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Serotonergic function in social phobia: comparison to normal control and obsessive–compulsive disorder subjects
Psychiatry Research 79 Ž1998. 213]217
Serotonergic function in social phobia: comparison to normal control and obsessive]compulsive disorder subjects Eric Hollander U , Jee Kwon, Fenia Weiller, Lisa Cohen, Dan J. Stein, Concetta DeCaria, Michael Liebowitz, Daphne Simeon Department of Psychiatry, Box 1230, Mt. Sinai School of Medicine, 1 Gusta¨ e L. Le¨ y Place, New York, NY 10029, USA Received 6 June 1996; received in revised form 5 August 1997; accepted 27 March 1998
Abstract Eighteen patients with social phobia, 21 normal control subjects, and 42 obsessive]compulsive disorder ŽOCD. control subjects were challenged with single doses of the partial serotonin agonist oral m-chlorophenylpiperazine Ž m-CPP. and placebo. Social phobics did not significantly differ from normal or OCD control subjects in prolactin response to m-CPP. There was a significant difference across groups in cortisol response to m-CPP, such that female social phobics had more robust cortisol responses to the m-CPP challenge. Pairwise comparisons only reached trend significance, perhaps due to the relatively small sample sizes. This study offers preliminary evidence for serotonin dysfunction in social phobia, particularly in female social phobics, but needs to be replicated in a larger sample size. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Social phobia; Serotonin Ž5-HT.; Obsessive]compulsive disorder; m-CPP; Prolactin; Cortisol
1. Introduction Social phobia is one of the most common psychiatric disorders, with an early age of onset and a usually chronic course ŽSchneier et al., 1992.. It results in significant long-term distress and social disability. Little is known about its etiology. Re-
U
Corresponding author. Tel.: q1 212 2413623; fax: q1 212 9874031.
cent evidence suggests that some serotonergic agents improve symptoms of social phobia. Preliminary studies with selective serotonin Ž5-HT. reuptake blockers such as fluoxetine have shown therapeutic efficacy in the treatment of social phobia ŽBlack et al., 1992; Van Ameringen et al., 1993.. The 5-HT1a agonist buspirone has shown partial therapeutic efficacy in symptoms of generalized social phobia ŽMunjack et al., 1991; Schneier et al., 1993.. Pre-clinical studies also demonstrate that 5-HT is involved in anxiety and
0165-1781r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž98.00041-9
214
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
assessment of harm ŽGeller and Blum, 1970; Charney et al., 1990.. Taken together, this suggests that 5-HT might be involved in the pathophysiology of social phobia and social anxiety. Little work has been conducted to date with pharmacological challenges in social phobia, but preliminary studies suggest that social phobics may have an augmented cortisol response to the net 5-HT releaser fenfluramine ŽTancer et al., 1995.. Pharmacological challenge studies with 5-HT agonists ŽZohar et al., 1987; Bastani et al., 1990; Hollander et al., 1991, 1992. and antagonists ŽZohar et al., 1987; Benkelfat et al., 1989; Pigott et al., 1991. have demonstrated complex effects on behavioral and neuroendocrine responsivity in OCD in comparison to normal control subjects, suggesting 5-HT dysfunction in a subgroup of OCD patients. However, the specificity of these findings in OCD is unknown, since comparisons with other anxiety control groups have not been previously undertaken. This study was designed to measure abnormalities in the 5-HT function in social phobia via pharmacological challenges with the partial 5-HT agonist m-CPP and placebo, and to determine whether findings are specific to social phobia per se or also found in normal and OCD control subjects. It was expected that social phobics would have less serotonergic dysfunction than OCD patients because, while responsive to serotonergic medications, social phobics lack the selective responsivity to serotonin reuptake inhibitors found in OCD. To do this, we compared social phobic patients to normal control subjects and OCD patients on neuroendocrine responses to m-CPP and placebo. 2. Methods Adult social phobic patients Ž N s 18, nine males, nine females; mean age 36 years. were compared to matched normal control subjects Ž N s 21, 10 males, 11 females; mean age 30 years. and OCD control subjects Ž N s 42, 28 males, 14 females; mean age 34 years.. Findings for a subgroup of the OCD patients Ž N s 20. were previously reported ŽHollander et al., 1992.. Patients had either been referred by mental health practi-
tioners, or responded to advertisements or to media reports seeking participants for biological challenge research studies in social phobia or OCD. After a discussion of the potential risks of the pharmacological challenges, all patients signed informed consent forms and were compared on neuroendocrine responses following double-blind, randomized, single-dose challenge of the partial 5-HT receptor agonist m-CPP Ž0.5 mgrkg p.o.. and placebo. Social phobic patients met the DSM III-R criteria for generalized social phobia in that their fears included most social situations. No social phobic met the DSM III-R criteria for any comorbid Axis I or Axis II disorders other than avoidant personality disorder. None of the social phobic patients had ever received a 5-HT reuptake blocker. OCD patients met the DSM-III-R criteria for OCD on the basis of semi-structured diagnostic interviews and did not meet the criteria for any comorbid Axis I or Axis II disorders. Of the 42 OCD patients, 34 had previously received a 5-HT reuptake blocker Žfluoxetine or clomipramine. to which 22 were responders and 12 were non-responders. All subjects in the three groups were medication free for a minimum of 4 weeks prior to study Ž6 weeks for those previously on fluoxetine. and were medically healthy. Female subjects were all premenopausal and none were taking oral contraceptives. Normal control subjects were recruited from the normal control subject pool of either the Mental Health Clinical Research Center ŽMHCRC. or the Anxiety Clinic of the New York State Psychiatric Institute, and were determined to be free of all DSM III-R illnesses via semistructured diagnostic interviews. All diagnostic evaluations were conducted by experienced research psychiatrists specializing in anxiety disorders. Prior to the challenge procedures, subjects were maintained on a low monoamine diet for 72 h to minimize the effect of tyramine on prolactin. To control for the effects of circadium rhythms on cortisol response to m-CPP, all challenges were performed during the same time of day. During the challenge procedures, patients remained awake, at bed rest, and without food. One hour
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
215
after insertion of an indwelling intravenous catheter, each subject received either placebo or an identical capsule of m-CPP orally. The m-CPP dose was 0.5 mgrkg, to replicate our work in OCD ŽHollander et al., 1992.. The m-CPP and placebo challenges were randomized and separated by at least 72 h Žmean interval s 7.9 days.. The m-CPP and placebo procedures were identical in terms of medication administration and blood-drawing schedules. Blood samples for prolactin, cortisol, and m-CPP levels were drawn at y30, 0 Žbaseline ., 90, 120, 180, and 210 min following administration of m-CPP or placebo. To assess serotonergic sensitivity via neuroendocrine response to m-CPP, between-group comparisons utilized analysis of variance with repeated measures ŽANOVAR., and where significant, Student’s non-paired t-tests to assess pairwise contrasts. The peak change in prolactin and cortisol was calculated Žby subtracting the baseline value from the value at the time of maximum change following m-CPP administration.. Given that gender has been found to significantly affect prolactin and cortisol response, males and females were analyzed separately for prolactin and cortisol response. Pearson correlations between the peak m-CPP blood levels and the peak change in prolactin or cortisol levels were then conducted. Significance levels for all analyses are two-tailed, at PF 0.05.
CPP significantly correlated with peak plasma m-CPP levels in social phobics Ž r s 0.67, n s 18, PF 0.045. and OCD control subjects Ž r s 0.57, n s 39, PF 0.001. but not normal control subjects Ž r s 0.23, n s 21, PF 0.32.. The peak increase in cortisol level following m-CPP significantly correlated with peak plasma m-CPP levels in social phobics Ž r s 0.64, n s 18, PF 0.005. and OCD control subjects Ž r s 0.29, n s 39, PF 0.07. but not normal control subjects Ž r s 0.31, n s 21, Ps 0.17.. The m-CPP caused a significant drug= time rise in prolactin Ž F s 0.68, d.f.s 4,119, PF 0.001. and cortisol levels Ž F s 0.71, d.f.s 4,114, PF 0.001., consistent with stimulation of hypothalamic 5-HT receptors. There were no differences in prolactin response to m-CPP across groups ŽTable 1.. Within males, social phobics did not differ from OCD or normal control subjects in prolactin response to m-CPP Ždrug= time = group effect. Ž F s 0.16, d.f.s 8,118, PF 0.32.. Within females, there was a marginal difference in prolactin response to m-CPP across groups Ž F s 0.30, d.f.s 8,98, PF 0.075.. However, pairwise comparisons did not reach significance. There was a significant difference across groups in cortisol response to m-CPP Ž F s 0.14, d.f.s 8,226, PF 0.046. such that social phobics had a
3. Results
Table 1 Prolactin levels in social phobic ŽSP., normal control ŽNC. and obsessive-compulsive disorder ŽOCD. subjects
Age differed between groups, such that the normal control subjects Žmean age " S.D., 29.8" 5.93. were younger than the social phobics Ž35.6 " 9.31; t s y2.27, d.f.s 28.29, PF 0.031. and OCD Ž34.2" 10.06; t s 2.17, d.f.s 57.11, PF 0.034. control subjects. However, age did not significantly affect either prolactin Ž r s y0.09, n s 80, PF 0.41. or cortisol Ž r s 0.05, n s 80, PF 0.68. response to m-CPP. The m-CPP plasma levels in social phobic patients Ž28.11" 22.21 ngrml. did not significantly differ from those in normal control subjects Ž24.67" 15.15 ngrml. or OCD Ž26.91" 23.57 ngrml. control subjects Ž F s 0.135, d.f.s 2, PF 0.874.. Peak increase in prolactin level following m-
Baseline Mean " S.D.
