title: Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial.
abstract: OBJECTIVE
  A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects.
  
  
  OBJECTIVE
  To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia.
  
  
  METHODS
  This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis.
  
  
  METHODS
  Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks.
  
  
  METHODS
  The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed.
  
  
  RESULTS
  Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups.
  
  
  CONCLUSIONS
  Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00361543.
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Jayashri
authors.initials: J
authors.lastname: Kulkarni
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Emorfia
authors.initials: E
authors.lastname: Gavrilidis
authors.affiliation: Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Australia.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Gwini
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Roisin
authors.initials: R
authors.lastname: Worsley
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Grigg
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Warren
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Gurvich
authors.affiliation: Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Gilbert
authors.affiliation: Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Women's Health Research Program, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Davis
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology*; D020849:Raloxifene Hydrochloride / Q000009:adverse effects / Q000627:therapeutic use*; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D020849:Raloxifene Hydrochloride