Clinical trial NCT01965925: Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil
Official title: Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bipolar Disorder
Keywords: Cognition
Sleep problems
Bipolar Disorder
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2013-10-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: safety of adjunctive modafinil
timeFrame: up to 8 weeks
Secondary outcomes:
measure: MCCB
timeFrame: baseline
measure: MCCB
timeFrame: week 4
measure: MCCB
timeFrame: week 8
measure: sleep quality
timeFrame: baseline
measure: sleep quality
timeFrame: week 4
measure: sleep quality
timeFrame: week 8
measure: UPSA
timeFrame: baseline
measure: UPSA
timeFrame: week 4
measure: UPSA
timeFrame: week 8
measure: QoL
timeFrame: baseline
measure: QoL
timeFrame: week 4
measure: QoL
timeFrame: week 8
measure: Vital signs
timeFrame: up to 8 weeks
measure: Electrocardiogram
timeFrame: baseline and week 8
measure: liver function tests
timeFrame: baseline and week 8
measure: chemistry panel
timeFrame: baseline and week 8
measure: Complete blood count
timeFrame: baseline and week 8
measure: urinalysis
timeFrame: baseline and week 8
measure: Suicide risk scale
timeFrame: up to 8 weeks
measure: Medication log
timeFrame: up to 8 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Katherine Burdick, PhD
role: PRINCIPAL_INVESTIGATOR
References: