The estrogen-related drug raloxifene can improve attention and memory in men and women with schizophrenia, according to a new study published in the journal Molecular Psychiatry.

University of New South Wales researcher Cynthia S. Weickert, Ph.D., a 1999 and 2001 NARSAD Young Investigator and 2004 Independent Investigator grantee, and her colleagues say their raloxifene findings could help improve some cognitive problems related to schizophrenia that have been the most difficult to treat with drugs. Dr. Weickert’s research team included NARSAD Young Investigator grantees Rhoshel K. Lenroot, M.D., (2003), and Ans Vercammen, Ph.D., (2010), along with Independent Investigator grantee Jayashri Kulkarni, Ph.D., (2000), and her husband and first author Tom Weickert, Ph.D.

A growing body of evidence suggests that estrogen plays a beneficial role in the brain, supporting growth and protecting neurons from damage. From work supported by her NARSAD Young Investigator awards, Dr. Weickert and her colleagues found that brain estrogen receptors are altered in some people with schizophrenia, blunting their ability to respond to estrogen’s beneficial effects. Raloxifene stimulates estrogen receptors and can help overcome a blunted estrogen response. Raloxifene is probably best known as a treatment for osteoporosis in women, where it mimics estrogen’s beneficial action in bones. The drug also stimulates estrogen receptors in the brain and may guard against memory loss in aging, making it potentially useful for cognitive problems in schizophrenia patients.

The research team examined the drug’s effect in 98 people diagnosed with schizophrenia or schizoaffective disorder (which combines symptoms of schizophrenia and depression). All of the patients received a daily dose of raloxifene along with their usual antipsychotic medications in one phase of the clinical trial and a placebo in another phase. 

After the first six-week period, patients taking raloxifene had improved scores on memory and attention, compared to those taking placebo. When considering all the people in the study during both phases, raloxifene treatment significantly improved attention and thought processing speed. Raloxifene didn’t reduce the severity of schizophrenia symptoms more than the placebo did, but both groups showed less symptoms overall during the study, and none of the patients had severe side effects from the treatment.

Dr. Weickert and colleagues did detect some signs that the positive impact of raloxifene lasted more than one month after the treatment stopped. Although the researchers do not know the exact reasons for the lasting effects, they note that stimulating estrogen receptors might protect neurons, reduce inflammation, and increase connections between nerve cells in the brain over a longer time frame than drugs working on other neurotransmitter receptors. In light of their findings, they suggest future studies should replicate these results in a larger group of schizophrenia patients and also determine how long the cognitive benefits of a six-week treatment with raloxifene may last. 

Read the abstract.