Estrogen augmentation in schizophrenia: a quantitative review of current evidence

Sex differences in the incidence, onset and course of schizophrenia have led to the hypothesis that estrogens play a protective role in the pathophysiology of this disorder. Several trials have assessed the potential of estrogens in reducing schizophrenia symptoms, showing inconsistent results. This quantitative review summarizes available evidence on the efficacy of estrogens in the treatment of schizophrenia.

Only double-blind, placebo-controlled, randomized studies were included. Primary outcome measure was total symptom severity, secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated for individual studies and, if possible, pooled in meta-analyses to obtain combined, weighted effect sizes (Hedges's g).

Superior efficacy was found for estrogen treatment in female patients (four RCTs, 214 patients) on total symptom severity (Hedges's g=0.66), although heterogeneity was moderate to high. Estrogens were also superior in reducing positive (Hedges's g=0.54) and negative symptoms (Hedges's g=0.34), with low heterogeneity. As the included studies applied different forms of estrogens, a separate analysis was conducted on the trials applying estradiol (three RCTs, 170 patients). Even larger effect sizes were found for total symptom severity (Hedges's g=0.79), positive (Hedges's g=0.57) and negative symptoms (Hedges's g=0.45), with reduced heterogeneity. Estrogen treatment in male patients (one study, 53 patients) was not superior to placebo.

Our results suggest that estrogens, especially estradiol, could be an effective augmentation strategy in the treatment of women with schizophrenia. However, future larger trials are needed before recommendations on clinical applications can be made.