Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder.

Bipolar disorder (BD) is a major cause of social morbidity, accounting for 14.4 million disability-adjusted life years lost worldwide due to uncontrolled mood variations (Collins et al. 2011). Women of reproductive age with BD often find that mood variation can be linked to menstrual cycle phase, termed “menstrually entrained” (Rasgon et al. 2003, Blehar et al. 1998). The nature and degree of this effect, however, varies greatly between individuals (Leibenluft et al. 1999, Shivakumar et al. 2008, Teatero et al. 2013). BD is often comorbid with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD), and individuals with BD who experience menstrually-entrained exacerbations exhibit more severe symptoms, more frequent relapses, and impaired therapeutic response (Cirillo et al. 2012). Although the physiology of menstrual entrainment remains unclear, it has been suggested that hormonally influenced exacerbations of mood symptoms may be affected by cyclic variations of excitatory and inhibitory neurotransmitters across the menstrual cycle. Glutamate levels have been found to be inversely correlated with plasma estrogen and progesterone levels (Zlotnick et al. 2011, Casas et al. 2013), and accordingly glutamate levels vary across the menstrual cycle (Batra et al. 2008). Similarly, several lines of evidence point to changes in GABAergic activity that accompany alterations in steroid hormone milieu (Backstrom et al. 2003). Both the density and subunit composition of GABAA receptors in the central nervous system vary over the estrous cycle in response to fluctuations in neurosteroid levels (Maguire et al. 2005, Maguire et al. 2007, Maguire et al. 2009, and Porcu et al. 2014). Lamotrigine, an anticonvulsant used in maintenance treatment of BD, has been implicated in the modulation of glutamatergic (Leach et al. 1986) and potentially of GABAergic (Kuzniecky et al. 2002, Wang et al. 2001) signaling, and could potentially affect menstrual cycle-related alterations in neurotransmitter activity. Hence, it is plausible to speculate that use of lamotrigine might ameliorate cyclic variation in levels of excitatory or inhibitory central neurotransmitters and thereby enhance mood stability across the menstrual cycle for women with BD. Individual psychiatric case reports (Becker et al. 2004, Sepede et al. 2013, Skokou et al. 2013) as well as a single controlled study performed in women with epilepsy (Herzog et al. 2011) have supported the utility of lamotrigine as pharmacotherapy for menstrually entrained mood lability. However, to date no controlled study has examined the use of lamotrigine specifically for this purpose. Mood lability in bipolar disorder is moderated by alterations in sleep, and regular sleep is crucial to maintenance of mood stability (Plante et al. 2008). Disruptions in sleep rhythms can often precipitate episodes of mood instability (Bauer et al. 2006). Self-perceived sleep quality may vary across the menstrual cycle in healthy women (Baker et al. 2004), and disruption in circadian rhythms is associated with disruption in menstrual function (Labyak et al. 2002). Thus it is possible that variations in sleep quality across the menstrual cycle could also have bearing on mood stability in women with bipolar disorder. Lamotrigine has been reported in some studies to enhance sleep continuity and promote REM sleep (Placidi et al. 2000, Foldvary et al. 2001), suggesting that it could also have beneficial effects on sleep-related mood instability. No controlled study to date has specifically compared lamotrigine to other therapies for the management of variability in mood and sleep over the course of the menstrual cycle in women with BD. We report on an investigation of mood and sleep stability across the phases of the menstrual cycle in women with BD taking lamotrigine, compared to mood stabilizing regimens that did not contain lamotrigine. Hypotheses Our first hypothesis was that variability in mood and sleep across phases of the menstrual cycle would be more prevalent and more severe in women with BD compared to women without BD. A second hypothesis was that, in those women with BD whose regimens included lamotrigine, variations in mood and sleep across menstrual cycle phases would be attenuated compared to women with BD whose regimens did not include lamotrigine. In an additional exploratory analysis, the effects on mood and sleep of combining oral contraceptives (OCP) with lamotrigine and other psychiatric medications commonly used in our study sample were examined.