murphy et al 1989a). In two prior studies in OCD patients, single doses of metergoline had no significant effe~:s on mood or OCD symptoms (Zohar et al 1987; Benkelfat et al 1989). Repeated administration of oral metergoline was found to worsen obsessive-compulsive symptoms in OCD patients who had improved during clomipramine treatment (Benkelfat et al 1989); presumably this resulted from metergoline acting as a serotonin antagonist to partially reverse clomipramine's effects on serotonergic neurotransmission. Mueller et al (1986) utilized oral metergoline pretreatment with oral m-CPP (0.75 mg/kg) in normal volunteers and reported that metergoline blocked the m-CPP-induced hormonal and physiological changes. Though this observation supported the validity, of m-CPP as a postsynaptic serotonergic probe in terms of neuroendocrine effects, behavioral responses [which were minimal in the first study with oral m-CPP in healthy volunteers ~Mueller et al 1985)] were not evaluated in this earlier m-CPP/metergoline study (Mueller et al 1986). Because OCD patients appear to exhibit a reproducible, characteristic behavioral response to oral m-CPP, notably OCD symptom exacerbation, it was of special importance to assess the effects of a serotonin antagonist in this population of patients. Despite the attainment of relatively equivalent m-CPP concentrations during concomitant metergoline treatment, metergoline pretreatment resulted in blockade of m-CPP's ability to elicit OCD symptom exacerbation and mood effects; metergoline also prevented m-CPP's elevation of prolactin and, possibly, cortisol levels. This observation lends further support to the hypothesis that the effects of orally administered m-CPP are primarily mediated via serotonergic mechanisms. There has been a brief repo~ (Seibyl et al 1989) of the use of the 5-HT2 antagonist, ritanserin, in controls and neuroleptic-free schizophrenic patients in conjunction with intravenous m-CPP. Seibyl et al reported that ritanserin attenuated m-CPP's ability to increase plasma prolactin, cortisol, and growth hormone levels. In addition, ritanserin administration led to an attenuation of some of m-CPP's behavioral responses~ notably "anxiety," "drowsiness," and "feeling high." These data are thus in keeping with metergoline's actions in our study. Though ritanserin has frequently been described as a selective 5-HT2 antagonist, and, in fact, has a very low affinity for 5-HT~a and 5-HT~b sites, it (like metergoline) has nearly as high an affinity for 5-HT~c as 5-HTe sites (Hoyer 1988). This is consistent with two bodies of recent data, one obtained from the cloning and sequencing of these receptors which demonstrated considerable homology between 5-HT2 and 5-HT~c receptors, and the other from second messenger studies which documented that phosphotidylinositol hydrolysis is the signal transduction mechanism for 5HT~c and 5-HT2 receptors, unlike the 5-HTI~ and 5-HTmb receptors which act via adenylate cyclase (reviewed in Schmidt and Peroutka 1989). Although antagonist studies of m-CPP's actions in humans are limited to those of metergoline (Mueller et al 1986) and ritanserin (Seibyl et al 1989), data from a wider range of antagonists in animal studies have led to the conclusion that many of m-CPP's effects (at least when m-CPP is given in low doses) are mediated by m-CPP's 5-HT~c

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agonist actions (Fozard and Gray 1989; Kennett and Curzon 1988; Keener et al 1989; Kennett et al 1987; Curzon and Kennett 1990; Berendsen et al 1990; Whitton and Curzon 1990). This is compatible with m-CPP's approximate tenfold higher affinity for 5-HTt¢ receptor sites versus 5-HT~a, 5-HT~b, and 5-HT2 sites in vitro (Hoyer 1988). In addition, m-CPP's actions in several animal models of anxiety such as social interactions and light/dark box explorations have been interpreted as resulting from effects at 5-HTtc receptor sites (Kennett et al 1989; Curzon and Keanett 1990). Thus, metergoline's ability te block m-CPP's elicitation of OCD symptom exacerbation in patients with OCD suggests that this response is mediated by a serotonin-mediated mechanism, most likely at 5-HT~c sites, although additional receptor binding studies using human brain tissue are needed. Further delineation of the specific site of this response may lead to a better understanding of the process that contributes to the expression of OCD symptoms, and may ultimately contribute to the discovery of additional therapeutic agents for OCD. Perhaps OCD patients who differentially exhibit hyperresponsivity to m-CPP represent patients who will benefit from therapeutic agents that may down-regulate serotonergic processes. If so, it might be possible that pretreatment with such serotonergic probes as m-CPP might prove useful in the prediction of eventual treatment responses. Further investigations appear indicated to clarify these intriguing issues.

