REVIEW OF: Li Z et al, Act Psychiatrica Scandinavica 2023;147(4):360–372

STUDY TYPE: Meta-analysis of randomized, double-blind, placebo-controlled trials

Estrogen has long been thought to play a protective role in schizophrenia. The onset of the illness is delayed in women, and psychotic symptoms tend to worsen in women when estrogen wanes, such as during premenstruation, postpartum, and menopause. The estrogen hypothesis, which suggests that estrogen has neuroprotective properties and regulates dopamine activity while preserving cognitive function, has prompted investigations into estrogen therapy as a potential adjunctive treatment for schizophrenia in women.

In this meta-analysis, the authors examined 13 randomized, placebo-controlled, double-blind trials that evaluated the efficacy of adjunctive hormonal treatments in women with schizophrenia. The hormonal options considered were estradiol and raloxifene, a selective estrogen receptor modulator used for the treatment of osteoporosis and menopausal symptoms. Six trials focused on estradiol versus placebo in women of childbearing age (n=724, average age 36.6 years), while seven studies compared raloxifene to placebo in menopausal women (n=419, average age 57.4). All participants continued their current psychotropic regimen, which included antipsychotics. The duration and dosage of adjunctive treatments varied across studies. The primary outcome measured was the change in severity of psychotic symptoms, assessed using the Positive and Negative Syndrome Scale (PANSS). 

Adjunctive treatment with estradiol demonstrated superior outcomes compared to placebo, as indicated by a significant improvement in PANSS scores (mean difference -7.29, 95% confidence interval [CI] -10.67 to -3.91, p<0.001). Similarly, adjunctive treatment with raloxifene also outperformed placebo, resulting in a significant reduction in PANSS scores (mean difference -6.83, 95% CI -11.69 to -1.97, p=0.006). Estradiol studies also showed significant improvements in the positive and negative symptom subscales. Menstrual irregularities were the most frequently reported adverse event.

Factors such as baseline estradiol levels, menstrual cycle stage, and concurrent therapies (eg, oral contraceptives) were not considered in this study but may influence treatment outcomes.

CARLAT TAKE

Estrogen is worth considering in women with schizophrenia, although it is best to defer to OB-GYN for the decision as the treatment carries cardiac and cancer risks. In postmenopausal women with schizophrenia and osteoporosis, raloxifene may offer dual benefits.