Depression is a major health problem, on par with heart disease in its annual cost of $43.7 billion (112). Women, compared with men, have a 2 to l incidence of major depression, and are prone to develop depressive episodes particularly at times of reproductive hormonal change premenstrually, postpartum and at menopause. The focus of the P.I. is to investigate how reproductive hormonal change, by interacting with circadian physiology, may contribute to precipitating depressive episodes at these times of high vulnerability in women. In the proposed studies, mood disorders linked to the premenstruum, named premenstrual dysphoric disorder (PMDD) in the DSM-IV, will serve as the clinical model to investigate the influence of spontaneous changes in estradiol and progesterone on circadian dynamics. We hypothesize that women's vulnerability for depression premenstrually stems from the effects of declining levels of estradiol and progesterone, which by altering the circadian clock, disrupt healthy temporal relationships and secretion patterns of melatonin and other circadian rhythms. This alteration disturbs the normal internal synchronization of circadian rhythms and their external synchronization with the environment. In women at risk for depression, these desynchronized rhythms contribute to the expression of mood disorders. Relevant to our proposal is that light has the capacity to resynchronize rhythms and based on our previous experience, to improve mood in PMDD (38,40,105). In the proposed experiments, we will test the hypothesis that the circadian system, when challenged with a light probe, responds differently in l) PMDD vs. NC subjects (i.e., the response is a trait marker), 2) PMDD subjects when they are symptomatic vs. when they are asymptomatic (i.e., the response is a state marker), 3) the follicular vs. the luteal menstrual cycle phase (i.e., the response is a hormonal effect). These studies extend our previous and now replicated work (supported by an NIMH FIRST Award), by investigating: l) the mechanisms by which light therapy and sleep deprivation exert their therapeutic effects in PMDD (40,41,105,106), 2) the basis for baseline abnormalities in melatonin and other circadian rhythms that we have observed in PMDD,(39,107) and 3) the effects of dim light and sleep deprivation on circadian dynamics and mood.