Peak Mean " S.D.
Peak delta Mean " S.D.
SP NC OCD
9.18" 4.09 9.26" 3.14 7.68" 2.40
18.68" 12.07 18.67" 8.39 15.61" 11.60
9.50" 9.89 9.27" 6.65 7.85" 11.23
Males SP NC OCD
7.39" 1.81 7.72" 1.96 7.30" 2.35
14.30" 5.10 15.65" 9.48 12.37" 6.67
6.91" 5.13 7.63" 8.83 4.95" 6.14
Females SP NC OCD
10.98" 5.00 10.65" 3.43 8.44" 2.40
23.07" 15.50 21.42" 6.52 22.10" 16.26
12.09" 12.90 10.76" 3.61 13.66" 16.27
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
216
greater cortisol response Žpeak change " S.D., 9.07" 7.50. than the normal control subjects Ž5.89" 5.93. and OCD control subjects Ž7.04" 7.35. ŽTable 2.. However, pairwise comparisons did not reach significance. There were no differences between male social phobic patients vs. male normal and OCD control subjects. However, female social phobics had a trend toward augmented cortisol response Ž9.06" 8.85. to m-CPP in comparison to female normal control subjects Ž3.96" 4.18; t s 1.7, d.f.s 18, PF 0.10., but did not differ from OCD control subjects Ž6.70" 8.30; t s 0.65, d.f.s 21, PF 0.524. ŽTable 2.. The small sample size of female patients may make it difficult to detect mild or moderate differences between groups. 4. Discussion Similar to the findings from Tancer et al. Ž1995., the social phobics in this study had a normal prolactin response and an augmented cortisol response to m-CPP in comparison to normal control subjects. The increased cortisol response was more robust among the female social phobics than in female normal control subjects. However, the relatively small sample sizes resulted in only trend significance in pairwise comparisons.
Table 2 Cortisol levels in social phobic ŽSP., normal control ŽNC. and obsessive-compulsive disorder ŽOCD. subjects Baseline Mean " S.D.
Peak Mean " S.D.
Peak delta Mean " S.D.
SP NC OCD
10.95" 3.27 9.30" 2.45 10.40" 5.20
20.03" 7.69 15.66" 4.83 17.89" 5.71
9.07" 7.50 5.89" 5.93 7.04" 7.35
Males SP NC OCD
10.63" 3.67 9.15" 1.99 9.83" 4.19
19.72" 7.50 17.68" 5.20 17.09" 5.44
9.09" 6.43 8.01" 7.01 7.20" 6.98
Females SP NC OCD
11.27" 3.01 9.45" 2.90 11.53" 6.85
20.33" 8.33 13.82" 3.80 19.49" 6.10
9.06" 8.85 3.96" 4.18 6.70" 8.30
This pattern of neuroendocrine responsivity to m-CPP in social phobics differs from that seen in OCD patients. Previously, we had reported significant blunting of prolactin response to m-CPP in OCD patients vs. normal control subjects, especially in male OCD patients and no differences in cortisol response. In the current sample, while male OCD patients tended to have less robust prolactin response to m-CPP Ž4.95q 6.14. than normal control subjects Ž7.63q 8.83., they did not reach significance. This may be due to differences in the OCD patient sample and heterogeneity of 5-HT function in OCD. Social phobics are clinically distinct from OCD patients ŽLiebowitz et al., 1985a. and may be pathophysiologically distinct as well, as suggested by their good responses to monoamine oxidase inhibitors ŽLiebowitz et al., 1988. and high potency benzodiazapines ŽLydiard et al., 1988; Reiter et al., 1990., but poor response to clomipramine ŽVersiani et al., 1988.. Social phobics, in contrast to patients with other anxiety disorders, such as panic disorder, lack an anxiogenic response to lactate ŽLiebowitz et al., 1985b. and epinephrine ŽPapp et al., 1988. challenges. We now report that social phobics have a normal prolactin but augmented cortisol response to mCPP, in contrast to normal control subjects and OCD patients. However, further studies are required in larger sample sizes to replicate these preliminary findings. A methodological limitation of this study is the sample size. The