Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone

Abstract

Rationale: The pharmacological profile of risperidone is that of an atypical neuroleptic regarding its serotonin 5-HT2A and dopamine D2 receptor blocking properties. Treatment with risperidone, though, results in considerably elevated plasma prolactin (PRL) levels which are not observed with other atypical neuroleptics, such as clozapine, indicating a differentiated action on receptors that are involved in PRL release, mainly dopaminergic and serotonergic.

Objective: To assess the responsivity of serotonergic and dopaminergic receptors during treatment with neuroleptics and after switch to risperidone, using neuroendocrine paradigms.

Methods: Two neuroendocrine challenge tests, measuring the PRL increases induced by acute administration of serotonergic (clomipramine, 25 mg i.v.) and dopaminergic (haloperidol, 5 mg i.m.) drugs were performed in 13 male schizophrenic patients during treatment with typical neuroleptics and, later, after 6 weeks of treatment with risperidone. The tests were also performed in a group of nine healthy male volunteers. PRL was estimated in blood samples taken every 15 min for 1 h for clomipramine and every 30 min for 2 h for haloperidol. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS).

Results: During treatment with neuroleptics (mean dose 1354 mg chlorpromazine equivalents, range 300-2400 mg), i.m. haloperidol caused significant elevations in plasma PRL, which were totally abolished after 6 weeks treatment with risperidone (mean dose 12.1 mg/day, range 8-16 mg/day), indicating complete D2 receptor blockade. In contrast, the PRL increases obtained after clomipramine administration during neuroleptic treatment were preserved after treatment with risperidone. Both PRL response patterns to clomipramine were similar to that of healthy controls. BPRS score was 50.2+/-9.3 points during neuroleptic treatment and was reduced after risperidone to 30.1+/-6.6 points, i.e., 40% in the mean.

Conclusions: During treatment with typical neuroleptics, the PRL responses to clomipramine are normal, and they are preserved after switch to risperidone in doses that cause complete dopamine receptor blockade. Risperidone, a dopamine and 5-HT receptor blocker, does not affect 5-HT receptors that are involved in the PRL release by the 5-HT uptake blocker clomipramine, indicating a different behavior than other atypical neuroleptics such as clozapine or olanzapine, for which a reduction of the PRL release induced by serotonergic agents like fenfluramine or mCPP has been reported. A conclusive identification of the 5-HT receptor subtypes that are involved in this different action cannot be identified at present, but it should be taken into account that risperidone differs from clozapine, showing higher affinity for 5-HT2A than 5-HT2C receptors and lacking the marked affinity of clozapine to 5-HT1A receptors.