Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder; Cognitive Dysfunction
Study type: Interventional
Phase: Phase 4

Summary: 
      This is an 8-week, randomized, placebo-controlled trial of modafinil in stable bipolar
      disorder patients. Results will provide information on a promising treatment for
      simultaneously treating both sleep and cognitive problems in stable bipolar patients. These
      disabling symptoms persist despite stable mood and are strongly associated with functional
      disability, making them important treatment targets that have not yet been adequately
      addressed.
    

Detailed description: 
      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.
    

Intervention name(s): Modafinil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ratio of 2:1 subjects will be in the experimental arm receiving modafinil for 8 weeks.; For every randomly assigned 2 subjects receiving active drug, 1 will be randomly assigned to receive placebo for 8 weeks.
Intervention MeSH terms: Modafinil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Cognition; Sleep problems; Bipolar Disorder