Using Chronobiological Phenotypes to Address Heterogeneity in Bipolar Disorder

Bipolar disorder (BD) is a neuropsychiatric mood disorder characterized by recurrent episodes of mania and depression in addition to disruptions in sleep, energy, appetite, and cognitive functions-rhythmic behaviors that typically change on daily cycles. BD symptoms can also be provoked by seasonal changes, sleep, and/or circadian disruption, indicating that chronobiological factors linked to the circadian clock may be a common feature in the disorder. Research indicates that BD exists on a clinical spectrum, with distinct subtypes often intersecting with other psychiatric disorders. This heterogeneity has been a major challenge to BD research and contributes to problems in diagnostic stability and treatment outcomes. To address this heterogeneity, we propose that chronobiologically related biomarkers could be useful in classifying BD into objectively measurable phenotypes to establish better diagnoses, inform treatments, and perhaps lead to better clinical outcomes. Presently, we review the biological basis of circadian time keeping in humans, discuss the links of BD to the circadian clock, and pre-sent recent studies that evaluated chronobiological measures as a basis for establishing BD phenotypes. We conclude that chronobiology may inform future research using other novel techniques such as genomics, cell biology, and advanced behavioral analyses to establish new and more biologically based BD phenotypes.