Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil

Sponsor

Icahn School of Medicine at Mount Sinai (Other)

Overall Status

Completed

CT.gov ID

NCT01965925

Collaborator

National Institute of Mental Health (NIMH) (NIH)

Enrollment

Location

Arms

46.3

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Modafinil Drug: Placebo	Phase 4

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:

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.
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.
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.

Study Design

Study Type:

Interventional

Actual Enrollment :

18 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil

Study Start Date :

Jan 1, 2014

Actual Primary Completion Date :

Nov 9, 2017

Actual Study Completion Date :

Nov 9, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Modafinil Modafinil will be administered at baseline with a single dose of 100 mg/day QAM increased at week 1 to a single dose 200mg/day QAM. Patients will take drug upon waking with no adjustment in sleep schedule. Dosing will be flexible based on side effects with a maximum dose of 200 mg/day. Subjects will be discontinued if 100mg/day is not tolerated.	Drug: Modafinil Ratio of 2:1 subjects will be in the experimental arm receiving modafinil for 8 weeks.
Placebo Comparator: Placebo Subjects will take placebo upon waking once per day.	Drug: Placebo For every randomly assigned 2 subjects receiving active drug, 1 will be randomly assigned to receive placebo for 8 weeks.

Arm

Intervention/Treatment

Experimental: Modafinil

Modafinil will be administered at baseline with a single dose of 100 mg/day QAM increased at week 1 to a single dose 200mg/day QAM. Patients will take drug upon waking with no adjustment in sleep schedule. Dosing will be flexible based on side effects with a maximum dose of 200 mg/day. Subjects will be discontinued if 100mg/day is not tolerated.

Drug: Modafinil

Ratio of 2:1 subjects will be in the experimental arm receiving modafinil for 8 weeks.

Placebo Comparator: Placebo

Subjects will take placebo upon waking once per day.

Drug: Placebo

For every randomly assigned 2 subjects receiving active drug, 1 will be randomly assigned to receive placebo for 8 weeks.

Outcome Measures

Primary Outcome Measures

safety of adjunctive modafinil [up to 8 weeks]
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.

Secondary Outcome Measures

MCCB [baseline]
MATRICS Cognitive Consensus Batter to assess cognitive functioning
MCCB [week 4]
MATRICS Cognitive Consensus Batter to assess cognitive functioning
MCCB [week 8]
MATRICS Cognitive Consensus Batter to assess cognitive functioning
sleep quality [baseline]
To evaluate the effects of adjunctive modafinil in euthymic BD on measures of sleep quality and daytime wakefulness, using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS)
sleep quality [week 4]
To evaluate the effects of adjunctive modafinil in euthymic BD on measures of sleep quality and daytime wakefulness, using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS)
sleep quality [week 8]
To evaluate the effects of adjunctive modafinil in euthymic BD on measures of sleep quality and daytime wakefulness, using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS)
UPSA [baseline]
UCSC Performance Skills Assessment assess functional ability
UPSA [week 4]
UCSC Performance Skills Assessment assess functional ability
UPSA [week 8]
UCSC Performance Skills Assessment assess functional ability
QoL [baseline]
Quality of Life Scale
QoL [week 4]
Quality of Life Scale
QoL [week 8]
Quality of Life Scale
Vital signs [up to 8 weeks]
vital signs including blood pressure
Electrocardiogram [baseline and week 8]
comparison of electrocardiogram (EKG) results from week 8 to baseline.
liver function tests [baseline and week 8]
comparison of liver function test results from week 8 to baseline
chemistry panel [baseline and week 8]
comparison of chemistry panel results from week 8 to baseline
Complete blood count [baseline and week 8]
comparison of complete blood count (CBC) results from week 8 to baseline
urinalysis [baseline and week 8]
comparison of urinalysis results from week 8 to baseline
Suicide risk scale [up to 8 weeks]
Beck Scale for Suicidal Ideation and Columbia Suicide Severity Rating Scales
Medication log [up to 8 weeks]
Medication log for current medications and all medications administered

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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