Raloxifene Helps Improve Attention in Younger People With Schizophrenia

While hallucinations and delusions are often viewed as the hallmark symptoms of schizophrenia, many people with this condition also experience cognitive problems. Deficits in attention, working memory, and processing information, which can create barriers at work and reduce overall quality of life, are generally not responsive to antipsychotic medications.

Studies have linked the cognitive problems in people with schizophrenia to defects in estrogen signaling, which suggests that targeting this hormone or its receptor may be an option for improving some outcomes of this disorder.

Previous studies have suggested that the synthetic agent raloxifene (an estrogen receptor medication used to treat osteoporosis and breast cancer in postmenopausal women) can improve cognitive and noncognitive symptoms in postmenopausal women with schizophrenia.

According to a recent study published in Molecular Psychiatry, adding raloxifene to regular antipsychotic therapy may improve memory and attention in younger women and men with schizophrenia as well.

The study, by a research team in Australia, enrolled 98 patients with schizophrenia between the ages of 18 and 51 in a randomized, crossover trial—half the participants received 120 mg adjunctive raloxifene while the other half had placebo for six weeks; then, following a one-week washout period, the two groups switched.

During the first six-week period, the group receiving raloxifene showed significant improvement relative to placebo in memory and processing speed (the women in the group also showed improvements in verbal fluency). Overall, 40 percent of raloxifene users showed a clinically meaningful change in their cognition compared with 15 percent in the placebo group.

During the crossover cycle, the differences between the raloxifene and placebo groups were not as robust, which may suggest that some of the improvements to the group that received raloxifene first persisted even after they stopped taking the medication. This was a somewhat unexpected discovery, given raloxifene’s known short half-life in the body, though the authors suggested the drug’s effect on estrogen or other hormone levels may induce some long-term changes.

Contrary to some of the findings in postmenopausal women, raloxifene did not provide any benefits in relation to non-cognitive symptoms such as emotional or functional well-being in this population, so it may not have much potential as a stand-alone medication in younger people with schizophrenia.

“Even so, these are very significant findings,” said lead author Shannon Weickert, Ph.D., a professor of psychiatry and chair of the Schizophrenia Research Institute at the University of New South Wales in Australia. “Until now, only a couple of drugs, including galantamine and minocycline, have shown any cognitive benefits for schizophrenia. And in both cases, the effects were modest and possibly outweighed by their side effects.”

In contrast, Weickert noted that the adverse effects of raloxifene were mild in this study, though she acknowledged that raloxifene does pose some risks of blood clots.

“This positive effect on attention is encouraging and certainly warrants further exploration,” said Jeffrey Lieberman, M.D., the Lawrence C. Kolb Professor and Chair of the Department of Psychiatry at Columbia University College of Physicians and Surgeons and a former APA president. “By using a crossover design, however, the second half of this study was not as useful, so we are limited to about six weeks of data.”

Lieberman also acknowledged the good safety profile of raloxifene, but noted that many risks associated with estrogen therapy take years to materialize. “Raloxifene is not as potent as estrogen because it only partially activates the receptor, but there may still be long-term effects, which we will not appreciate until we have substantial clinical experience.”

This study was supported by the University of New South Wales School of Psychiatry, the National Health and Medical Research Council of Australia, Neuroscience Research Australia, the Schizophrenia Research Institute, and the Australian Schizophrenia Research Bank. ■