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Bipolar disorder (BD) is a mood disorder with genetic and neurobiological underpinnings, characterized primarily by recurrent episodes of mania and depression, with notable disruptions in rhythmic behaviors such as sleep, energy, appetite and attention. The chronobiological links to BD are further supported by the effectiveness of various treatment modalities such as bright light, circadian phase advance, and mood-stabilizing drugs such as lithium that have effects on the circadian clock. Over the past 30 years, the neurobiology of the circadian clock has been exquisitely described and there now exists a detailed knowledge of key signaling pathways, neurotransmitters and signaling mechanisms that regulate various dimensions of circadian clock function. With this new wealth of information, it is becoming increasingly plausible that new drugs for BD could be made by targeting molecular elements of the circadian clock. However, circadian rhythms are multidimensional and complex, involving unique, time-dependent factors that are not typically considered in drug development. We review the organization of the circadian clock in the central nervous system and briefly summarize data implicating the circadian clock in BD. We then consider some of the unique aspects of the circadian clock as a drug target in BD, discuss key methodological considerations and evaluate some of the candidate clock pathways and systems that could serve as potential targets for novel mood stabilizers. We expect this work will serve as a roadmap to facilitate the development of compounds acting on the circadian clock for the treatment of BD. [ABSTRACT FROM AUTHOR]

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment. [ABSTRACT FROM AUTHOR]

Many psychiatric disorders are characterized by circadian rhythm abnormalities, including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian 'clock genes' commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors, further supporting the idea of a connection between the circadian clock and psychiatric disorders. However, if circadian clock dysfunction is a common risk factor for multiple psychiatric disorders, it is unknown if and how these putative clock abnormalities could be expressed differently, and contribute to multiple, distinct phenotypes. One possible explanation is that the circadian clock modulates the biological responses to stressful environmental factors that vary with an individual's experience. It is known that the circadian clock and the stress response systems are closely related: Circadian clock genes regulate the physiological sensitivity to and rhythmic release of glucocorticoids (GC). In turn, GCs have reciprocal effects on the clock. Since stressful life events or increased vulnerability to stress are risk factors for multiple psychiatric disorders, including post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), alcohol use disorder (AUD) and schizophrenia (SCZ), we propose that modulation of the stress response is a common mechanism by which circadian clock genes affect these illnesses. Presently, we review how molecular components of the circadian clock may contribute to these six psychiatric disorders, and present the hypothesis that modulation of the stress response may constitute a common mechanism by which the circadian clock affects multiple psychiatric disorders. [ABSTRACT FROM AUTHOR]