A few years ago on our blog, we reviewed a paper suggesting that estrogen may be a beneficial treatment for women with schizophrenia.  In this study patients with schizophrenia receiving estrogen showed significant improvement in their positive symptoms (hallucinations, delusions), but no difference in negative symptoms (reduction in range of emotional expression, poverty of speech, lack of motivation).1, 2   Additional studies have also found estrogen to be effective in improving positive and general symptoms in patients with schizophrenia. 3, 4

Lindamer and colleagues demonstrated in a post hoc analysis of postmenopausal women with schizophrenia that patients receiving hormone replacement therapy required lower doses of antipsychotic drugs and presented with fewer negative symptoms. 5  While there may be benefits to using adjunctive estrogen in this patient population, long-term treatment with estrogen may increase the risk of cardiovascular disease and invasive breast cancer.

Thus, the recent study using a selective estrogen receptor modulator (SERM), raloxifene, which does not affect breast or uterine tissue, is particularly promising.  Raloxifene (marketed as Evista) is a first- generation SERM that is used currently as a preventive treatment for postmenopausal osteoporosis, and it appears to act in a similar way to conjugated estrogens in modulating dopamine and serotonergic neurotransmitter systems.  The primary aim of this study published in the Journal of Clinical Psychiatry was to assess the utility of raloxifene as an adjunctive treatment in postmenopausal women with schizophrenia in a 12 week, double-blind, randomized, placebo-controlled study. 6

To be included in the study, women needed to meet DSM-IV criteria for schizophrenia, be postmenopausal (defined as a period of 1 year of spontaneous amenorrhea and a serum follicle stimulating hormone level > 20 IU/L), be receiving stable doses of an antipsychotic agent for 1 month prior to study initiation, and have significant negative symptoms (defined as 1 or more negative symptom scores greater than 4 on the Positive and Negative Syndrome Scale [PANSS]).  Women were excluded if they had a history of substance abuse/dependence diagnosis in the previous 6 months, a diagnosis of mental retardation, endocrine abnormalities, acute or chronic liver disease or several other medical issues including history of breast cancer, or current administration of hormone replacement therapy.

Thirty three subjects with prominent negative symptoms were randomized to receive either adjunctive raloxifene or placebo.  Women were required to continue to take their regular medications throughout the study and to not change the dosages.   Symptoms were assessed at baseline and at weeks 4, 8, and 12 using the PANSS. Breast and uterine tissue effects were also assessed.

There were no statistical differences between the 16 women in the raloxifene group and the 17 women in the placebo group in terms of age, age at illness onset or years of education.  There were no significant differences with regard to regular antipsychotic medication or other medication, and there were no differences in mean daily dose of antipsychotic medications (expressed in risperidone equivalents).

The addition of raloxifene (60 mg/day) to regular antipsychotic treatment significantly reduced the negative (P=.044), positive (P=.031), and general psychopathological (P=.045) symptoms during the 12 week trial, as compared to women receiving placebo.  No differences in adverse effects were measured.  No adverse effects on breast or uterine tissue were observed.

The findings are consistent with pilot data reported by Kulkarni and colleagues, where a dose of 120 mg/day of raloxifene was found to be more effective than 60 mg day or placebo in patients with schizophrenia. 7  The current study used only the 60 mg/day dose this dose is consistent with the approved indication of raloxifene.   The main limitations of the current study are the small number of subjects, the short duration of the study, and the fact that the authors did not control for change in depression or other psychiatric symptoms.

Although the authors took steps to include only medically appropriate women treated with raloxifene, they do not specifically discuss the fact that raloxifene, similar to hormone replacement therapy and estrogen therapy in postmenopausal women, has also been shown in studies to increase the risk of deep vein thrombosis, as well as the risk of major coronary events and death due to stroke.  Therefore the risks and benefits of raloxifene, like all medications, would need to be carefully reviewed on an individual case basis.

The authors conclude the paper by reviewing how estrogenic compounds may affect symptomatology in schizophrenia.  Estrogen appears to alter functional activity in both the dopamine and serotonergic neurotransmitter systems and also promotes neuronal regeneration and blocks mechanisms of cell death.  Yet estrogen has also been shown to have specific adverse effects on breast and uterine tissue.  The finding that raloxifene, a selective estrogen receptor modulator, improved all psychotic symptoms in postmenopausal patients is important finding as it indicates that SERMs may be a useful adjunctive treatment in postmenopausal women with schizophrenia.

April Hirschberg, MD

1. Milanovic S. Estrogen for the Treatment of Women with Schizophrenia. Published: September 22, 2008.

2. Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C, Burger H. Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry. 2008 Aug; 65(8):955-60.

3. Kulkarni J, Riedel A, de Castella AR, et al. Estrogen –a potential treatment  for schizophrenia. Schizophr Res. 2001; 48(1):137-144.

4. Akhondzadeh S, Nejatisafa AA, Amini H, et al. Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(6):1007-1012.

5. Lindamer LA, Buse DC, Lohr JB, et al. Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms? Biol Psychiatry. 2001; 49(1):47-51.

6. Usall J, Huerta-Ramos, Iniesta R, et al. Raloxifene as Adjunctive Treatment for Postmenopausal Women with Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled trial. J Clin Psychiatry 2011; 72(11):15552-1557.

7. Kulkarni J, Gurvich C, Lee SJ, et al. Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. Psychoneuroendocrinology. 2010;35(8):1142-1147.