Menstrual effects on mood symptoms in treated women with bipolar disorder.

Bipolar disorder (BD) type I (BD-I) affects women and men equally (1). In contrast, variants of bipolar illness such as BD type II (BD-II), mixed states, and rapid-cycling illness are more common in women (2, 3). Once the mood episode has resolved, residual symptoms persist in 50% of patients (4). Women with BD are burdened with considerable family, social, and occupational dysfunction and lowered quality of life (5). The pattern of mood variability related to menstrual cycles in women with bipolar illness has not been well-characterized. As high as 66% of women with BD-I regularly experience perimenstrual mood worsening (6). In case series and retrospective reviews, patients reported heightened perimenstrual mood symptoms and the onset of rapid-cycling that required hospitalization during the premenstrual phase (7, 8). Oral contraception (OC) has shown to alleviate mood variability in 50% patients with BD who suffer menstrual-related mood worsening (7), with monophasic pills alleviating dysphoria more effectively than phasic pills (9). However, increased aggression and irritability have been noted in patients who received androgenic progestins compared to the newer progestins (desogrestrel, levonorgestrel, norgestimate, or drospirenone) (10, 11). Therefore, it is difficult to interpret data without precise descriptions of the OC agents that women received. Interpretation of earlier data are limited in other ways: (i) failure to control for the current mood episode, (ii) retrospective reporting, (iii) small samples, (iv) insufficient observational period from a single cycle or single menstrual phase; (v) no objective measure to confirm ovulation, and (vi) unclear methodology (12). Women with premenstrual dysphoria are more likely to experience mood disorders compared to women without premenstrual symptoms (13, 14), and Premenstrual Dysphoric Disorder (PMDD) is one such discrete menstrual-related mood disorder. The defining characteristics of PMDD [a cyclic pattern of dysphoria, irritability, and mood lability (15)] suggests clinical similarities to bipolar illness; for example, a rapid-cycling illness or mixed episodes in which patients have concurrent symptoms of a depressive and hypomanic/manic episode. Despite clinical similarities between PMDD and BD in women, few studies have been undertaken to investigate associations between menstrual cycles and BD. The rate of PMDD in women who also have bipolar illness is unknown. Leibenluft (2) was unable to detect a predictable or specific pattern of menstrual-linked mood variability in women with BD and rapid cycling. Controlled, prospective research to elucidate the link between these disorders is needed (2). Physical problems related to the menstrual cycle affect a subset of women with BD. Among 80 patients with BD, 65% had menstrual irregularities and 38% developed new menstrual abnormalities after starting medications (16). Although the antimanic agent valproate disrupts ovarian function and is associated with polycystic ovarian syndrome in 10% of women receiving this agent (16, 17), women who tolerate maintenance valproate therapy benefited from improved mood stability and resolution of troubling premenstrual symptoms, even compared to healthy controls (18). The induction of anovulation is beneficial for reducing symptoms of PMDD. Treatments for PMDD include the suppression of ovulation with OC treatment or gonadotropin releasing hormone (GnRH) agonists, and the adding back of estradiol and progesterone results in the re-emergence of mild to severe menstrual symptoms (19). However, some patients may be susceptible to the mood-impairing effects of anovulation. Stress-induced functional hypothalamic amenorrhea has been described in women with severe depression and interpersonal sensitivity when compared to healthy controls (20) indicating that the data on anovulation and mood symptoms is not entirely consistent. Anovulation from peripheral hormone therapy is associated with menstrual related dysphoria, whereas anovulation from central stress factors could exacerbate mood symptoms. From these reports, the connection between menstrual cycles and bipolar mood exacerbations remains unclear. In this prospective observational study, the authors characterized mood symptoms, psychosocial functioning, and perceived stress throughout the menstrual cycle. We hypothesized that depressed or euthymic women with BD would have (i) increased levels of depression and hypomanic/manic symptoms, (ii) decreased psychosocial functioning, (iii) elevated levels of perceived stress, and (iii) physical discomfort in the late luteal (LL) phase compared to the early follicular (EF) phase when compared to healthy controls.