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Richard R. Owen, Jr, MD; Rolando Gutierrez-Esteinou, MD; John Hsiao, MD; Kayleen Hadd, MSN; Brian A. Lawlor, MD; Dennis L. Murphy, MD; David Pickar, MD

Arch Gen Psychiatry. 1993;50(8):636-644.

Abstract
Objective
To explore serotonin function in patients with schizophrenia during typical and atypical neuroleptic treatment. We hypothesized that clinically relevant doses of the atypical neuroleptic clozapine would attenuate responses to the serotonin agonist m-chlorophenylpiperazine (m-CPP).

Design and Interventions
m-CPP or placebo was administered intravenously over 90 seconds to patients who had been receiving no medications for at least 3 weeks. m-CPP was also administered during treatment with the typical neuroleptic fluphenazine and the atypical neuroleptic clozapine.

Patients
Fifteen inpatients (two women and 13 men) who met DSM-III-R criteria for chronic schizophrenia (n=13) or schizoaffective disorder (n=2) participated in the study. Mean age (±SD) was 33.8±8.0 years.

Main Outcome Measures
Measures of m-CPP effects included plasma cortisol and prolactin, body tempera- ture, and the Brief Psychiatric Rating Scale (BPRS). The final BPRS total score at approximately 12 weeks of treatment was used to assess response to clozapine.

Results
m-CPP infusion significantly increased plasma cortisol and prolactin levels in drug-free patients. There was a range of behavioral responses while drug-free, but no statistically significant effects on BPRS total or BPRS factor scores. Clozapine treatment significantly blocked neuroendocrine responses to m-CPP, whereas fluphenazine had no effect. Clozapine also appeared to attenuate behavioral responses.

Conclusions
These results demonstrate that clozapine treatment has potent serotonin antagonist effects in patients with schizophrenia. This may be related to clozapine's therapeutic effects since patients with greater cortisol response to m-CPP while drug-free had a better subsequent response to clozapine.

Author Affiliations
From the Experimental Therapeutics Branch (Drs Owen, Gutierrez-Esteinou, Hsiao, and Pickar) and the Laboratory of Clinical Sciences (Drs Benkelfat, Lawlor, and Murphy), National Institute of Mental Health, and the Warren Grant Magnuson Clinical Center, Nursing Department (Mrs Hadd), National Institutes of Health, Bethesda, Md; and Little Rock Veterans Affairs Medical Center and Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock (Dr Owen).

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