PREMAP - Predictors and Risk Evaluation for Menopause-Associated Psychosis

Schizophrenia and other psychotic disorders are typically thought of as disorders of adolescence and early adulthood: the peak incidence of new psychotic disorder diagnoses is from 15 to 19 in men and 20 to 24 in women. However, women also demonstrate a second peak of incidence and vulnerability to the illness in their 40s and early 50s. Theories have been proposed to explain this second peak, including appeals to the neuroprotective effects of estrogen and other reproductive hormones, which wane in the years preceding menopause. Despite these observations and theoretical groundwork, very little evidence exists to identify risk factors for development of psychosis in women experiencing the menopause transition. This is partly because development of psychosis in this population is relatively rare and is thus difficult to observe. In response to the NIMH funding opportunity announcement entitled, “Mood and Psychosis Symptoms during the Menopause Transition”, we propose a two-pronged approach to identify risk factors for development of psychosis during the menopause transition. In our first aim, we propose to recruit from established local and national sources 179 individuals who have developed a first episode of psychosis during the menopause transition and to retrospectively identify elements of medical, reproductive, psychiatric, and family history that predispose to the development of psychosis when compared to 144 matched controls who developed depression in the same period. We hypothesize that women who developed psychosis during the menopause transition will report a prodromal period of attenuated symptoms preceding the development of frank psychosis, that factors generally predisposing to psychosis onset will be relatively over-represented in the psychosis cohort, and that psychiatric disorders tied to hormone fluctuations will be elevated in both cohorts relative to population rates. In our second aim, we propose to leverage our team’s established expertise in identifying risk factors for psychosis to prospectively study women who have attenuated psychotic symptoms, elevating their risk for developing psychosis. From established sources, we will identify 196 women who are at clinical high risk for psychosis during the earliest phases of the menopause transition. We will then follow these women and 98 matched healthy controls over 2 years, collecting clinical, behavioral, computational, endocrinological, and (in an exploratory subset) imaging and electrophysiological data as they transition toward menopause. We hypothesize that baseline psychotic and cognitive symptom severity will predict conversion to psychosis and that the worsening of these symptoms will correspond to specific clinical and hormonal markers of the menopause transition. We also hypothesize that candidate psychosis biomarkers will predict conversion and functional decline and will be impacted by markers of the menopause transition. Together, these studies will be the first to identify definitive risk factors for psychosis development in aging women. Our goal is to use the data generated to develop specific interventions to mitigate risk for psychosis in this vulnerable population.