small number of subjects may make it difficult to detect mild or moderate differences between groups and thus the possibility of a type II error. Another limitation is that this study did not control for seasonality and menstrual fluctuations, although these factors may influence serotonin function. This study provides preliminary evidence for 5-HT dysfunction in social phobics, particularly in female social phobics. The augmented cortisol response in female social phobics is reminiscent of the increased cortisol response in panic patients who were late panickers to sodium lactate infusions, in contrast to the normal cortisol response found in early panickers to sodium lactate ŽHollander et al., 1991., and may be associated with
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
anticipatory anxiety as opposed to panic anxiety. This is of interest since social phobic patients have considerable anticipatory anxiety about social situations. Acknowledgements We acknowledge the helpful contributions of Franklin Schneier, M.D., Brian Fallon, M.D., and Raphael Campeas, M.D., to this study. Supported in part by Research Scientist Development Award MH-00750 ŽE. Hollander. from the NIMH, Bethesda, MD; the Seaver Foundation; and the Mount Sinai General Clinical Research Center from the National Center for Research Resources, NIH ŽM01 RR00071.. References Bastani, B., Nash, J.F., Meltzer, H.Y., 1990. Prolactin and cortisol responses to MK-212, a serotonin agonist, in obsessive]compulsive disorder. Archives of General Psychiatry 47, 833]839. Benkelfat, C., Murphy, D.L., Zohar, J., Hill, J.L., Grover, G., Insel, T.R., 1989. Clomipramine in obsessive]compulsive disorder: further evidence for serotonergic mechanism of action. Archives of General Psychiatry 46, 23]28. Black, B., Uhde, T.W., Tancer, M.E., 1992. Fluoxetine for the treatment of social phobia Žletter.. Journal of Clinical Psychopharmacology 12, 293]295. Charney, D.S., Woods, S.W., Krystal, J.H., Heninger, G.R., 1990. Serotonin function and human anxiety disorders. Annals of the New York Academy of Science 600, 558]573. Geller, I., Blum, K., 1970. The effects of 5-HTP on parachlorophenylalanine Žp-CPA. attenuation of ‘conflict’ behavior. European Journal of Pharmacology 9, 319]324. Hollander, E., DeCaria, C., Gulley, R., Nitescu, A., Suchow, R.F., Gorman, J.G., Klein, D.F., Liebowitz, M.R., 1991. Effects of chronic fluoxetine treatment on behavioral and neuroendocrine response to meta-chlorophenylpiperazine in obsessive]compulsive disorder. Psychiatry Research 36, 1]17. Hollander, E., DeCaria, C., Nitescu, A., Gully, R., Suckow, R.F., Cooper, T.B., Gorman, J.M., Klein, D.F., Liebowitz, M.R., 1992. Serotonergic function in OCD: behavioral and neuroendocrine responses to oral m-CPP and fenfluramine in patients and healthy volunteers. Archives of General Psychiatry 49, 21]28. Liebowitz, M.R., Gorman, J.M., Fyer, A.J., Campeas, R., Levin,
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A.P., Sandberg, D., Hollander, E., Papp, L., Goetz, D., 1988. Pharmacotherapy of social phobia: an interim report of a placebo controlled comparison of phenelzine and atenolol. Journal of Clinical Psychiatry 49, 252]257. Liebowitz, M.R., Gorman, J.M., Fyer, A.J., Klein, D.F., 1985a. Social phobia: review of neglected anxiety disorder. Archives of General Psychiatry 42, 729]736. Liebowitz, M.R., Fyer, A.J., Gorman, J.M., Dillon, D., Davies, S., Stein, J.M., Cohen, B.S., Klein, D.F., 1985b. Specificity of lactate infusions in social phobia versus panic disorders. American Journal of Psychiatry 142, 947]950. Lydiard, R.B., Laraia, M.T., Howell, E.F., 