Adjunctive Raloxifene for Women With Schizophrenia


This hormone-based therapy shows promise for older women with refractory symptoms.


Many patients with schizophrenia have symptoms that inadequately respond to currently available treatments. 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 females, declining estradiol levels may be associated with exacerbation of symptoms,1 and estradiol plays an important role in many brain functions.

Adjunctive estradiol has been associated with improvements in symptoms in women with treatment-refractory schizophrenia, but the use of hormone-replacement therapy also raises concerns about risks of breast and endometrial cancer.

Raloxifene is a selective estrogen receptor modulator (with mixed agonist and antagonist activity) approved for the treatment of osteoporosis in postmenopausal women and for breast cancer in women. There is some evidence for the efficacy of raloxifene in older women with schizophrenia, and a recent study in younger patients with schizophrenia found that adjunctive raloxifene was associated with improvements in cognition but not symptoms.2

Kulkarni and colleagues3 conducted a 12-week randomized, double-blind, placebo-controlled trial of raloxifene-given as an adjunct to antipsychotics-versus adjunctive placebo in Australia. The authors hypothesized that 120 mg/d of adjunctive raloxifene would improve both refractory symptoms and cognition in women with schizophrenia.

Women with schizophrenia or schizoaffective disorder were recruited from 1 of 2 sites in Australia. All patients were age 40 to 70, had a Positive and Negative Syndrome Scale (PANSS) score of at least 60, and had been taking a stable dose of antipsychotic medication for at least 4 weeks.

Patients were also required to have a normal mammogram within the past year, and a normal Papanicolaou test and breast and pelvic examination within the past 2 years. Women were excluded if they were premenopausal, currently taking systemic estrogen therapy, at increased risk of venous thromboembolism stroke or transient ischemic attack, had current substance dependence, or smoked more than 20 cigarettes per day.

Fifty-six women were randomized to receive either adjunctive raloxifene (n = 26) or placebo (n = 30) for 12 weeks. All subjects had assessments every 2 weeks, including assessments of symptoms using the PANSS and cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Randomized subjects had a mean age of 53 and illness duration of 24 years. An intention-to-treat analysis was used.

Forty-six of 54 women who received at least 2 weeks of treatment completed the study. Treatment with raloxifene was associated with significantly greater improvement in PANSS total (6.4 points) and general subscale (3.7 points) scores from baseline to endpoint compared with placebo. There was also a significantly higher prevalence of clinical response (> 20% reduction in PANSS total score) in the raloxifene (42%) versus placebo (13%) group.

By contrast, there was no difference in the change in depression scores between treatment groups, as measured by the Montgomery-Asberg Depression Rating Scale. Furthermore, there were no significant differences in changes in cognition, hormone levels, or adverse events between the 2 groups.

However, the authors note that the potential risks of raloxifene therapy include thromboembolic events and stroke. Potential limitations of the trial include the heterogeneity of antipsychotic and other psychotropic medications in the study sample.

The bottom line
This study supports growing evidence that raloxifene is a promising, well-tolerated adjunctive treatment for older women with schizophrenia and refractory symptoms.


Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.


1. Riecher-Rössler A, Häfner H. Schizophrenia and oestrogens: is there an association?Eur Arch Psychiatry Clin Neurosci. 1993;242:323-328.

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.

3. Kulkarni J, Gavrilidis E, Gwini SM, et al. Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. JAMA Psychiatry. 2016 Jul 20; doi:10.1001/jamapsychiatry.2016.1383.

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