Estradiol for treatment-resistant schizophrenia

Researchers from Australia have conducted the first controlled trial of estrogen in premenopausal women with treatment-resistant psychosis (1). They recruited 183 women with schizophrenia or schizoaffective disorder who were not pregnant, lactating, or postmenopausal; and who had no history of breast cancer, endocrine disorders, migraine with aura, or thromboembolism. Patients with acute mania were excluded. Patients were randomly assigned to receive either transdermal estradiol 100 mcg daily, transdermal estradiol 200 mcg daily, or placebo patch. The primary outcome measure during the 56-day trial was the Positive and Negative Syndrome Scale (PANSS). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Repeatable Battery of Neuropsychological Status, adverse-effects monitoring, and serum estradiol concentration at the baseline and during treatment.

The baseline demographic, illness, and treatment characteristics did not differ among the placebo, 100 mcg-estradiol, and 200-mcg estradiol groups. Most subjects were outpatients, and the three groups had mean PANSS total scores of 72-75. Compared with the placebo group, both treatment groups had significant increases in serum estradiol concentration; and greater decreases in mean PANSS positive, general, and total scores. The effect size for positive symptoms, however, was 0.0 for the 100 mcg group and 0.44 for the 200 mcg group, which reflected a mean 3.3-point reduction in PANSS-positive score with the higher dose. No significant treatment effect was found for negative symptoms or cognition. The only significant adverse effect was an increase of irregular menses in the 200 mcg group compared with the placebo group.

The investigators acknowledge that this trial was short-term and that the risks of thromboembolism and endometrial carcinoma may accumulate during longer-duration therapy. Raloxifene, a selective estrogen receptor modulator, entails a lower risk of these adverse effects. In 2011, investigators from Spain reported on a randomized trial of 16 postmenopausal women who had significant mean reduction of positive, negative, and general symptoms compared with a comparable placebo group (2). Case reports exist of raloxifene use in premenopausal women with treatment-resistant schizophrenia (3,4), but controlled trials in this population have not been published.


1. Kulkarni J, Gavrilidis E, Wang W. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Molecular Psychiatry. Published online 15 Apr 2014. Abstract

2. Usall J, Huerta-Ramos E, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557. Abstract

3. Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G. Beneficial effects of add-on raloxifene in schizophrenia. Arch Womens Ment Health. 2012;15(2):147-148. Abstract

4. Shivakumar V, Venkatasubramanian G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia. Indian J Psychiatry. 2012;54(4):394. Full text