Pharmacologic therapy for sleep-related breathing disorders.

Sleep-related breathing disorders (SRBDs) are characterized by disruptions in normal breathing patterns, typically caused by increased upper airway resistance or diminished ventilatory drive. SRBDs are often accompanied by impairment in sleep continuity and wakefulness. The full spectrum of features associated with SRBD syndromes can be divided into three components, each of which can be a target for pharmacological intervention: the sleep-breathing event and its immediate physiological consequences; the adverse effects of these events on sleep continuity; and impairment in daytime waking function. A number of pharmacologic agents have been studied for their ability to reduce upper airway resistance or increase ventilatory drive. Other medications have been tested for their ability to treat one or more of the symptoms of sleep or wakefulness in SRBD patients. The purpose of this article is to provide a review of the status of research related to the pharmacologic treatment of SRBDs.

Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness.

BACKGROUND: Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue. METHODS: This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4). RESULTS: Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI. CONCLUSIONS: Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.

Sleep and wakefulness out of phase with internal biological time impairs learning in humans.

Sleep-wake homeostatic and internal circadian timedependent brain processes interact to regulate human brain function so that alert wakefulness is promoted during the daytime and consolidated sleep is promoted at nighttime. The consequence of chronically altering the normal relationship between these processes for human brain function is largely unknown. We tested cognitive and vigilance performance while subjects lived in the laboratory for over a month. The subjects lived on either 24.0- or 24.6-hr day lengths. Half of the subjects tested maintained a normal relationship between sleep-wakefulness and internal circadian time (synchronized group), whereas the other half did not (nonsynchronized group). Levels of the sleep-promoting hormone melatonin were high during scheduled sleep in the synchronized group, whereas melatonin levels were high during scheduled wakefulness in the nonsynchronized group. Failure to adapt to the scheduled day length was dependent upon individual differences in intrinsic circadian period. Total sleep time was reduced, sleep latency and Rapid Eye Movement (REM) latency were shortened, and wakefulness after sleep onset was increased in the nonsynchronized group. Cognitive performance improved (i.e., learning) in the synchronized group, whereas learning was significantly impaired in the nonsynchronized group. Attention progressively declined in both groups, suggesting that 8 hr of scheduled sleep per night is insufficient to maintain brain vigilance even when sleep occurs at an appropriate biological time. Our results establish that proper alignment between sleep-wakefulness and internal circadian time is crucial for enhancement of cognitive performance. In addition, our results demonstrate that exposure to dim light (approximately 25 lx) is sufficient to expand the range of entrainment in humans.

Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study.

INTRODUCTION: Many patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitors have residual symptoms (eg, persistent fatigue, excessive sleepiness) despite an overall antidepressant response. Placebo-controlled studies indicate that modafinil, a wake-promoting agent, may relieve residual symptoms. METHODS: This 12-week, open-label, dose titration, extension study followed an 8-week placebo-controlled study of modafinil augmentation in patients with MDD. The dose was 100-400 mg/day. The median stable dose was 300 mg/day. Assessments were the Epworth Sleepiness Scale, Brief Fatigue Inventory, Clinical Global Impression of Improvement scale, 17-item Hamilton Rating Scale for Depression, and Montgomery-Asberg Depression Rating Scale. RESULTS: Of the 245 patients treated, 194 completed the study; 70% reported Clinical Global Impression of Improvement scale responses of "much improved" or "very much improved" between open-label baseline and final visit (previous randomized modafinil group: 74%; placebo group: 66%). When data were analyzed for four subsets of patients (former modafinil responders, placebo responders, modafinil nonresponders, and placebo nonresponders), improvements in scores on all outcome measures were at least twice as great among former modafinil and placebo nonresponders compared with responders. Most common adverse events were headache (18%), nausea (9%), and dizziness (7%); all were generally mild to moderate in severity. CONCLUSION: Twelve weeks of modafinil augmentation relieved excessive sleepiness, reduced fatigue, and improved patients' overall clinical condition, including mood.

Modafinil for excessive sleepiness associated with shift-work sleep disorder.

