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Original Investigation |

Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women A Randomized Clinical Trial

Jayashri Kulkarni, MBBS, PhD1; Emorfia Gavrilidis, BAppSc1; Stella M. Gwini, MSc2; Roisin Worsley, MBBS, FRACP1; Jasmin Grigg, PhD1; Annabelle Warren, MBBS1; Caroline Gurvich, DPsych1; Heather Gilbert, RN1; Michael Berk, MBBCh, PhD3; Susan R. Davis, MBBS, PhD4
[+] Author Affiliations
1Monash Alfred Psychiatry Research Centre, Alfred Hospital and Monash University Central Clinical School, Monash University, Melbourne, Australia
2Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, Australia
3Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia
4Women’s Health Research Program, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
JAMA Psychiatry. 2016;73(9):947-954. doi:10.1001/jamapsychiatry.2016.1383.
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Importance  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.

Design, Setting, and Participants  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.

Interventions  Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00361543

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Figure 1.
CONSORT Diagram of the Progress of Patients Through the Trial

Analysis for all randomized patients was based on intention to treat.

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Figure 2.
Kaplan-Meier Failure Curves for Proportion of Patients Who Achieved Clinical Response at Week 12

Log-rank test P = .02.

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Response to Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers
Posted on August 5, 2016
Stephen N. Xenakis, M.D., Brigadier General (Ret), U.S. Army
Austen Riggs Center and Uniformed Services University of Health Sciences
Conflict of Interest: None Declared
Stein, et. al. propose the identification of a biomarker, “…genome-wide significant association with ANKRD55—associated in prior research with several autoimmune and inflammatory disorders—and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.” There is no data to indicate that the researchers documented exposure to IED blasts and concussions. Inflammatory factors are associated with traumatic brain injury (Blood-based Diagnostics of traumatic brain injuries, Expert. Rev. Mol. Diagn. 11(1), 65-78 2011). A significant cohort of war fighters has been exposed to IED blasts and impact concussions that are as likely to have contributed to the proposed inflammatory markers. Clearly, more research is needed before associating the biomarkers to PTSD and overlooking co-morbidities of traumatic brain injury, pain, and exposure to environmental factors.
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