Circadian rhythm and sleep disturbances in bipolar disorder: from the associations with clinical and cognitive variables to the chronobiotic effect of exogenous melatonin

Bipolar Disorder (BD) is characterized by a variable course with some patients that present progressive impairment in functioning and cognition, more frequent relapses, and treatment refractoriness; while other patients maintain high functioning after each episode and show longer remission periods. Therefore, identifying and treating factors that may improve the prognosis of the disease reducing the risk of a neuroprogressive course in BD is highly relevant. Psychiatric comorbidities, sleep and circadian rhythm disturbances are factors related to a worse prognosis of BD. Although some studies have evaluated the effect of exogenous melatonin (exo-MEL) in BD, none of these studies has been focused on BD with comorbid delayed sleep-wake phase disorder (DSWPD), a circadian rhythm sleep disorder highly prevalent in BD that has been successfully treated with exo-MEL in non-psychiatric populations. The main aim of this research was to explore the role of circadian rhythm and sleep disturbances in BD, their possible correlations with clinical variables such as post-traumatic stress symptoms, mood, anxiety, and cognitive performance, and the effect of exo-MEL in patients with BD and circadian rhythm sleep disturbances. This research also includes an additional study to explore signatures of neurodegeneration in elderly patients with BD. This research has the following specific objectives: 1) To evaluate how sleep-related and circadian rhythm parameters, with a particular focus on the circadian typology (chronotype), are associated with lifetime post-traumatic stress, panic-agoraphobic and mood spectrum symptoms in healthy controls (HC) and patients with BD. 2) To compare sleep/circadian parameters and sustained attention profiles in BD with DSWPD comorbidity (BD-DSWPD) compared to BD without DSWPD (BD-Control) and HC. 3) To conduct a systematic and comprehensive review of the literature on the chronobiotic and sleep-promoting properties of exo-MEL. 4) To conduct an observational study to evaluate the effect of exo-MEL on sleep and circadian parameters in BD-DSWPD. 5) To describe the neuropsychological, brain morphometry, and structural connectivity profiles in patients with early onset older age bipolar disorder (EO-OABD) compared with patients with behavioral variant of frontotemporal dementia (bvFTD) and HC. Patients with BD in euthymic phase (N=83) and HC (N=207) were evaluated with a protocol that included actigraphy, the Pittsburgh Sleep Quality Index, the reduced Morningness-Eveningness Questionnaire, the Psychomotor vigilance task, and structured scales evaluating lifetime mood, panic-agoraphobic, and trauma and loss spectrum symptoms. Patients with BD that fulfilled criteria for DSWPD (N=25) were treated with exo-MEL for three months and evaluated in a longitudinal follow-up. Neuropsychological, brain morphometry and structural brain connectivity data from a sample of HC (N=28) and patients with EO-OABD (N=17) and bvFTD (N=25) were analyzed in an international collaborative study. Our results showed that: 1) The prevalence of evening chronotype (ET) was higher in BD compared to HC. Moreover, ET was related to more severe post-traumatic stress spectrum symptoms, lifetime depressive mood and disrupted rhythmicity in both HC and BD. 2) Patients with BD-DSWPD showed greater disturbances in sleep and circadian parameters compared to both HC and BD-Control. Likewise, patients with BD-DSWPD showed significantly increased response times and lapses compared to HC. 3) The systematic literature review provided evidence on the chronobiotic and sleep-promoting properties of exo-MEL describing the possible underlying mechanisms, clinical evidence, and implications for clinical practice. 4) The observational study showed that exo-MEL modified the self-reported chronotype, advanced the sleep onset time, and increased the sleep efficiency, confirming its effectiveness in improving sleep patterns in BD-DSWPD. 5) EO-OABD and bvFTD showed similarities in cognitive, brain morphometry, and structural connectivity profiles, thus highlighting the risk of neurodegeneration in BD, and the need for interventions that may contribute to a better prognosis of the disease. Proving the chronotherapy based on exo-MEL effective to improve sleep-wake patterns in BD will pave the way for future studies designed to investigate whether exo-MEL might contribute to improve clinical outcomes reducing relapses and eventually reducing the risk of neurodegeneration in BD.