BACKGROUND: Patients with shift-work sleep disorder chronically have excessive sleepiness during night work and insomnia when attempting to sleep during the day. We evaluated the use of modafinil for treating sleepiness in patients with this disorder. METHODS: In a three-month, double-blind trial, we randomly assigned 209 patients with shift-work sleep disorder to receive either 200 mg of modafinil or placebo before the start of each shift. Assessments were performed with the use of the nighttime Multiple Sleep Latency Test, the Clinical Global Impression of Change, the Psychomotor Vigilance Test, diaries of patients, and daytime polysomnography. After randomization, we conducted monthly assessments. RESULTS: Treatment with modafinil, as compared with placebo, resulted in a modest improvement from baseline in mean (+/-SEM) nighttime sleep latency (the interval between the time a person attempts to fall asleep and the onset of sleep) (1.7+/-0.4 vs. 0.3+/-0.3 minutes, respectively; P=0.002), and more patients had improvement in their clinical symptoms (74 percent vs. 36 percent, respectively; P<0.001). Patients who were receiving modafinil also had a reduction in the frequency and duration of lapses of attention during nighttime testing of their performance on the Psychomotor Vigilance Test (change from baseline, a reduction in lapse frequency of 2.6 vs. an increase of 3.8, respectively; P<0.001), and proportionally fewer patients reported having had accidents or near accidents while commuting home (29 percent vs. 54 percent, respectively; P<0.001). Despite these benefits, patients treated with modafinil continued to have excessive sleepiness and impaired performance at night. Modafinil did not adversely affect daytime sleep as compared with placebo. Headache was the most common adverse event. CONCLUSIONS: Treatment with 200 mg of modafinil reduced the extreme sleepiness that we observed in patients with shift-work sleep disorder and resulted in a small but significant improvement in performance as compared with placebo. However, the residual sleepiness that was observed in the treated patients underscores the need for the development of interventions that are even more effective.

Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness.

OBJECTIVES: A modafinil daily dosing strategy promotes wakefulness in narcolepsy patients experiencing excessive daytime sleepiness; however, some patients may continue to experience late-day sleepiness. Excessive sleepiness in narcolepsy is associated with cognitive impairment. Modafinil has improved executive function in other models of excessive sleepiness. This study evaluated the effects of once-daily vs. split doses of modafinil on wakefulness and of combined doses on executive function in narcolepsy patients experiencing late-day sleepiness despite satisfactory modafinil treatment earlier in the day. METHODS: After a 2-week washout, 24 patients received 3 weeks of double-blind treatment with modafinil 400-mg once daily (7 AM) plus placebo (noon) or modafinil 600-mg split dose (400 mg, 7 AM; 200 mg, noon). Assessments included a Maintenance of Wakefulness Test (MWT) for individual regimens and the Wisconsin Card Sort Test (WCST) for treatments combined. RESULTS: Modafinil 600-mg split dose was significantly more effective than modafinil 400-mg once daily in improving late-day MWT scores (5 PM-7 PM; P < 0.05). Significant mean (+/- SEM) reductions from baseline of 8.2 +/- 2.7 in the total number of errors and 5.9 +/- 1.9 in total percent of errors (P < 0.05, both) were demonstrated for modafinil on the WCST. Modafinil was well tolerated; adverse events included headache (n = 1), emotional lability (n = 1), bronchitis (n = 1), and accidental injury (n = 2), with no reports of insomnia. CONCLUSIONS: For patients with residual late-day sleepiness associated with narcolepsy, an additional 200-mg dose of modafinil taken at midday was effective in sustaining wakefulness throughout the entire waking day. Treatment with modafinil also significantly improved executive function.

Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light.

