Treatment of Bipolar Disorder

Steven Kushner (Erasmus MC)
Bert van der Horst (Erasmus MC)
Ed Jacobs (Erasmus MC)

Commonly, BD patients also experience episodes of depression. These manic and depressive episodes are separated by periods of normal mood, but many patients experience rapidly alternating episodes. During the manic episodes there is an elevated state of mood, by which the patient is much more energetic, more active, less attentive, euphoric, impaired in judgement, more sensitive for drugs of abuse, engages in higher risk taking, often has delusional ideas and with a nearly pathognomonic decreased need for sleep. During the depressive episodes patients feel sad, lose interest in normal daily activities, experience a decreased appetite and become apathic. During both the manic and depressive episodes they have disturbances in sleep-wake patterns. Days before overt manic symptoms are manifest, the circadian patterns of activity and sleep-wake cycles begin to shift, up to the point that during the manic episode patients often experience multiple consecutive days without sleep. Conversely, disruptions of the sleep-wake pattern represent one of the highest risk triggers for the initiation of manic and depressive episodes in BD patients. Accordingly, with a tightly-controlled daily routine, a significant reduction in the onset of affective episodes has been observed. First-line treatment of BD requires pharmacotherapy using lithium or anticonvulsants, but relapse rates remain high. Strong efforts have been made towards developing novel treatment strategies, but the lack of a satisfactory animal model for this devastating disease has severely limited our ability to identify novel drug targets for treatment.

The aim of the project is to develop a robust and validated animal model, defined fundamentally through a quintessential symptom of BD: disturbance of the circadian clock. While the neurobiology and genetics of circadian rhythms have been elegantly defined, and the clinical phenomenology of BD is so deeply rooted in sleep-wake disturbances, no major academic-industry partnership has yet been initiated to explore chronobiological targets for the treatment of BD. Our consortium is a powerful one in that it combines two academic partners that have strong roots into BD (Department of Psychiatry) and into chronobiology (Department of Genetics) with one of the leading pharmaceutical companies in psychiatric diseases having the experience and tools to study the link between circadian neurobiology and BD with the aim towards identifying novel targets for drug development.