There is cumulative evidence suggesting that estrogen might play a role in the development of schizophrenia and therefore may be useful in the treatment of this illness. On average, the first signs of schizophrenia appear 3 to 4 years later in women than in men, with a second peak in women around menopause, suggesting that estrogen may be neuroprotective.  Estrogen has been demonstrated to have beneficial effects in treating hormonally mediated affective disorders such as postnatal depression or perimenopausal depression.  A recent study published in the Journal of American Psychiatry suggests that estrogen may also be beneficial for the treatment of patients with schizophrenia.

In an 8-week randomized, placebo-controlled trial, 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder were randomized to receive a 200-?g estradiol or placebo patch added to their antipsychotic treatment.  The median age at baseline for the entire group was 38.0 years (range, 19.5-46.0 years).  Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS).

At baseline, the mean positive PANSS scores were 19.6 in both groups; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group.  This was a small but statistically significant improvement in positive symptoms (-0.94; 95% CI, -1.64 to -0.24; P?=?.008; effect size?=?0.38). Post hoc analyses found that this beneficial  effect occurred almost entirely in participants older than 38.0 years (46 in placebo group vs 54 in estradiol group; difference, -1.98 points on the PANSS positive subscale; 95% CI, -2.94 to -1.02; P?<?.001). Younger participants did not appear to benefit from adjunctive treatment with estradiol.  

These findings are similar to a study we reviewed several years ago suggesting that estrogen may have beneficial effects for women of childbearing age with schizophrenia (mean age 33.5 years).  In this study, women with schizophrenia were treated with 100-?g of transdermal estradiol  in addition to their antipsychotic medications. Adjunctive treatment with estrogen was associated with significant improvement in their positive symptoms (hallucinations, delusions), but the women experienced no improvement in the severity of negative symptoms (reduction in range of emotional expression, poverty of speech, lack of motivation).  

Based on the findings of these studies, one can imagine a variety of clinical settings where estrogen may be a useful treatment option.  For example, estrogen might be used as an adjunctive treatment in women whose symptoms worsen during periods of hormonal change (i.e., during the luteal phase of the menstrual cycle or during the menopausal transition).  Estrogen may also be used to augment treatment in women who have either residual positive symptoms or who cannot tolerate higher doses of standard antipsychotic medications. Although the earlier study did not find a difference in response related to age, the current study suggests that older women may experience more benefit from estrogen augmentation than younger women.  According to the inclusion criteria of the current study, these women were not peri- or post-menopausal; however, this finding suggests that there may be hormonal factors which distinguish older from younger premenopausal women and that these factors may influence which women benefit from augmentation with estrogen.  

Ruta Nonacs, MD PhD

 

Weiser M, Levi L, Zamora D, Biegon A, et al.  Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing Age: A Randomized Clinical Trial.  JAMA Psychiatry. 2019 Jul 31. 

 

 

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