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Further Evidence for a Serotonergic Mechanism of Action

Chawki Benkelfat, MD; Dennis L. Murphy, MD; Joseph Zohar, MD; James L. Hill, PhD; Gay Grover, RN, MS; Thomas R. Insel, MD

Arch Gen Psychiatry. 1989;46(1):23-28.

Abstract
• Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.

Author Affiliations
From the Section on Clinical Neuropharmacology, Laboratory of Clinical Science, National Institute of Mental Health (Drs Benkelfat, Murphy, Zohar, and Hill), and Nursing Department (Ms Grover), National Institutes of Health Clinical Center, Bethesda, Md; and the Section on Comparative Studies of Brain and Behavior, Laboratory of Clinical Science, National Institute of Mental Health, Poolesville, Md (Dr Insel).

Footnotes
Accepted for publication April 27, 1988.

Reprint requests to LCS, NIMH, NIH Clinical Center, 10-3D41, 9000 Rockville Pike, Bethesda, MD 20892 (Dr Benkelfat).

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