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.

Inclusion Criteria:

- Ages between 18 and 55

- Bipolar Disorder Type I or II, with current major depression.

- Currently receiving active treatment from a psychiatrist for bipolar disorder

Exclusion Criteria:

- Recent history of, or current Diagnostic and Statistical Manual IV, Text Revision
criteria for alcohol or substance abuse/dependence disorders

- circadian rhythm sleep disorders or sleep apnea

- current stimulant use

- any recent or planned transmeridian travel across more than two time zones

- recent, current, or planned shift work schedules

- pregnancy or plan to become pregnant

- a Young Mania Rating Scale Score of greater than or equal to seven

- received in the past two weeks or plan to receive bright light therapy, dawn
simulation, sleep deprivation, or other forms of chronotherapy.