Hormonal Mechanisms of Perimenopausal Risk for Psychosis in Women

PROJECT SUMMARY Women show a heightened risk for psychosis in midlife that is not observed in men. The menopausal transition (i.e., perimenopause) is presumed to account for these midlife changes in risk, but data examining this possibility are wholly lacking. Information on mechanisms of midlife risk is largely absent as well. Ovarian hormones are key to menopausal changes in women and are known to have wide-reaching effects on brain and behavior. Thus, it has been theorized that changes in these hormones during perimenopause drive midlife psychosis risk in women, and studies during other reproductive events (e.g., the menstrual cycle) show increased psychotic symptoms in women with lower levels of ovarian hormones. However, to date, no studies have examined if changes in ovarian hormones are mechanisms of midlife psychosis risk in women. Consequently, the Specific Aims of the proposed project are to isolate the perimenopausal period as a critical period of risk (Aim 1) and examine ovarian hormones as mechanisms of effects (Aim 2). We will address these aims using an innovative, multi-method (behavioral, neuroendocrine, multi-informant), and intensive daily study design in a large, population-based sample of women (N = 750) that varies in menopausal status (i.e., premenopause, perimenopause, postmenopause) and is enriched for psychosis risk. Women will collect daily data on psychotic (and related) symptoms across 35 consecutive days, and we will use these data to confirm that perimenopausal stage, rather than age or other factors (e.g., midlife stress), drive increased psychosis risk in women (Aim 1). We will then extend these data by collecting daily saliva samples of estrogen and progesterone across the 35-day study period in the perimenopausal women and examining whether levels and changes in these hormones are mechanisms underlying midlife psychosis risk in women (Aim 2). We will assess a range of psychotic symptoms across the study period to capture the full spectrum of psychosis risk, and we will collect informant and clinician symptom ratings to validate and confirm symptom reports. Importantly, our proposed study addresses the RFA high priority area “Research clarifying the mechanistic role of reproductive steroids in generating, moderating, or mitigating mood and psychosis symptoms during the menopausal transition.” Indeed, our novel, longitudinal study will allow us to quantify population- level risk for midlife psychosis as well as elucidate the critical hormonal mechanisms that are necessary to inform women's health policy and devise translational approaches to prevention and intervention.