Send Orders for Reprints to reprints@benthamscience.ae Current Pharmaceutical Design, 2015, 21, 000-000 1 1381-6128/15 $58.00+.00 © 2015 Bentham Science Publishers Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders Pierre Alexis Geoffroy 1,2,3,4* , Bruno Etain 4,5,6,7 , Jean-Arthur Micoulaud Franchi 8,9 , Frank Bellivier 1,2,4,10 and Philipp Ritter 11 1 INSERM, UMR-S 1144, Paris, 75006, France; 2 AP-HP, GH Saint-Louis - Lariboisière - Fernand Widal, Pôle Neurosciences, 75475 Paris Cedex 10, France; 3 Université Paris Descartes, UMR-S 1144, Paris, 75006, France; 4 Fondation FondaMental, Créteil, 94000, France; 5 AP-HP, Hopitaux Universitaires Henri Mondor, DHU PePsy, Pôle de Psychiatrie, Créteil, 94000, France; 6 INSERM, U955, Psychiatrie génétique, Créteil, 94000, France; 7 Université Paris Est Créteil, Créteil, 94000, France; 8 Services d'explorations fonctionnelles du système nerveux, Clinique du sommeil, CHU de Bordeaux, 33076 Bordeaux; 9 USR CNRS 3413 SANPSY, CHU Pellegrin, Univer- sité de Bordeaux, France; 10 Université Paris Diderot, UMR-S 1144, Paris, 75013, France; 11 Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Fetscherstraße 74, 01307 Dresden Abstract: Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psy- chiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this compre- hensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in pa- tients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and de- lineate the routine use of melatonin-agonists in the treatment of BD. Keywords: Bipolar disorders, Melatonin, Ramelteon, Tasimelteon, Sleep, Circadian rhythms. INTRODUCTION Bipolar disorder (BD) is a severe psychiatric disorder character- ized by recurrent manic and depressive episodes that affect 1% to 4% of the general population worldwide [1]. BD is ranked as one of the most burdensome diseases globally due to its peak age at onset in adolescence and early adulthood, consequently leading to poor functioning and diminished quality of life throughout adulthood [2- 4]. BD has a complex inheritance pattern implicating both genetic and environmental factors, with increasing evidence that abnormali- ties of circadian rhythmicity and sleep homeostasis contribute to the underlying neurobiology of and genetic susceptibility to BD [5, 6]. Indeed, these abnormalities are part of the diagnostic criteria for the acute phases of BD, with the classic patterns being the presence of insomnia or hypersomnia during major depressive episodes and a decreased need for sleep without subsequent fatigue in (hypo)manic episodes [7, 8]. It is now recognized that BD cases experience pervasive sleep and circadian abnormalities during remission phases (i.e. when no or minimal other bipolar symptoms are present) [9]. Firstly, 83% BD patients in remission reported poor sleep quality compared to 21% of healthy controls [10] and Harvey et al. observed that 55% BD cases also met diagnostic criteria for insomnia [11]. Insomnia is thus a frequent comorbidity of BD. Secondly, BD patients exhibit *Address correspondence to this author at the Service de Psychiatrie Adulte (Pr. Frank BELLIVIER), Groupe Hospitalier Saint-Louis-Lariboisière- Fernand Widal, 200 rue du Faubourg Saint Denis, 75475 Paris Cedex 10 France; Tel: +33 (0) 1 40 05 48 69; Fax: +33 (0) 1 40 05 49 33; E-mail: pierre.a.geoffroy@gmail.com circadian abnormalities with evening chronotype [12] and more than 60% of young patients with BD when depressed presented with a delayed sleep phase, compared with 30% of those with unipolar depression and 10% of control participants [13]. And thirdly, sleep parameters (in particular sleep onset latency, total sleep time and sleep efficiency) are abnormal in patients with BD [9, 14]. Sleep and circadian abnormalities during the remission period are associated with mood relapses as well as functioning, quality of life and metabolic syndrome [15-17]. Therefore, sleep and circadian abnormalities in BD have been considered as possible therapeutic targets using chronobiotic drugs [18, 19]. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses [20]. Melatonin secre- tion is nocturnal and influenced by photoperiod (dark-light periods), with its synthesis determined by the activity of the serotonin N- acetyltransferase (AANAT) enzyme in a reaction that requires ace- tyl coenzyme A (AcCoA) [21]. Exogenous melatonin has demon- strated efficacy with both objective (polysomnography or actigra- phy) and subjective measures (scales, questionnaires, sleep logs) in: i) treating primary insomnia in adults and children in numerous trials [22, 23], ii) treating patients with delayed sleep phase disorder [24], iii) improving sleep parameters (sleep onset latencies and total sleep time) and overall sleep quality [23], and iv) improving some sleep and behavioural disorders in children with autistic spectrum disorders (ASD) [25-27]. The whole of these proofs of efficacy of exogenous melatonin is strongly in favor of its possible interest of use in patients with BD. Pierre Alexis Geoffroy