1988. Alprazolam in the treatment of social phobia. Journal of Clinical Psychiatry 49, 17]19. Munjack, D.J., Bruns, J., Baltazar, P.L., Brown, R., Leonard, M., Nagy, R., Koek, R., Crocker, B., Schafer, S., 1991. A pilot study of buspirone in the treatment of social phobia. Journal of Anxiety Disorders 5, 87]98. Papp, L.A., Gorman, J.M., Liebowitz, M.R., Fyer, A.J., Cohen, B., Klein, D.F., 1988. Epinephrine infusions in patients with social phobia. American Journal of Psychiatry 145, 733]736. Pigott, T.A., Zohar, J., Hill, J.L., Bernstein, S.E., Grover, G.N., Zohar-Kadouch, R.C., Murphy, D.L., 1991. Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-CPP in patients with OCD. Biological Psychiatry 29, 418]426. Reiter, S.R., Pollack, M.H., Rosenbaum, J.F., 1990. Clonazepam for the treatment of social phobia. Journal of Clinical Psychiatry 51, 470]472. Schneier, F.R., Johnson, J., Hornig, C.D., Liebowitz, M.R., Weissman, M., 1992. Social phobia comorbidity and morbidity in an epidemiologic sample. Archives of General Psychiatry 49, 282]288. Schneier, F.R., Saoud, J.B., Campeas, R., Fallon, B.A., Hollander, E., Coplan, J., Liebowitz, M.R., 1993. Buspirone in social phobia. Journal of Clinical Psychopharmacology 13, 251]256. Tancer, M.E., Mailman, R.B., Stein, M.B., Mason, G.A., Carson, S.W., Golden, R.N., 1995. Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1Ž5., 216]223. Van Ameringen, M., Mancini, C., Streiner, D.L., 1993. Fluoxetine efficacy in social phobia. Journal of Clinical Psychopharmacology 54, 27]32. Versiani, M., Mundim, D.F., Nardi, A.E., Liebowitz, M.R., 1988. Tranylcypromine in social phobia. Journal of Clinical Psychopharmacology 8, 279]283. Zohar, J., Mueller, E.A., Insel, T.R., Zohar-Kadouch, R.C., Murphy, D.L., 1987. Serotonergic responsivity in obsessive]compulsive disorder: comparison of patients and healthy controls. Archives of General Psychiatry 44, 946]951.
Serotonergic function in social phobia: comparison to normal control and obsessive]compulsive disorder subjects Eric Hollander U , Jee Kwon, Fenia Weiller, Lisa Cohen, Dan J. Stein, Concetta DeCaria, Michael Liebowitz, Daphne Simeon Department of Psychiatry, Box 1230, Mt. Sinai School of Medicine, 1 Gusta¨ e L. Le¨ y Place, New York, NY 10029, USA Received 6 June 1996; received in revised form 5 August 1997; accepted 27 March 1998
Abstract Eighteen patients with social phobia, 21 normal control subjects, and 42 obsessive]compulsive disorder ŽOCD. control subjects were challenged with single doses of the partial serotonin agonist oral m-chlorophenylpiperazine Ž m-CPP. and placebo. Social phobics did not significantly differ from normal or OCD control subjects in prolactin response to m-CPP. There was a significant difference across groups in cortisol response to m-CPP, such that female social phobics had more robust cortisol responses to the m-CPP challenge. Pairwise comparisons only reached trend significance, perhaps due to the relatively small sample sizes. This study offers preliminary evidence for serotonin dysfunction in social phobia, particularly in female social phobics, but needs to be replicated in a larger sample size. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Social phobia; Serotonin Ž5-HT.; Obsessive]compulsive disorder; m-CPP; Prolactin; Cortisol
1. Introduction Social phobia is one of the most common psychiatric disorders, with an early age of onset and a usually chronic course ŽSchneier et al., 1992.. It results in significant long-term distress and social disability. Little is known about its etiology. Re-
U
Corresponding author. Tel.: q1 212 2413623; fax: q1 212 9874031.
