Raloxifene May Improve Symptoms in Older Women With Refractory Schizophrenia

Adding raloxifene—a drug that targets the estrogen receptor—to the antipsychotic medication regimens of postmenopausal women with treatment-resistant schizophrenia may help to reduce the severity of the illness, according to a study in JAMA Psychiatry.

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“Our results support growing evidence that, in this patient group, raloxifene is a promising, well-tolerated adjunctive treatment with potential future application in clinical practice,” Jayashiri Kulkarni, M.B.B.S., Ph.D., a professor of psychiatry at the Alfred and Monash University in Melbourne, Australia, and colleagues wrote.

In women, the risk and/or severity of schizophrenia increases during periods of lower estrogen activity—notably right after giving birth and menopause. Past studies have found that women with treatment-resistant schizophrenia who receive estrogen therapy report improvements in symptoms, but hormone replacement therapy comes with increased risks of breast and uterine cancer.

Raloxifene, which is approved by the Food and Drug Administration for the treatment of osteoporosis, specifically boosts estrogen levels in the brain. This drug actually lowers estrogen in other tissues and is used preventively in women at high cancer risk.

Several case reports and pilot studies have demonstrated the positive effects of raloxifene as an adjunctive treatment for older women with schizophrenia. A clinical study in 2015 found that adjunctive raloxifene may also benefit younger women and men with schizophrenia, though in this case the improvements were limited to memory and processing speed.

To determine the efficacy of raloxifene in reducing illness severity in postmenopausal women with schizophrenia, Kulkarni and colleagues randomly assigned 56 women aged 40 to 70 with refractory schizophrenia to 120 mg adjunctive raloxifene or placebo daily for 12 weeks. All the participants had a minimum score of 60 on the Positive and Negative Syndrome Scale (PANSS) and had been on a stable dose of antipsychotics for at least four weeks.

After 12 weeks, PANSS scores dropped by 10.18 points in the raloxifene group compared with 3.82 in the placebo group. A total of 42 percent of raloxifene users experienced a 20 percent or more decrease in PANSS total score from baseline compared with 13 percent of those on placebo.

When the authors took a look at changes in the individual PANSS subscales, they found that the largest impact of raloxifene was in the general symptom category, which includes items such as anxiety, depression, impulse control, and social avoidance. While there were also some improvements in positive and negative symptom scores, these improvements were not statistically significant.

There were also no differences in the rate of adverse events between the groups, though the authors did exclude women with a history of cardiovascular problems. This was done to reduce the odds of stroke, which is a rare but serious side effect of raloxifene. The risk of stroke in patients with schizophrenia is higher than that of the general population, due in part to the high rates of smoking and metabolic problems seen in this group.

“This study represents, to our knowledge, the largest trial of raloxifene in this patient population to date, which provides important evidence regarding raloxifene’s beneficial effects on brain function in women with refractory schizophrenia,” the authors wrote.

Kulkarni noted that the participants in this study had been living with schizophrenia for over two decades (on average) and still had symptoms despite taking numerous medications. Several participants were taking clozapine, which is considered to be the best pharmacological option for refractory schizophrenia.

“Although consideration of sex, age, and other heterogeneous factors in schizophrenia should always drive treatment decision making, this investigation represents an important development regarding the evidence base for central nervous system–estrogenic agents and schizophrenia tractability,” the authors concluded.

This study was funded by a grant from the National Health and Medical Research Council. ■