Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil

Changes in the sleep-wake cycle are other circadian rhythms represent core features of
Bipolar Disorder (BD), with sleep abnormalities in approximately 90% of patients during acute
episodes. Even when euthymic, many BD patients continue to demonstrate circadian disruptions,
including diminished sleep efficiency and lower daytime activity levels (Plante, 2008).
Moreover, unaffected offspring of BD patients demonstrate sleep and activity abnormalities
(Ankers, 2009), and variation within several circadian-related genes (e.g. CLOCK) has been
associated with risk for BD (Dallaspezia, 2009). These trait-like circadian disruptions are
of particular clinical relevance as chances in sleep are highly predictive of impending
affective instability (Plante, 2008) and BD patients with poor sleep quality report
diminished quality of life (Gruber, 2009). Psychosocial treatments that incorporate the
regulation of sleep and activity in BD have been successful in reducing recurrence,
highlighting the important of stabilizing circadian rhythms in BD (Frank, 2005); yet
treatment remains suboptimal and, to date, no pharmacological intervention using circadian
measures as outcomes in BD has been published.

The exact nature of the circadian abnormality in BD is known; theories posit a potential
uncoupling of the biological clock from external variables that entrain circadian rhythms
(e.g. light) versus the desynchronization of the sleep-wake cycle such that it falls out of
phase with other biological rhythms (Dallaspezia, 2009). Euthymic BD patients are commonly
characterized by an eveningness chronotype, such that their time-to-sleep preference is
phase-shifted to a later than average hour, one that is not typically aligned with the
24-hour light-dark cycle (Plante, 2008; Ahn, 2008). Potential consequences related to these
persistent circadian abnormalities include significant reductions in daytime wakefulness and
neurocognitive impairment.

While sleep deprivation induced by single-trial phase-shifts only impairs cognition until
sleep in recovered, chronic deprivation such as those noted in BD individuals, have been
implicated in significant learning and memory deficits in animal models (Craig, 2008).
Moreover, humans who are unable to synchronize normal sleep-wakefulness schedules with their
own internal biological clocks are impaired on tasks of processing speed, working memory, and
learning (Wright, 2006). Indeed, a majority of BD patients demonstrate deficits in attention,
memory, and executive function even when affectively stable (Goldberg & Burdick, 2008).
Although several features of the illness potentially contribute to the persistent cognitive
impairment noted during euthymic periods, the circadian-based deficits in sleep quality and
daytime wakefulness are likely to exacerbate cognitive problems in BD (Giglio, 2010), as has
been shown in healthy controls, sleep disordered subjects and other clinical conditions
(Benca, 2009). Preliminary data support this relationship in BD. The possible influence of
chronic circadian disruption on cognition in BD is of critical importance because of a strong
association between cognition during euthymic and functional disability (Sanchez-Moreno,
2009).

When considering agents that may simultaneously improve upon sleep quality and enhance
cognition, the wake-promoting agents, modafinil, is an ideal candidate. It is FDA approved
for improving wakefulness in adults with excessive daytime sleepiness due to primary sleep
disorders (Provigil, 2007) and is characterized as a psychostimulant but has been
differentiated from amphetamine by a lower liability for abuse and a more favorable risk
profile. Modafinil has been shown to enhance cognition in healthy controls, sleep-disordered
individuals, neurological patients, and patients with schizophrenia (Minzenberg, 2008).
Preliminary data indicate that modafinil is safe and effective as an adjunctive in depressed
BD patients, with no risk for mania-induction vs placebo (Frye, 2007); however there has not
yet been a systematic trial in euthymic BD patients with sleep and cognitive dysfunction as
outcome measures. Thus, adjunctive modafinil (200 mg/day) vs placebo will be administered to
48 euthymic patients with BD for 8 weeks with three specific aims:

1. To evaluate the safety of adjunctive modafinil in euthymic BD. Adverse events will be
carefully measured and recorded in an effort to determine the base rates for common side
effects in BD. Specifically, mood and psychosis ratings will be conducted weekly to
address the potential for modafinil to exacerbate manic and/or psychotic symptoms.

2. To evaluate the effects of adjunctive modafinil in euthymic BD on measures of sleep
quality and daytime wakefulness. Patients' subjective experience of sleep disruption and
daytime wakefulness will be measured weekly using several standard questionnaires and
daily diaries.

3. To evaluate the effects of adjunctive modafinil in euthymic BD on measures of
neurocognition. Cognitive functioning will be assayed using the MATRICS Consensus
Cognitive Battery supplemented by several domain-specific tasks at baseline, 4-weeks,
and at the end of the 8-week study.

Inclusion Criteria:

- DSM-IV Bipolar Disorder I or Bipolar Disorder II diagnosis

- Affectively stable

- Clinically acceptable, stably-dosed, mood stabilizing medication regimen for > 1 month
prior to enrollment, with no medication changes planned over the 8-week study period.

- Objective evidence of either a subjective sleep quality complaint and/or
clinically-significant cognitive impairment at screening.

Exclusion Criteria:

- History of Central Nervous System trauma, neurological disorder, ADHD, or a learning
disability.

- Positive urine toxicology or DSM-IV diagnosis of substance abuse/dependence within 3
months

- Active, unstable medical problem that may interfere with sleep and/or cognition.

- History of substance induced mania

- Recent history of rapid cycling

- Score of 2 or greater on the decreased need for sleep item on CARS-M

- Any drug known to interfere with modafinil

- More than 2 psychotropic medications

- Abnormal lab or ECG result at screen

- Significant suicidal ideation at baseline or at risk for suicidal behavior based on
clinical judgment

- participation in any other investigational cognitive enhancement study within 6 months