Premenstrual Exacerbations of Mood Disorders: Findings and Knowledge Gaps

Abstract

Purpose of Review In contrast to premenstrual dysphoric disorder (PMDD), premenstrual exacerbations (PMEs) of ongoing mood disorders are understudied. The aim of this review is to describe diagnostic issues, epidemiology, underlying mechanisms, and treatment for PME in unipolar depression and bipolar disorder, and to discuss clinical and research implications. Recent Findings Community-based and clinical studies estimate that in women with mood disorders around 60% report PME, while some women with bipolar disorder also show symptom exacerbations around ovulation. In general, PME predicts a more severe illness course and an increased burden. While heightened sensitivity to fluctuations of sex hormone levels across the menstrual cycle appears to contribute to PME and PMDD, the overlap of their underlying biological mechanisms remains unclear. Beneficial treatments for PMDD show less or no efficacy in PME. Pharmacological treatments for PME in mood disorders predominantly seem to profit from adjustable augmentation of treatment dosages during the luteal phase for the underlying disorder. However, the evidence is sparse and mainly based on earlier small studies and case reports. Summary Previous research is mainly limited by the lack of a clear differentiation between PME and PMDD comorbidity with mood disorders. More systematic research with uniformly defined and prospectively assessed subgroups of PME in larger epidemiological and clinical samples is needed to receive reliable prevalence estimates and information on the clinical impact of PME of mood disorders, and to uncover underlying mechanisms. In addition, larger randomized controlled trials are warranted to identify efficacious pharmacological and psychotherapeutic treatments for affected women.

Why the estrous cycle matters for neuroscience

“…This is important because it was suggested that the old tests that were developed for males, such as the elevated plus maze, may not be applicable to females as they cannot re-create increased female risk for anxiety disorders reported in humans [23,41]. What we demonstrate, though, is that proper classification of females will show the same trend that we see in humans, which is that low-estrogenic female mice (diestrus) show higher anxiety indices than highestrogenic females (proestrus) and males, thus recreating the fact that sex hormone withdrawal in humans is a trigger for increased anxiety and depression symptoms [8,9] or other reproduction-related disorders such as PMDD [10], postpartum depression [11,12], and perimenopausal depression [8,14]. At the structural level, this vulnerability is seen as a drop in dendritic spines in the mouse ventral hippocampus following estrogen withdrawal; a similar finding is also reported in humans as reduced hippocampal gray matter following an estrogen drop [2,42].…”

“…Ovarian hormone fluctuation shapes brain physiology [1][2][3][4][5][6][7] and represents a major psychiatric risk factor in humans [8][9][10][11][12][13][14], yet this variable is largely ignored in preclinical neuroscience research, clinical studies, and psychiatric practice [8,[15][16][17]. The psychiatric risk in women is elevated throughout the reproductive period and is directly linked to hormonal changes [17].…”

“…5-8% of women suffer from premenstrual dysphoric disorder (PMDD) due to an increased sensitivity to physiological hormone fluctuations [10]. More than 50% of patients with depression, bipolar, and anxiety disorders also report worsening of their symptoms premenstrually [9,18]. During menopausal transition, with the most erratic hormone changes and severe estrogen drop, the risk for depression increases 2-5 times [14].…”

A DSM-5-based tool to monitor concurrent mood and premenstrual symptoms: the McMaster Premenstrual and Mood Symptom Scale (MAC-PMSS)

“…The profile of symptoms is similar throughout the cycle but the intensity is significantly greater in the premenstrual phase” [ 38 ]. Previous reviews on this topic have highlighted the various methodological flaws of previous studies, which led to over- or underestimates of the prevalence of premenstrual exacerbation of mood disorders [ 39 , 40 ]. Notwithstanding these methodological limitations, available evidence suggests that premenstrual exacerbation may occur in 44–68% of individuals with mood disorders [ 39 ].…”

Effects of an Oral Contraceptive on Dynamic Brain States and Network Modularity in a Serial Single-Subject Study

“…Sex-steroid milieu changes have been found to alter brain biology, including hippocampal plasticity ( Barth et al, 2016 ; Taylor et al, 2020 ) and serotonergic neurotransmission ( Barth et al, 2015 ), both crucial to maintaining mental health ( Frokjaer, 2020 ). In addition, mental disorders, such as anxiety and mood disorders, can be exacerbated during certain menstrual cycle phases, including premenstrual symptom worsening ( Pinkerton et al, 2010 ; Green and Graham, 2022 ; Kuehner and Nayman, 2021 ). Hormonal fluctuations across the menstrual cycle putatively trigger severe depressive symptoms in some women, i.e., premenstrual dysphoric disorder (PMDD), which can be treated with specific OCs but worsened by others ( Rapkin et al, 2019 ).…”