Am J Psychiatry 1993; 150:1337-1342
Copyright © 1993 by American Psychiatric Association
Serotonin function and treatment response to clozapine in schizophrenic patients
RS Kahn, M Davidson, L Siever, S Gabriel, S Apter and KL Davis
Department of Psychiatry, Mount Sinai School of Medicine/Bronx VA Hospital, New York.
OBJECTIVE: Clozapine is the only compound proven to be effective in the 20%
of schizophrenic patients refractory to treatment with conventional
neuroleptics. Although its mechanism of action has not been elucidated,
clozapine appears, in contrast to most conventional neuroleptics, to be a
potent serotonin (5-HT) antagonist. This study hypothesized that 5-HT
function is increased in patients who benefit from clozapine treatment
relative to patients who fail to improve on it. METHOD: The 5-HT receptor
agonist m-chlorophenylpiperazine (MCPP) was used as a probe to examine 5-HT
function. MCPP (0.35 mg/kg p.o.) was administered in a placebo-controlled
design after a 3-week drug-free period to 19 schizophrenic patients. ACTH,
prolactin, body temperature, behavior, and MCPP blood level were measured.
Patients were then treated with a conventional neuroleptic, and, having
failed to respond to it, were treated with clozapine for 5 weeks (up to 600
mg/day). RESULTS: Patients who responded to clozapine had significantly
higher ACTH responses to MCPP during the drug-free state than the patients
who failed to benefit from clozapine. Moreover, the degree of improvement
with clozapine, particularly the improvement in psychotic symptoms, was
strongly correlated with the magnitude of MCPP-induced ACTH release. Other
MCPP-induced responses and MCPP blood level were similar for the two groups
and did not correlate with the degree of symptomatic improvement with
clozapine. CONCLUSIONS: Results of this study suggest that MCPP-induced
ACTH release, and by inference 5-HT receptor function, may be increased in
patients who benefit from treatment with clozapine relative to patients who
fail to improve on this drug.
