Is Flunarizine a Long-Acting Oral Atypical Antipsychotic? A Randomized Clinical Trial Versus Haloperidol for the Treatment of Schizophrenia

Background: Flunarizine is known as a nonspecific calcium channel blocker that has been used for decades for the treatment of migraine, vertigo, and cognitive deficits related to cerebrovascular disorders. Flunarizine also has dopamine D₂ receptor blocking properties and was effective in animal models of predictive validity for antipsychotics. However, its clinical antipsychotic efficacy has never been investigated.

Objective: To evaluate the therapeutic efficacy and tolerability of flunarizine compared to haloperidol in outpatients with stable and chronic DSM-IV-defined schizophrenia and schizoaffective disorder.

Method: Seventy patients from 2 centers were randomly assigned and participated in a double-blind, parallel-group, flexible-dose study comparing flunarizine (10-50 mg/day) and haloperidol (2.5-12.5 mg/day) for 12 weeks. Patients were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Improvement (CGI-I) scale, the Extrapyramidal Symptom Rating Scale (ESRS), a battery for cognitive performance, and laboratory examinations. The study was conducted from September 2004 to May 2007.

Results: Mean doses at endpoint were 29.7 mg/day for flunarizine and 6.4 mg/day for haloperidol. Both groups showed significant symptom improvement during the study, with a reduction of 21% in the flunarizine group and 19% in the haloperidol group in PANSS total scores (p < .05). There were no significant differences in PANSS overall score and all subscales, CGI-I score, or cognitive performance. Dropout rates, ESRS scores, and prolactin levels were not different between groups, but significantly more patients reported emergence of akathisia in the haloperidol group (p = .04), and weight gain was significantly higher with flunarizine (1.2 kg) than with haloperidol (-0.8 kg) (p < .05).

Conclusion: This is the first study evaluating the antipsychotic properties of flunarizine, which showed good efficacy and tolerability for the treatment of schizophrenia, with a possible atypical profile. Its unique pharmacokinetic profile as an oral drug with long half-life (2-7 weeks), low cost, and low induction of extrapyramidal symptoms warrants further investigation, particularly in psychiatric patients with low adherence to treatment.

Trial Registration: clinicaltrials.gov Identifier: NCT00740259