Clozapine as a drug of dependence

Rationale: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chro nic treatment. Objective: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temper ature measures. Methods: Two groups of 15 female Wistar rats were treated c hronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 da ys prior to cessation of drug treatment, withdrawal being studied over 4 co nsecutive days. Body temperatures were assessed daily throughout the study. Results: Acutely, clozapine induced dose-related hypothermia, to which com plete tolerance developed in both groups, the development of tolerance bein g more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per inje ction of clozapine showed rapid onset significant hyperthermia. This dissip ated progressively over days, and was completely absent after 4 days of wit hdrawal. Conclusions: Clozapine induced a clear somatic withdrawal sign aft er chronic treatment. It is suggested that, in future research in both huma ns and animals, it is important to attempt to differentiate between clozapi ne withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in a nimals; to establish the neurochemical mechanisms involved in such withdraw al; and to determine which novel antipsychotics are most efficacious in ind ucing clozapine-like withdrawal effects, in suppressing clozapine withdrawa l, and in preventing relapse to psychosis in patients being transferred fro m clozapine to novel atypical antipsychotic drugs.