Effect of Adjunctive Estradiol on Schizophrenia Among Women of Childbearing Age

Abstract

IMPORTANCE Several lines of evidence suggest that estradiol influences the course of schizophrenia, and a previous randomized controlled trial demonstrated that transdermal estradiol improved symptoms in female patients of childbearing age. However, many initial positive findings in schizophrenia research are not later replicated. OBJECTIVE To independently replicate the results of the effect of estradiol on schizophrenia in women of childbearing age. DESIGN, SETTING, AND PARTICIPANTS An 8-week randomized, placebo-controlled trial performed in the Republic of Moldova between December 4, 2015, and July 29, 2016, among 200 premenopausal women aged 19 to 46 years with schizophrenia or schizoaffective disorder as defined by the DSM-5. INTERVENTION Patients were randomized to receive a 200-μg estradiol patch or placebo patch changed twice a week added to their antipsychotic treatment. MAIN OUTCOMES AND MEASURES The primary outcome was the positive subscale of the Positive and Negative Syndrome Scale (PANSS; lower scores indicated fewer symptoms and higher scores indicated more symptoms), analyzed with mixed models for repeated measures on an intention-to-treat basis. RESULTS A total of 100 women (median age, 38 years; interquartile range, 34-42 years) were randomized to receive an estradiol patch and 100 women (median age, 38 years; interquartile range, 31-41 years) were randomized to receive a placebo patch; the median age at baseline for the entire group of 200 women was 38.0 years (range, 19.5-46.0 years). At baseline, the mean positive PANSS score was 19.6 for both groups combined; at week 8, the mean positive PANSS score was 14.4 in the placebo group and 13.4 in the estradiol group. Compared with placebo, participants receiving add-on estradiol patches had statistically significant improvements in the primary outcome measure, PANSS positive subscale points (-0.94; 95% CI,-1.64 to-0.24; P = .008; effect size = 0.38). Post hoc heterogeneity analyses found that this effect occurred almost entirely in 100 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 benefit from estradiol (difference, 0.08 points on the PANSS positive subscale; 95% CI,-0.91 to 1.07; P = .87). Breast tenderness was more common in the estradiol group (n = 15) than in the placebo group (n = 1) as was weight gain (14 in estradiol group vs 1 in placebo group). CONCLUSIONS AND RELEVANCE The results independently replicate the finding that transdermal estradiol is an effective add-on treatment for women of childbearing age with schizophrenia and extend it, finding improvements in negative symptoms and finding that the effect could be specific to those older than 38 years. The results should be viewed in the context of the differences in the natural course of schizophrenia between females and males. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03848234

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology

“…Meta-analyses of double-blind RCTs of adjunctive treatment with oestrogen or the selective oestrogen receptor modulator raloxifene (Heringa et al, 2015;de Boer et al, 2018) in women have reported an improvement in positive, negative and total symptom scores with a small to moderate effect size. These findings were replicated by an RCT of the adjunctive use of an oestradiol patch in premenopausal women, but only in a subset of 100 women aged over 38 years (Weiser et al, 2019b). Whether positive results relate to anti-inflammatory or endocrine effects has yet to be established.…”

Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

“…Recent clinical studies have demonstrated that adjunct treatment with 17βestradiol and estrogen-based compounds ameliorate positive, negative and cognitive symptoms experienced by patients diagnosed with schizophrenia or depression [29][30][31][32][33][34] .…”

“…Recent work has suggested that DISC1 forms aggregates under physiological and pathological conditions 34,41,42 . The formation of aggregates has been proposed to contributes to DISC1's cellular function and the cellular pathology associated with the altered expression of this protein 39,46,47 .…”

“…The effect of 17β-estradiol, the principal biologically active estrogen, on cognition is thought to be driven, in part, by activation of specific signaling pathways resulting in alternations in dendritic spine number and the trafficking of key synaptic proteins (reviewed in 13). Recently, clinical studies have shown that treatment with 17β-estradiol has beneficial effects for patients diagnosed with SCZ or MDD, when given as an adjunct treatment to ongoing antipsychotic or antidepressant therapies [29][30][31][32][33][34] . However, the molecular and cellular mechanisms by which 17β-estradiol exert these beneficial effects are currently unknown.…”

Schizophrenia Psychosis in Women

“…Estradiol and the selective estrogen receptor modulator, raloxifene, have been used as augmentation therapy for women with schizophrenia (and sometimes men), lessening symptom severity and, therefore, potentially leading to reduced doses of antipsychotic medication and fewer adverse effects [63,64]. The effectiveness of estrogen has been attributed to its many neuroprotective actions [58,65], one of which is its anti-inflammatory effect.…”