References Benkelfat C, Murphy DL, Zohar J, et all (1989): Clomipramine in obsessive-corrp, ilsive aisorder. Further evidence for a serotonergic mechanism of action. Arch Gen Psychiatry 46:23-28. Berendsen HHG, Jenck F, Broekkamp CLE (1990): Involvemem of 5-HT~c-receptors in druginduced penile erections in rats. Psychopharmacology 101:57-6 I. Caccia S, Ballabio M, Samanin R, et al (1981): ra-Chlorophenylpiperazine, a central 5-hydroxytryptamine agonist, is a metabolite of trazodone. J Pharm Pharrnacol 34:477--478. Charney DS, Goodman WK, Price LH, et al (1988): Serotonin function in obsessive-compulsive disorder: A comparison of the effects of tryptophan and m-CPP in patients and healthy subjects. Arch Gen Psychiatry 45:177-185. Curzon G, Kennett GA (1990): m-CPP: A tool for studying behavioural respormes associated with 5-HT~c receptors. Trends Pharmacol Sci 11:181-182. Fozard JR, Gray JA (1989): 5-HT~c receptor activation: A key step in the initiation of migraine. Trends Pharmacol Sci 10:307-309. Goodman WK, Price LH, Rasmussen SA, et al (1989): Efficacy of fluvoxamine in obsessivecompulsive disorder: A double-blind comparison of fluvoxamine and placebo. Arch Gen Psychiatry 46:36-40. Hollander E, Fay M, Cohen B, et ai (1988): Serotonergic and noradrenergic sensitivity in obsessivecompulsive disorder: Behavioral findings. Am .l Psychiatry 145: I 015- I 017. Hoyer D (1988): Functional correlates of 5-HTt recoo~aition sites. J Recept Res 8:59-81. Kennett GA, Curzon G (1988): Evidence that m-CPP may have behavioral effects mediated by central 5-HT,c receptors. Br J Pharmacol 94:137-147. Kennett GA, Dourish CT, Curzon G (1987): Antidepressant-like action of 5-HT~a agonists and conventional antidepressants in an animal model of depression. Fur J Pharmacol 134:265-214. Kennett GA, Whitton P, Shah K, Curzon G (1989): Anrdogenic-like effects of m-CPP and TFMPP in animal models are apposed by 5-HT~c receptor antagonists. 164:445-454. Mueiler EA, Murphy DL, Sunderland T (1985) Neuroendocrine effects of m-CPP, a serotonin agonist in humans. J Clin Endocrinol Metab 61:1179-1184.

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Mueller EA, Murphy DL, Sunderland T (1986): Further studies of the putative serotonin agonist, m-CPP: Evidence for a serotonin receptor-mediated mechanism of action in humans. Psychopharmacology (Berlin) 89:388-391. Murphy DL, Pickar D, Alterman IS (1982): Methods for the quantitative assessment of depressive and manic behavior. In Burdock El, Sudilovsky A, Gershun S (eds), The Behavior of Psychiatric "atients. New York: Marcel Decker Inc, pp 355-391. Murphy DL, Zohar J, Benkelfat C, et al (1989a): Obsessive-co~pulsive disorder as a 5-HT subsystem-related behavioral disorder. Br J Pharmacol 155(suppl): 15-24. Murpily DL, Mueller EA, Hill JL, et al (1989b): Comparative anxiogenic, neuroendocrine, and other physiological effects of m-CPP given intravenously or orally to healthy volunteers. Psychopharmacology 98:275-282. Perse T, Greist JH, Jefferson JW, et al (1987): Fluvoxamine treatment of obsessive-compulsive disorder. Am J Psychiatry 144:1543-1548. Pigott TA, Pato MT, Bernstein SE, et al (1990): Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder: Behavioral and biological results. Arch Gen Psychiatr), (in press). Schmidt AW, Peroutka SJ (1989): 5-Hydroxytryptamine receptor families. J FASEB 3:2242-2249. Seibyl JP, Krystal JH, ~ c e LH, et al (1989): 5-HT function in the biochemical and behavioral responses to m-CPP in healthy subjects and schizophrenics (Abstract). Soc Neurosci 15:1236. Thoren P, Asberg M, Cronholm B, et al (1980): Clomipramine treatment of obsessive-compulsive disorder: I. A controlled clinical trial. Arch Gen Psychiatry 37:1281-1285. Turner SN, Jacob RG, Beidel DC, Himmelhoch J (1985): Huoxetine treatment of obsessivecompulsive disorder. J Clin Psychopharm 5:207-212. Whitton P, Curzon G (1990): Anxiogenic-like effect of infusing l-(3-cidorophenyl) piperazine (mCPP) into the hippocampus. Psychopharmacology 100:138-140. Zohar J, Mueller EA, Insel TR, et al (1987): Serotonergic responsivity in obsessive-compulsive disorder: Comparison of patients and healthy controls. Arch Gen Psychiatry 44:946-951. Zohar J, lnsel TR, Zohar-Kadouch RC, et al (1988): Serotonergic responsivity in obsessivecompulsive disorder: Effects of chronic clomipramine treatment. Arch Gen Psychiatry 45:167172.