Adding the selective estrogen receptor modulator (SERM) raloxifene (Evista, Lilly) to antipsychotic drug therapy can improve outcomes in men and women with schizophrenia, results of a systematic review and meta-analysis show.
Raloxifene has been “consistently shown to be effective as an augmentation to antipsychotic medication to ameliorate psychotic symptoms of schizophrenia. As this medication can be used by men and women for longer time periods, it appears to be a valuable addition to current therapeutic options,” report the investigators, led by Janna de Boer, MD, of University Medical Center Utrecht, the Netherlands.
The study was published online January 10 in NPJ Schizophrenia.
Sex Differences
The investigators point out that there are “robust” sex differences in the prevalence of schizophrenia, with men more likely to develop the disorder than women.
In addition, age of onset is significantly lower in men. In women, but not men, there is a second peak in incidence peak after age 50 years.
In addition, in premenopausal women, the disease course is typically more favorable than in men, with lower psychotic and negative symptoms, better cognitive and social functioning, and fewer hospitalizations.
“The most likely explanation for these sex differences is that estrogens have a protective role in the pathophysiology of schizophrenia,” the authors note. Raloxifene is a “likely candidate” for augmentation therapy, and several studies have assessed the potential effect of raloxifene on symptoms and comorbidities in schizophrenia.
The investigators conducted a quantitative systematic review of nine randomized controlled studies that tested the effect of raloxifene in comparison with placebo in a total of 561 patients with a schizophrenia spectrum disorder.
They found that raloxifene was superior to placebo in improving total symptom severity (Hedges g = 0.57; P = .009), as well as scores on positive (Hedges g = 0.32; P = .02), negative (Hedges g = 0.40; P = .02), and general (Hedges g = 0.46; P = .01) subscales of the Positive and Negative Syndrome Scale (PANSS).
“We found moderate, but significant positive effects of raloxifene on total symptom severity, as well as on positive, negative, and general PANSS subscales,” the authors report. Neither dosage nor treatment duration influenced these effects, they write.
There was no significant benefit of raloxifene augmentation on depression or cognitive outcomes, but few studies investigated these outcomes.
Estrogen augmentation has been shown to have beneficial effects in premenopausal women with schizophrenia. However, long-term use of estrogen is not safe, owing to side effects, and estrogen augmentation is not indicated in men, owing to its feminizing effects.
SERMs such as raloxifene do not have these side effects and could, therefore, have therapeutic benefits in schizophrenia patients of both sexes without being hazardous to gynecologic tissues or having feminizing effects.
“Altogether, these results confirm the potential of raloxifene augmentation in the treatment of schizophrenia,” the investigators conclude.
Useful Adjunctive Strategy
Reached for comment, Jayashri Kulkarni, MBBS, PhD, director, the Monash Alfred Psychiatry Research Center, Melbourne, Australia, said that this is an important topic, “since there are many people with schizophrenia who still have persistent symptoms despite utilizing the currently available antipsychotic treatments. The meta-analysis is done very well and provides some direction despite the conflicting individual study results.
“In essence,” said Kulkarni, “adding raloxifene to standard antipsychotic treatment is a useful clinical adjunctive strategy in a patient with persistent schizophrenia — although the best results are seen in women who are in the peri-postmenopausal age group.
“Clinicians would have to monitor for side effects and know when to use it, which requires education, since mental health practitioners rarely use medications from other fields of medicine — in this case, a hormone treatment. Nonetheless, many clinicians struggle to know what to do for their persistently ill patient who is not improving and experiencing the devastating effects of severe mental illness,” said Kulkarni.
The study received no commercial funding. The authors have disclosed on relevant financial relationships.
NPJ Schizophr. Published online January 10, 2018. Full text
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