Potential for SERMs as Adjunctive Therapy for Schizophrenia

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Raloxifene is the only selective estrogen receptor modulator approved for long-term treatment of schizophrenia.
Raloxifene is the only selective estrogen receptor modulator approved for long-term treatment of schizophrenia.

Preliminary signals indicate that the selective estrogen receptor modulator (SERM) raloxifene could become part of the armamentarium in the treatment of schizophrenia. In a 9-study meta-analysis of 561 patients with schizophrenia spectrum disorder, adjunctive raloxifene significantly improved psychotic symptoms, as reported by the Positive and Negative Syndrome Scale (PANSS).1

Janna de Boer, MD, of the department of psychiatry, University Medical Center Utrecht, Utrecht University & Brain Center Rudolf Magnus, in The Netherlands, and colleagues examined the effect of raloxifene on psychotic symptom severity, depression, and cognition.1 In the meta-analysis, study duration ranged from 6 to 24 weeks. While raloxifene was superior to placebo in improving total symptom severity (N=482; Hedge's g=.57; P =.009), it did not significantly reduce depression or improve cognitive functioning.1 Raloxifene, however, did improve the subscales of the PANSS: positive (N=561; Hedge's g=.32; P =.02), negative (N=561; Hedge's g=.40; P =.02), and general (N=526; Hedge's g=.46; P =.01).1

“I hope this study makes clear that at least for postmenopausal women, there is plenty of evidence that raloxifene is safe and effective,” said Dr de Boer. “This meta-analysis raises awareness for the large influence of sex hormones on the symptomatology and disease course of schizophrenia. The role of these hormones in the disease pathology is under-investigated and should receive more attention from the field.”

Why SERMs for Schizophrenia?

The interest in using SERMs stems from the stark sex differences in the incidence of schizophrenia.1 Men have a 1.4-greater risk for schizophrenia than women, and in women aged >50 years, there is a second peak of schizophrenia incidence, presumably due to lowered estrogen levels at menopause.1 Likewise, psychotic symptoms in women also worsen during the follicular phase of the menstrual cycle and postpartum.1

Estrogen supplementation, however, is not a solution because of its untoward effects on sex organs; therefore, men with schizophrenia would not benefit owing to its feminizing effects,1 and long-term use of estrogen is also not safe. In contrast, SERMs affect the brain and bones, and do not have deleterious effects on the sex organs.1

While there are other SERMs, raloxifene is the only one approved for long-term treatment.1 Raloxifene is not without consequences; its adverse event profile is comparable with that of hormonal contraceptives, with thromboembolic events being the primary adverse event.1

Jayashri Kulkarni, MBBS, PhD, director of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, and colleagues examined the effects of raloxifene in 56 perimenopausal and postmenopausal women with schizophrenia (mean age, 53; mean illness duration, 24 years) who were randomly assigned to raloxifene 120 mg/d (n=26) or placebo (n=30).2 During the 12-week study, patients were assessed every 2 weeks with PANSS. While there was a significant reduction in PANSS general symptom scores in the raloxifene vs the placebo group (β=−3.72; 95% CI: −6.83, −0.61; P =.02), there were no significant differences in positive symptom scores.2 Improvement in PANSS was defined as a ≥20% reduction in PANSS total score from baseline.2

As in the meta-analysis, there were no significant effects in comorbid depression or cognition, as measured by the Montgomery-Asberg Depression Rating scale (MADRS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively.2 Prior studies showed a positive effective of raloxifene on cognition but not on mood.2

There were no statistically significant differences in adverse events in either the raloxifene or the placebo group.2 Effects of antipsychotic medications such as abnormal movements, extrapyramidal effects, and akathisia were assessed with the Abnormal Involuntary Movement Scale, the Simpson Angus Scale, and the Barnes Akathisia Rating Scale.2

Because of the study's findings, “there is more interest in thinking about hormone treatments for women with schizophrenia who have not responded to standard treatment,” noted Dr Kulkarni. “However, psychiatrists are still somewhat reluctant to use the newer hormone strategies without assistance from an endocrinologist or gynecologist. I have received many requests from clinicians from all over the world for more information about raloxifene.”

When Will SERM Adjunctive Therapy Go Mainstream?

For raloxifene therapy to become more widespread, broader sections of the population need to be studied, specifically men and premenopausal women.1 The 9-study meta-analysis by de Boer and colleagues included only 2 studies with men: one with men and women and one single-sex study.1 Longer-term studies are needed; thus far, the longest study has lasted only 24 weeks.1

In one of the few studies to examine the effect of raloxifene on men with schizophrenia, Dr Khodaie-Ardakani, associate professor of psychiatry, University of Social Welfare & Rehabilitation Sciences, in Velenjak Teheran, Iran, and colleagues randomly assigned 42 men to raloxifene (mean age, 31.4) or placebo (mean age, 32.4) for 8 weeks.3 Like previous studies of postmenopausal women, the researchers found that raloxifene significantly reduced psychotic symptoms on total PANSS score (P <.001), the general psychopathology subscale (P =.002), and the negative subscale (P <.001) vs placebo, but they found no significant difference in reducing the positive symptom scores between the two groups (P =.525).3 The depression scores and extrapyramidal symptoms, as assessed by the Hamilton and extrapyramidal symptom rating scales, respectively, were similar in both groups.3

“More research is needed that focuses on the use of SERMs in men, because they might benefit most from the drug,” said Dr de Boer.

Dr Kulkarni concurred: “There needs to be further study of the area with trials studying the impact of raloxifene in different subgroups of people with schizophrenia. Once this work is done, then the evidence for the adjunctive use of raloxifene to treat symptoms of schizophrenia will be stronger and might then lead to greater use.”

Summary and Clinical Applicability

Raloxifene has demonstrated mostly positive results in meta-analyses of men and women with schizophrenia who received a SERM as adjunctive therapy. While there are stronger signals in women-only trials, more research is needed to determine SERMs' potential to improve the health of men and women with schizophrenia.

References

  1. de Boer J, Prikken M, Lei WU, Begemann M, Sommer I. The effect of raloxifene augmentation in men and women with a schizophrenia spectrum disorder: a systematic review and meta-analysis. NPJ Schizophr. 2018;4(1):1.
  2. Kulkarni J, Gavrilidis E, Gwini SM, et al. Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. JAMA Psychiatry. 2016;73(9):947-954.
  3. Khodaie-Ardakani MR, Khosravi M, Zarinfard R, et al. A placebo-controlled study of raloxifene added to risperidone in men with chronic schizophrenia. Acta Med Iran. 2015;53(6):337-345.
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