cent evidence suggests that some serotonergic agents improve symptoms of social phobia. Preliminary studies with selective serotonin Ž5-HT. reuptake blockers such as fluoxetine have shown therapeutic efficacy in the treatment of social phobia ŽBlack et al., 1992; Van Ameringen et al., 1993.. The 5-HT1a agonist buspirone has shown partial therapeutic efficacy in symptoms of generalized social phobia ŽMunjack et al., 1991; Schneier et al., 1993.. Pre-clinical studies also demonstrate that 5-HT is involved in anxiety and
0165-1781r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž98.00041-9
214
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
assessment of harm ŽGeller and Blum, 1970; Charney et al., 1990.. Taken together, this suggests that 5-HT might be involved in the pathophysiology of social phobia and social anxiety. Little work has been conducted to date with pharmacological challenges in social phobia, but preliminary studies suggest that social phobics may have an augmented cortisol response to the net 5-HT releaser fenfluramine ŽTancer et al., 1995.. Pharmacological challenge studies with 5-HT agonists ŽZohar et al., 1987; Bastani et al., 1990; Hollander et al., 1991, 1992. and antagonists ŽZohar et al., 1987; Benkelfat et al., 1989; Pigott et al., 1991. have demonstrated complex effects on behavioral and neuroendocrine responsivity in OCD in comparison to normal control subjects, suggesting 5-HT dysfunction in a subgroup of OCD patients. However, the specificity of these findings in OCD is unknown, since comparisons with other anxiety control groups have not been previously undertaken. This study was designed to measure abnormalities in the 5-HT function in social phobia via pharmacological challenges with the partial 5-HT agonist m-CPP and placebo, and to determine whether findings are specific to social phobia per se or also found in normal and OCD control subjects. It was expected that social phobics would have less serotonergic dysfunction than OCD patients because, while responsive to serotonergic medications, social phobics lack the selective responsivity to serotonin reuptake inhibitors found in OCD. To do this, we compared social phobic patients to normal control subjects and OCD patients on neuroendocrine responses to m-CPP and placebo. 2. Methods Adult social phobic patients Ž N s 18, nine males, nine females; mean age 36 years. were compared to matched normal control subjects Ž N s 21, 10 males, 11 females; mean age 30 years. and OCD control subjects Ž N s 42, 28 males, 14 females; mean age 34 years.. Findings for a subgroup of the OCD patients Ž N s 20. were previously reported ŽHollander et al., 1992.. Patients had either been referred by mental health practi-
tioners, or responded to advertisements or to media reports seeking participants for biological challenge research studies in social phobia or OCD. After a discussion of the potential risks of the pharmacological challenges, all patients signed informed consent forms and were compared on neuroendocrine responses following double-blind, randomized, single-dose challenge of the partial 5-HT receptor agonist m-CPP Ž0.5 mgrkg p.o.. and placebo. Social phobic patients met the DSM III-R criteria for generalized social phobia in that their fears included most social situations. No social phobic met the DSM III-R criteria for any comorbid Axis I or Axis II disorders other than avoidant personality disorder. None of the social phobic patients had ever received a 5-HT reuptake blocker. OCD patients met the DSM-III-R criteria for OCD on the basis of semi-structured diagnostic interviews and did not meet the criteria for any comorbid Axis I or Axis II disorders. Of the 42 OCD patients, 34 had previously received a 5-HT reuptake blocker Žfluoxetine or clomipramine. to which 22 were responders and 12 were non-responders. All subjects in the three groups were medication free for a minimum of 4 weeks prior to study Ž6 weeks for those previously on fluoxetine. and were medically healthy. Female subjects were all premenopausal and none were taking oral contraceptives. Normal control subjects were recruited from the normal control subject pool of either the Mental Health Clinical Research Center ŽMHCRC. or the Anxiety Clinic of the New York State Psychiatric Institute, and were determined to be free of all DSM III-R illnesses via semistructured diagnostic interviews. All diagnostic evaluations were conducted by experienced research psychiatrists specializing in anxiety disorders. Prior to the challenge procedures, subjects were maintained on a low monoamine diet for 72 h to minimize the effect of tyramine on prolactin. To control for the effects of circadium rhythms on cortisol response to m-CPP, all challenges were performed during the same time of day. During the challenge procedures, patients remained awake, at bed rest, and without food. One hour
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
215
after insertion of an indwelling intravenous catheter, each subject received either placebo or an identical capsule of m-CPP orally. The m-CPP dose was 0.5 mgrkg, to replicate our work in OCD ŽHollander et al., 1992.. The m-CPP and placebo challenges were randomized and separated by at least 72 h Žmean interval s 7.9 days.. The m-CPP and placebo procedures were identical in terms of medication administration and blood-drawing schedules. Blood samples for prolactin, cortisol, and m-CPP levels were drawn at y30, 0 Žbaseline ., 90, 120, 180, and 210 min following administration of m-CPP or placebo. To assess serotonergic sensitivity via neuroendocrine response to m-CPP, between-group comparisons utilized analysis of variance with repeated measures ŽANOVAR., and where significant, Student’s non-paired t-tests to assess pairwise contrasts. The peak change in prolactin and cortisol was calculated Žby subtracting the baseline value from the value at the time of maximum change following m-CPP administration.. Given that gender has been found to significantly affect prolactin and cortisol response, males and females were analyzed separately for prolactin and cortisol response. Pearson correlations between the peak m-CPP blood levels and the peak change in prolactin or cortisol levels were then conducted. Significance levels for all analyses are two-tailed, at PF 0.05.