Shift workers and transmeridian travelers are exposed to abnormal work-rest cycles, inducing a change in the phase relationship between the sleep-wake cycle and the endogenous circadian timing system. Misalignment of circadian phase is associated with sleep disruption and deterioration of alertness and cognitive performance. Exercise has been investigated as a behavioral countermeasure to facilitate circadian adaptation. In contrast to previous studies where results might have been confounded by ambient light exposure, this investigation was conducted under strictly controlled very dim light (standing approximately 0.65 lux; angle of gaze) conditions to minimize the phase-resetting effects of light. Eighteen young, fit males completed a 15-day randomized clinical trial in which circadian phase was measured in a constant routine before and after exposure to a week of nightly bouts of exercise or a nonexercise control condition after a 9-h delay in the sleep-wake schedule. Plasma samples collected every 30-60 min were analyzed for melatonin to determine circadian phase. Subjects who completed three 45-min bouts of cycle ergometry each night showed a significantly greater shift in the dim light melatonin onset (DLMO(25%)), dim light melatonin offset, and midpoint of the melatonin profile compared with nonexercising controls (Student t-test; P < 0.05). The magnitude of phase delay induced by the exercise intervention was significantly dependent on the relative timing of the exercise after the preintervention DLMO(25%) (r = -0.73, P < 0.05) such that the closer to the DLMO(25%), the greater the phase shift. These data suggest that exercise may help to facilitate circadian adaptation to schedules requiring a delay in the sleep-wake cycle.

Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy.

INTRODUCTION: In addition to excessive sleepiness, patients with narcolepsy often have significant fatigue, depressed mood, and decreased quality of life. OBJECTIVE: To determine whether treatment with modafinil for excessive sleepiness improves fatigue, mood, and health-related quality of life (HRQOL) in patients with narcolepsy. MATERIALS AND METHODS: Outpatients with narcolepsy underwent a 14-day washout of psychostimulants and then were enrolled in this 6-week, open-label, multicenter study. Patients received modafinil starting at 200 mg once daily for week 1, and then 200 or 400 mg daily for weeks 2 through 6. Efficacy was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS). Safety was assessed by monitoring adverse events (AE). RESULTS: At baseline, 151 patients had moderate to severe excessive sleepiness (mean Epworth Sleepiness Scale score=17.8+/-4.4). Most patients (> or =70% of 123 who completed the study) received 400 mg modafinil once daily during weeks 2 through 6. Modafinil significantly improved HRQOL, based on SF-36 measures of mental and physical component summary scores and subdomain scores of role-physical, social functioning, and vitality (each P<0.001). Modafinil treatment was also associated with significantly reduced fatigue and significantly improved vigor and cognition as assessed by the POMS (each P<0.001) from weeks 1 through 6. The most frequent AE with modafinil treatment were headache, nausea, and insomnia; most AE were mild or moderate in nature. Only seven patients (5%) withdrew from the study because of AE. CONCLUSION: In narcolepsy patients who were switched from psychostimulants, modafinil therapy improved HRQOL and subjective feelings of vigor and cognitive functioning and reduced fatigue.

Dosing regimen effects of modafinil for improving daytime wakefulness in patients with narcolepsy.

In a multicenter, randomized, double-blind study the authors compared the efficacy of modafinil 400 mg once daily, 400 mg given in a split dose, or 200 mg once daily for maintaining wakefulness throughout the day in patients (N = 32) with narcolepsy reporting a positive daytime response to modafinil but late-afternoon/evening sleepiness. Efficacy evaluations included an extended Maintenance of Wakefulness Test (9:00 am to 9:00 pm), the Clinical Global Impression of Change scale, and the Epworth Sleepiness Scale. Modafinil demonstrated significant improvement in wakefulness as assessed by the Epworth Sleepiness Scale compared with placebo at baseline (all P < 0.001). Modafinil significantly improved patients' ability to sustain wakefulness, as demonstrated by mean sleep latency at week 3 compared with placebo at baseline (all P < 0.001). The 400-mg split-dose regimen improved wakefulness significantly in the evening compared with the 200-mg and 400-mg once-daily regimen (both P < 0.05). The percentage of patients rated as "much improved" or "very much improved" with respect to evening sleepiness was 27%, 82%, and 80% in the 200-mg, 400-mg once-daily, and 400-mg split-dose groups, respectively. Adverse events were mild to moderate in nature and included headache, nausea, nervousness, dyspepsia, pain, and vomiting (all 6%). Some patients may benefit from 400-mg doses of modafinil taken once daily compared with 200-mg doses. A split-dose 400-mg regimen may be superior to once-daily dosing for sustaining wakefulness throughout the entire waking day.