Targeting the Estrogen Receptor for Cognitive Impairment in Schizophrenia

September 29, 2015

Treatment with a selective estrogen receptor modulator in adjunct to antipsychotics was associated with improvements in attention and memory in men and women with schizophrenia in a recent trial.

Schizophrenia is associated with impaired cognition-including memory and attention-which persists despite currently available treatments, and is an important determinant of quality of life and overall function. Thus, novel therapeutic strategies to improve cognition in schizophrenia represent a huge area of unmet need.

Sex hormones, including estrogen, are known to have beneficial effects on functioning of the prefrontal cortex and hippocampus, 2 brain regions that contribute to cognitive impairments in schizophrenia. Sex differences in the age of onset, illness course, and response to treatment in schizophrenia may be mediated, in part, by abnormalities in estrogen levels. In males, testosterone is converted to estrogen in the brain, and several studies have reported low testosterone levels in males with schizophrenia. One small, previous study found significant improvements in verbal memory in postmenopausal women with schizophrenia treated with estrogen replacement.1

Weickert and colleagues2 conducted a 13-week randomized, double-blind, placebo-controlled crossover trial of raloxifene-given in adjunct to antipsychotics-in patients with schizophrenia in Australia. Raloxifene is a selective estrogen receptor modulator approved for the treatment of osteoporosis in postmenopausal women and for breast cancer in women. The authors hypothesized that 120 mg/day of adjunctive raloxifene would improve cognition (particularly verbal memory) and reduce symptoms in both men and women with schizophrenia.

Patients with schizophrenia or schizoaffective disorder were recruited from one of two sites in Australia. All patients were aged 18 to 51 years and had been taking antipsychotic medication for at least one year. Patients with other comorbid psychiatric disorders or history of a substance use disorder in the past 5 years, as well as women who were pregnant or receiving hormone therapy and refused alternate forms of birth control were excluded. Eighty-seven healthy adults without a personal or family history (first-degree relative) of psychiatric or substance use disorder were also recruited for a baseline comparison group.

Ninety-three patients with schizophrenia were randomized to receive either adjunctive raloxifene or placebo for 6 weeks, followed by a 1-week washout, and then treatment with the alternative agent. All subjects had a cognitive assessment at baseline, and assessments were repeated in patients at weeks 6 and 13. Psychiatric symptoms in patients were assessed at all 3 time points (baseline, weeks 6 and 13) using the Positive and Negative Syndrome Scale (PANSS).

A clinically significant change occurred in at least one cognitive measure in 16 of 40 (40%) of patients randomized to raloxifene in the first 6 weeks. This was much greater than the proportion of placebo-treated subjects with this level of improvement (15%). Over the full 13 weeks with crossover, treatment with raloxifene was associated with significant improvement in the Trail Making Test, Part A, but no other cognitive measures. By contrast, there were no significant changes in PANSS scores over time throughout the trial. There were also no major differences in adverse events between the raolxifene and placebo groups, and no serious adverse events attributed to raloxifene.

Potential limitations of the trial include recruitment of subjects with less severe levels of psychopathology and no comorbidities; potential carryover effects; and potential effects of other medications (eg, benzodiazepines) on cognition.

The bottom line
This trial suggests that raloxifene may be a novel therapeutic agent for cognitive impairment in schizophrenia and provides additional evidence for the role of sex hormones in the pathophysiology of psychosis.

This article was originally published online on July 10, 2015 and has since been updated.


Dr Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Georgia Regents University and Schizophrenia Section Editor for Psychiatric Times. Full bio.


1. Good KP, Kopala LC, Martzke JS, et al. Hormone replacement therapy in postmenopausal women with schizophrenia: Preliminary findings. Schiz Research. 1999;36:131S.
2. Weickert TW, Weinberg D, Lenroot R, et al. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol Psychiatry. 2015;20:685-694.