Circadian Phase in Bipolar Depression: Is it Delayed and Does it Normalize With Remission?

Bipolar disorder is a prevalent, disabling, and chronic mood disorder characterized by depressive symptoms that alternate with hypomanic, manic or mixed states. The depressive phase of this illness predominates and is associated with cognitive, occupational and social impairment, psychiatric comorbidity, and increased mortality from suicide and general medical problems. Clarification of the pathophysiology of this illness is important to improve treatment effectiveness. Various lines of evidence suggest that circadian factors play a role in the onset and maintenance of bipolar depression. Rhythmic clinical disturbances are found in the altered sleep-wake cycle, diurnal mood shifts, rest-activity changes, seasonal features, the cyclic pattern of relapse and remission and the polarity inversions that define this disorder. Chronotherapeutic treatments that act by modifying circadian phase have been shown to be effective in ameliorating the depressive symptoms of this illness. In addition to this circumstantial evidence, there is some more direct data implicating circadian dysfunction in bipolar depression. Genetic studies have documented associations between various circadian genes and bipolar illness. Actigraphic studies of activity levels have demonstrated illness-remission differences and phase advances in manic states. Though these latter studies employ more direct assessment methodologies, there are few articles that have attempted to investigate circadian processes in bipolar depression with the use of the core clock processes. These basic clock rhythms include core body temperature, cortisol levels and dim light melatonin onset. Because these physiological oscillations are less influenced by behavior and less prone to masking, they more accurately reflect the intrinsic timing of the central pacemaker. This study will use dim light melatonin onset and actigraphy to assess the status and changes in circadian phase between states of bipolar depression and their remission. Using a case control methodology, adult subjects will be evaluated during, and after remission from the depressive phase of bipolar disorder. General Aim The overall aim of this project is to compare the timing of dim-light melatonin onset and actigraphy-based activity patterns in adult patients with bipolar disorder in depressed vs remitted states. These markers will enable characterization of changes in circadian phase between illness and recovery. A case control design will enable the use of small sample sizes capable of identifying statistically significant changes in the timing of circadian rhythms in the two states of interest. Hypotheses It is predicted that the dim light melatonin onset and activity profile will be delayed in the depressed vs. the euthymic state of bipolar disorder. It is further anticipated that this phase delay will lessen when bipolar subjects achieve remission from their depression. Last, it is predicted that the circadian phase of the dim light melatonin onset and the activity profile will correlate, both being delayed in the depressive phase, and less delayed in euthymia.