CPP significantly correlated with peak plasma m-CPP levels in social phobics Ž r s 0.67, n s 18, PF 0.045. and OCD control subjects Ž r s 0.57, n s 39, PF 0.001. but not normal control subjects Ž r s 0.23, n s 21, PF 0.32.. The peak increase in cortisol level following m-CPP significantly correlated with peak plasma m-CPP levels in social phobics Ž r s 0.64, n s 18, PF 0.005. and OCD control subjects Ž r s 0.29, n s 39, PF 0.07. but not normal control subjects Ž r s 0.31, n s 21, Ps 0.17.. The m-CPP caused a significant drug= time rise in prolactin Ž F s 0.68, d.f.s 4,119, PF 0.001. and cortisol levels Ž F s 0.71, d.f.s 4,114, PF 0.001., consistent with stimulation of hypothalamic 5-HT receptors. There were no differences in prolactin response to m-CPP across groups ŽTable 1.. Within males, social phobics did not differ from OCD or normal control subjects in prolactin response to m-CPP Ždrug= time = group effect. Ž F s 0.16, d.f.s 8,118, PF 0.32.. Within females, there was a marginal difference in prolactin response to m-CPP across groups Ž F s 0.30, d.f.s 8,98, PF 0.075.. However, pairwise comparisons did not reach significance. There was a significant difference across groups in cortisol response to m-CPP Ž F s 0.14, d.f.s 8,226, PF 0.046. such that social phobics had a
3. Results
Table 1 Prolactin levels in social phobic ŽSP., normal control ŽNC. and obsessive-compulsive disorder ŽOCD. subjects
Age differed between groups, such that the normal control subjects Žmean age " S.D., 29.8" 5.93. were younger than the social phobics Ž35.6 " 9.31; t s y2.27, d.f.s 28.29, PF 0.031. and OCD Ž34.2" 10.06; t s 2.17, d.f.s 57.11, PF 0.034. control subjects. However, age did not significantly affect either prolactin Ž r s y0.09, n s 80, PF 0.41. or cortisol Ž r s 0.05, n s 80, PF 0.68. response to m-CPP. The m-CPP plasma levels in social phobic patients Ž28.11" 22.21 ngrml. did not significantly differ from those in normal control subjects Ž24.67" 15.15 ngrml. or OCD Ž26.91" 23.57 ngrml. control subjects Ž F s 0.135, d.f.s 2, PF 0.874.. Peak increase in prolactin level following m-
Baseline Mean " S.D.
Peak Mean " S.D.
Peak delta Mean " S.D.
SP NC OCD
9.18" 4.09 9.26" 3.14 7.68" 2.40
18.68" 12.07 18.67" 8.39 15.61" 11.60
9.50" 9.89 9.27" 6.65 7.85" 11.23
Males SP NC OCD
7.39" 1.81 7.72" 1.96 7.30" 2.35
14.30" 5.10 15.65" 9.48 12.37" 6.67
6.91" 5.13 7.63" 8.83 4.95" 6.14
Females SP NC OCD
10.98" 5.00 10.65" 3.43 8.44" 2.40
23.07" 15.50 21.42" 6.52 22.10" 16.26
12.09" 12.90 10.76" 3.61 13.66" 16.27
E. Hollander et al. r Psychiatry Research 79 (1998) 213]217
216
greater cortisol response Žpeak change " S.D., 9.07" 7.50. than the normal control subjects Ž5.89" 5.93. and OCD control subjects Ž7.04" 7.35. ŽTable 2.. However, pairwise comparisons did not reach significance. There were no differences between male social phobic patients vs. male normal and OCD control subjects. However, female social phobics had a trend toward augmented cortisol response Ž9.06" 8.85. to m-CPP in comparison to female normal control subjects Ž3.96" 4.18; t s 1.7, d.f.s 18, PF 0.10., but did not differ from OCD control subjects Ž6.70" 8.30; t s 0.65, d.f.s 21, PF 0.524. ŽTable 2.. The small sample size of female patients may make it difficult to detect mild or moderate differences between groups. 4. Discussion Similar to the findings from Tancer et al. Ž1995., the social phobics in this study had a normal prolactin response and an augmented cortisol response to m-CPP in comparison to normal control subjects. The increased cortisol response was more robust among the female social phobics than in female normal control subjects. However, the relatively small sample sizes resulted in only trend significance in pairwise comparisons.
Table 2 Cortisol levels in social phobic ŽSP., normal control ŽNC. and obsessive-compulsive disorder ŽOCD. subjects Baseline Mean " S.D.
Peak Mean " S.D.
Peak delta Mean " S.D.
