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.

Caffeine modulates P50 auditory sensory gating in healthy subjects.

The P50 suppression paradigm is an index of sensory gating assumed to reflect an inhibitory process. Adenosine is a neuromodulator with mostly inhibitory activity that is released by physiological stimuli and can be blocked by non-selective adenosine receptor antagonists such as theophylline and caffeine. A previous study showed that a single dose of theophylline decreased P50 suppression in healthy volunteers. Here we investigated the effect of caffeine (0, 100, 200 and 400 mg p.o.) on P50 sensory gating in 24 healthy volunteers (15 habitual caffeine high-users and 9 low-users). The 200 and 400 mg doses reduced P50 gating, whereas 100 mg produced a non-significant effect. The effect of caffeine was independent of gender and habitual caffeine intake. High caffeine users also showed baseline differences, with lower S(2) amplitudes compared to low-users. These results reinforce the participation of adenosine in the modulation of P50 sensory gating and suggest that caffeine ingestion should be controlled for in the P50 sensory gating paradigm.

A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia.

OBJECTIVE: To evaluate the xanthine oxidase inhibitor allopurinol as an adjuvant treatment for patients with moderately refractory schizophrenia, with the objective of increasing the endogenous pool of purines, including the neuro-modulator adenosine. METHOD: A double-blind, placebo-controlled, crossover clinical trial of add-on allopurinol (300 mg b.i.d.) for poorly responsive schizophrenia or schizoaffective disorder (DSM-IV criteria) was conducted. Thirty-five patients were enrolled, of whom 22 completed the 12 weeks of the study. Eighteen of these patients also completed a P50 evoked potential evaluation. RESULTS: Allopurinol was well tolerated and produced significant improvement in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, particularly for positive symptoms compared with baseline and with placebo phase. Nine patients improved more than 20% in PANSS total score during allopurinol treatment, whereas none responded in the placebo phase. Responders had a shorter duration of illness than nonresponders. P50 auditory sensory gating failed to improve with allopurinol treatment. CONCLUSIONS: Allopurinol was an effective and well-tolerated adjuvant treatment for poorly responsive schizophrenia, especially for refractory positive symptoms.