Despite advances in the treatment of bipolar disorder, most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience sleep disturbances, reduced daytime activity levels, and neurocognitive dysfunction. These persistent features of the illness represent critical treatment targets, as they do not adequately improve with standard mood stabilizing medications and they are strongly associated with functional disability and poor quality of life. Psychosocial therapies have focused on the importance of stabilizing sleep-wake cycles and daily routines such as mealtimes and regular social interactions, resulting in significant reductions in affective relapse. No study, to date, has attempted to stabilize circadian rhythms using a pharmacologic intervention in bipolar patients. Thus, the proposed 8-week, randomized, placebo-controlled pilot study will evaluate the safety and preliminarily assess the efficacy of the wake-promoting drug, modafinil (Provigil(R)), on sleep, daytime activity, and neurocognitive functioning in 48 euthymic bipolar patients. Modafinil is approved by the US Food and Drug Administration (FDA) for excessive daytime sleepiness associated with several sleep disorders (narcolepsy, sleep apnea, and shift-work disorder). In an off-label application, we will administer randomize in a 2:1 ratio to active modafinil (200mg/day) or placebo to 48 affectively stable patients with bipolar I disorder for 8 weeks. We will measure patients'subjective experience of sleep disruption and daytime wakefulness by questionnaires and daily diaries. In addition, we will focus on modafinil's potential to improve neurocognitive functioning, including attention, memory and higher order cognitive processes in patients with bipolar disorder, as it has previously been shown to enhance cognition in psychiatrically healthy individuals, patients with sleep disorders, and patients with schizophrenia. To measure cognitive functioning, we will deploy several paper-pencil and computerized tests before modafinil is administered and again at the end of the 8-week study. Finally, although not a primary focus of the current study, we will also investigate the effects of modafinil on low-grade depressive symptoms independent of sleep ratings, regularity of social rhythms, and patient-reported quality of life. We will closely monitor patiets for unforeseen changes in mood symptoms that are deemed to place them at risk for developing mania or depression and will discontinue the trial as deemed necessary. We expect that findings from this study will identify a novel approach for treating those persistent symptoms of bipolar disorder not adequately addressed with current mood stabilizing agents, potentially resulting in a more complete recovery and improvement in day-to-day functioning.

Public Health Relevance

Converging evidence suggests that patients with bipolar disorder do not achieve complete inter-episode recovery, particularly with regard to circadian-related sleep and daytime activity levels and neurocognitive functioning. These persistent problems, despite remission of acute affective symptoms, contribute directly to functional disability, highlighting the need for interventions above and beyond the standard treatments to achieve a full inter-episode recovery. The current study aims to investigate th effects of a novel psychostimulant, modafinil, on these persistent circadian and cognitive abnormalities in affectively-stable bipolar outpatients using a placebo-controlled, adjunctive, 8 week trial design.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Planning Grant (R34)
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Interventions Committee for Adult Disorders (ITVA)
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Muehrer, Peter R
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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