Effects of chronic administration of olanzapine, amitriptyline, haloperidol or sodium valproate in naive and anhedonic rats

Although in bipolar patients the main therapeutic indication of atypical antipsychotics is the management of acute mania, several observations suggest that these agents may exert antidepressant as well as anti-manic effects. The main goal of the present work was to evaluate the putative antidepressant effect of chronic olanzapine (Ola) (0.02-0.1 or 0.5 mg/kg.d), in comparison to haloperidol (Hal) (0.2 mg/kg.d) and sodium valproate (VPA) (5 or 30 mg/kg.d), in rats exposed to a protocol of chronic mild stress. The tricyclic compound amitriptyline (Ami) (5 mg/kg.d) was used as reference drug. The results indicate that Ola, in a rodent model of depression, has protective effects against the stress-induced anhedonia. Compared to Hal and VPA, Ola shows a greater antidepressant activity and is as effective as Ami in preventing the anhedonic state. The effects of Ola and Ami, however, have a different time-course. A full reversion of the anhedonia by Ami appears after a latency of 4 wk, whereas the effect of Ola is already evident 1 wk after the beginning of the chronic treatment. Moreover, the recovery from anhedonia at the end of the stress protocol and after drug cessation was more rapid in groups of rats pretreated with Ola or VPA than in the group of saline-pretreated rats. In conclusion, the results indicate that 0.02 mg/kg.d Ola causes a rapid and sustained antidepressant-like effect, while all other anti-manic treatments show loss of efficacy at 3 wk. Taken together, these observations support the hypothesis that Ola has a broader pharmacotherapeutic profile than solely as an antipsychotic or anti-manic agent.