SP NC OCD
10.95" 3.27 9.30" 2.45 10.40" 5.20
20.03" 7.69 15.66" 4.83 17.89" 5.71
9.07" 7.50 5.89" 5.93 7.04" 7.35
Males SP NC OCD
10.63" 3.67 9.15" 1.99 9.83" 4.19
19.72" 7.50 17.68" 5.20 17.09" 5.44
9.09" 6.43 8.01" 7.01 7.20" 6.98
Females SP NC OCD
11.27" 3.01 9.45" 2.90 11.53" 6.85
20.33" 8.33 13.82" 3.80 19.49" 6.10
9.06" 8.85 3.96" 4.18 6.70" 8.30
This pattern of neuroendocrine responsivity to m-CPP in social phobics differs from that seen in OCD patients. Previously, we had reported significant blunting of prolactin response to m-CPP in OCD patients vs. normal control subjects, especially in male OCD patients and no differences in cortisol response. In the current sample, while male OCD patients tended to have less robust prolactin response to m-CPP Ž4.95q 6.14. than normal control subjects Ž7.63q 8.83., they did not reach significance. This may be due to differences in the OCD patient sample and heterogeneity of 5-HT function in OCD. Social phobics are clinically distinct from OCD patients ŽLiebowitz et al., 1985a. and may be pathophysiologically distinct as well, as suggested by their good responses to monoamine oxidase inhibitors ŽLiebowitz et al., 1988. and high potency benzodiazapines ŽLydiard et al., 1988; Reiter et al., 1990., but poor response to clomipramine ŽVersiani et al., 1988.. Social phobics, in contrast to patients with other anxiety disorders, such as panic disorder, lack an anxiogenic response to lactate ŽLiebowitz et al., 1985b. and epinephrine ŽPapp et al., 1988. challenges. We now report that social phobics have a normal prolactin but augmented cortisol response to mCPP, in contrast to normal control subjects and OCD patients. However, further studies are required in larger sample sizes to replicate these preliminary findings. A methodological limitation of this study is the sample size. The small number of subjects may make it difficult to detect mild or moderate differences between groups and thus the possibility of a type II error. Another limitation is that this study did not control for seasonality and menstrual fluctuations, although these factors may influence serotonin function. This study provides preliminary evidence for 5-HT dysfunction in social phobics, particularly in female social phobics. The augmented cortisol response in female social phobics is reminiscent of the increased cortisol response in panic patients who were late panickers to sodium lactate infusions, in contrast to the normal cortisol response found in early panickers to sodium lactate ŽHollander et al., 1991., and may be associated with
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anticipatory anxiety as opposed to panic anxiety. This is of interest since social phobic patients have considerable anticipatory anxiety about social situations. Acknowledgements We acknowledge the helpful contributions of Franklin Schneier, M.D., Brian Fallon, M.D., and Raphael Campeas, M.D., to this study. Supported in part by Research Scientist Development Award MH-00750 ŽE. Hollander. from the NIMH, Bethesda, MD; the Seaver Foundation; and the Mount Sinai General Clinical Research Center from the National Center for Research Resources, NIH ŽM01 RR00071.. References Bastani, B., Nash, J.F., Meltzer, H.Y., 1990. Prolactin and cortisol responses to MK-212, a serotonin agonist, in obsessive]compulsive disorder. Archives of General Psychiatry 47, 833]839. Benkelfat, C., Murphy, D.L., Zohar, J., Hill, J.L., Grover, G., Insel, T.R., 1989. Clomipramine in obsessive]compulsive disorder: further evidence for serotonergic mechanism of action. Archives of General Psychiatry 46, 23]28. Black, B., Uhde, T.W., Tancer, M.E., 1992. Fluoxetine for the treatment of social phobia Žletter.. Journal of Clinical Psychopharmacology 12, 293]295. Charney, D.S., Woods, S.W., Krystal, J.H., Heninger, G.R., 1990. Serotonin function and human anxiety disorders. Annals of the New York Academy of Science 600, 558]573. Geller, I., Blum, K., 1970. The effects of 5-HTP on parachlorophenylalanine Žp-CPA. attenuation of ‘conflict’ behavior. European Journal of Pharmacology 9, 319]324. Hollander, E., DeCaria, C., Gulley, R., Nitescu, A., Suchow, R.F., Gorman, J.G., Klein, D.F., Liebowitz, M.R., 1991. Effects of chronic fluoxetine treatment on behavioral and neuroendocrine response to meta-chlorophenylpiperazine in obsessive]compulsive disorder. Psychiatry Research 36, 1]17. Hollander, E., DeCaria, C., Nitescu, A., Gully, R., Suckow, R.F., Cooper, T.B., Gorman, J.M., Klein, D.F., Liebowitz, M.R., 1992. Serotonergic function in OCD: behavioral and neuroendocrine responses to oral m-CPP and fenfluramine in patients and healthy volunteers. Archives of General Psychiatry 49, 21]28. Liebowitz, M.R., Gorman, J.M., Fyer, A.J., Campeas, R., Levin,
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