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The Retinoid X Receptor Agonist Bexarotene Relieves Positive Symptoms of Schizophrenia: A 6-Week, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

J Clin Psychiatry 2013;74(12):1224-1232
10.4088/JCP.12m08160

Objective: The limitations of antipsychotic therapy in schizophrenia and schizoaffective disorder led to the investigation of the putative utility of pharmacologic augmentation strategies. The antitumor agent bexarotene via nuclear retinoid X receptor (RXR) activation might modulate numerous metabolic pathways involved in the pathogenesis of schizophrenia and schizoaffective disorder. This trial aimed to investigate efficacy and safety of add-on bexarotene to ongoing antipsychotic treatment of patients with schizophrenia or schizoaffective disorder.

Method: Ninety inpatients and outpatients that met DSM-IV-TR criteria for schizophrenia or schizoaffective disorder participated in a 6-week, double-blind, randomized, placebo-controlled multicenter study. Bexarotene (75 mg/d) was added to ongoing antipsychotic treatment from October 2008 to December 2010. The reduction in the severity of symptoms on the Positive and Negative Syndrome Scale (PANSS) was a primary outcome. Secondary outcomes included general functioning, quality of life, and side effect scales.

Results: Seventy-nine participants (88%) completed the protocol. Controlling for antipsychotic agents, a mixed model showed that patients who received adjunctive bexarotene had significantly lower PANSS positive scale scores compared to patients who received placebo (F = 8.6, P = .003; treatment arms × time, F = 2.7, P = .049), with moderate effect size (d = 0.48; 95% CI,0.04–0.93). Patients with mean or higher baseline PANSS positive scale scores and patients who did not take lipid-reducing agents revealed greater amelioration of positive symptoms (F = 7.4, P = .008). Other symptoms and secondary outcome measures were not affected by adjunctive bexarotene. Bexarotene was well tolerated, though 2 reversible side effects were reported: a significant increase in total cholesterol levels (P < .001) and a decrease in total thyroxine levels (P < .001).

Conclusions: Bexarotene might potentially be a novel adjuvant therapeutic strategy for schizophrenia, particularly for the reduction of positive symptoms. The potential benefits and risks of ongoing administration of bexarotene warrant further evaluation.

Trial Registration: ClinicalTrials.gov identifier: NCT00535574

J Clin Psychiatry 2013;74(12):1224–1232

Submitted: September 12, 2012; accepted February 27, 2013 (doi:10.4088/JCP.12m08160).

Corresponding author: Michael S. Ritsner, MD, PhD, Director, Acute Department, Sha’ar Menashe Mental Health Center, Mobile Post Hefer 38814, Hadera, Israel (ritsner@sm.health.gov.il; ritsnerm@gmail.com).