Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review (2015)

Sex hormones and oxytocin augmentation strategies in schizophrenia: A quantitative review


Sex differences in incidence, onset and course of schizophrenia suggest sex hormones play a protective role in the pathophysiology. Such a role is also proposed for oxytocin, another important regulator of reproduction function. Evidence on the efficacy of sex hormones and oxytocin in the treatment of schizophrenia is summarized.


Double-blind, placebo-controlled, randomized studies were included, examining augmentation with estrogens, selective estrogen receptor modulators (SERMs), testosterone, dehydroepiandrosterone (DHEA), pregnenolone, and oxytocin. Outcome measures were total symptom severity, positive and negative symptom subscores, and cognition. In meta-analyses, combined weighted effect sizes (Hedges’ g) per hormone were calculated.


Twenty-four studies were included, examining 1149 patients. Significant effects were found for estrogen action (k = 10), regarding total symptoms (Hedges’ g = 0.63, p = 0.001), positive (Hedges’ g = 0.42, p < 0.001), and negative symptoms (Hedges’ g = 0.35, p = 0.001). Subgroup analyses yielded significant results for estrogens in premenopausal women (k = 6) for total, positive, and negative symptoms, and for the SERM raloxifene in postmenopausal women (k = 3) for total and negative, but not positive symptoms. Testosterone augmentation in males (k = 1) was beneficial only for negative symptoms (Hedges’ g = 0.82, p = 0.027). No overall effects were found for DHEA (k = 4), pregnenolone (k = 4), and oxytocin (k = 6). Results for cognition (k = 12) were too diverse for meta-analyses, and inspection of these data showed no consistent benefit.


Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account. Future trials are needed to study long-term effects and effects on cognition.

Meta-analysis of estrogen action augmentation on total symptom severity. Studies above the red line used estrogens (in premenopausal women, and in one study in men), and studies below the red line used raloxifene (in postmenopausal women).

Meta-analysis of dehydroepiandrosterone (DHEA) augmentation on total symptom severity

Meta-analysis of pregnenolone augmentation on total symptom severity.

Meta-analysis of oxytocin augmentation on total symptom severity.

“Cognitive results were available for studies on estrogens, DHEA, pregnenolone, and oxytocin, with most studies describing several cognitive domains. Raw data per domain or composite scores were sparse, therefore meta-analyses could not be performed. Memory was most frequently tested (ten studies), significant effects were observed in three studies: raloxifene improved verbal learning more than placebo (Huerta-Ramos et al., 2014), pregnenolone improved visual memory (Ritsner et al., 2010), and verbal memory was higher in the oxytocin versus placebo group (Feifel et al., 2012). Executive function, attention, and processing speed were each examined in seven studies. Significant improvements relative to placebo were found in executive functioning after pregnenolone (Kreinin et al., 2014), in visual attention after DHEA (Ritsner et al., 2010) and pregnenolone (Kreinin et al., 2014), and in processing speed after pregnenolone (Ritsner et al., 2010). Five studies examined visuospatial, constructional, and movement skills; significant effects were found only for DHEA (Ritsner et al., 2006a and Ritsner et al., 2006b). One study examined verbal fluency and found a significant effect of raloxifene on phonemic fluency (Huerta-Ramos et al., 2014). Social cognition was examined in five studies; two studies on oxytocin found significant effects for second order false belief identification (Pedersen et al., 2011) and fear recognition and perspective taking (Gibson et al., 2014).”

“In conclusion, hormonal augmentation strategies are an interesting direction in the development of new treatment methods for schizophrenia. Especially estrogen augmentation in women warrants further investigation, as beneficial effects on total, positive and negative symptom severity were found. However, risks of side effects of estrogens, partially associated with longer duration use, should be taken into account. For this reason, SERMs may serve as a favorable alternative for estrogens that is also appropriate for use in men. Testosterone could be effective in reducing negative symptom severity in men, but this finding needs replication. The precursors DHEA and pregnenolone do not seem to be of therapeutic value for schizophrenia, neither does oxytocin. Regarding cognition, some promising results were found for each of the studied hormones. Future research is needed to carefully examine the therapeutic effects of hormone augmentation, especially in the long term and effects on cognition, as new treatment strategies could emerge from which patients with schizophrenia may benefit.”

See also:

Neurosteroids as therapeutics

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