title: The retinoid X receptor agonist bexarotene relieves positive symptoms of schizophrenia: a 6-week, randomized, double-blind, placebo-controlled multicenter trial.
abstract: 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.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00535574.
authors.affiliation: Division of Psychiatry, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lerner
authors.forename: Chanoch
authors.initials: C
authors.lastname: Miodownik
authors.forename: Anatoly
authors.initials: A
authors.lastname: Gibel
authors.forename: Pinchas
authors.initials: P
authors.lastname: Sirota
authors.forename: Ilan
authors.initials: I
authors.lastname: Bush
authors.forename: Hadi
authors.initials: H
authors.lastname: Elliot
authors.forename: Ruben
authors.initials: R
authors.lastname: Benatov
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ritsner
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000077610:Bexarotene; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000523:psychology; D011788:Quality of Life; D047488:Retinoid X Receptors / Q000819:agonists*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy; D012565:Schizophrenic Psychology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene