Thomas Roth

Sleep disturbance and psychiatric disorders: A longitudinal epidemiological study of young Adults

In a longitudinal epidemiological study of young adults, we estimated the association between sleep disturbance and psychiatric disorders, cross-sectionally and prospectively. A random sample of 1200 was drawn from all 21-30-year-old members of a large health maintenance organization (HMO) in Michigan; 1007 were interviewed in 1989 and 979 were reinterviewed in 1992. Lifetime prevalence of insomnia alone was 16.6%, of hypersomnia alone, 8.2%, and of insomnia plus hypersomnia, 8%. The gender-adjusted relative risk for new onset of major depression during the follow-up period in persons with history of insomnia at baseline was 4.0 (95% confidence interval [CI] 2.2-7.0) and in persons with baseline history of hypersomnia, 2.9 (95% CI 1.5-5.6). When history of other prior depressive symptoms (e.g., psychomotor retardation or agitation, suicidal ideation) was controlled for, prior insomnia remained a significant predictor of subsequent major depression. Complaints of 2 weeks or more of insomnia nearly every night might be a useful marker of subsequent onset of major depression.

Sleep Problems, Comorbid Mental Disorders, and Role Functioning in the National Comorbidity Survey Replication

BACKGROUNDnLittle is known about the population prevalence of sleep problems or whether the associations of sleep problems with role impairment are due to comorbid mental disorders.nnnMETHODSnThe associations of four 12-month sleep problems (difficulty initiating or maintaining sleep, early morning awakening, nonrestorative sleep) with role impairment were analyzed in the National Comorbidity Survey Replication controlling 12-month DSM-IV anxiety, mood, impulse-control, and substance disorders. The WHO Composite International Diagnostic Interview was used to assess sleep problems and DSM-IV disorders. The WHO Disability Schedule-II (WHO-DAS) was used to assess role impairment.nnnRESULTSnPrevalence estimates of the separate sleep problems were in the range 16.4-25.0%, with 36.3% reporting at least one of the four. Mean 12-month duration was 24.4 weeks. All four problems were significantly comorbid with all the 12-month DMS-IV disorders assessed in the survey (median OR: 3.4; 25(th)-75(th) percentile: 2.8-3.9) and significantly related to role impairment. Relationships with role impairment generally remained significant after controlling comorbid mental disorders. Nonrestorative sleep was more strongly and consistently related to role impairment than were the other sleep problems.nnnCONCLUSIONSnThe four sleep problems considered here are of public health significance because of their high prevalence and significant associations with role impairment.

The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy.

ABSTRACT Objective: This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy. Research design and methods: This was a multicenter double-blind study with 196 patients (aged 18–65 years) randomized to receive armodafinil 150u2009mg (n = 65), armodafinil 250u2009mg (n = 67), or placebo (n = 64) once daily for 12 weeks. Main outcome measures: Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20‐min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory). Results: Armodafinil significantly increased MWT mean sleep latency (at 0900–1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9u2009min in the 150‐mg, 250‐mg, and combined groups, respectively, compared with a decrease of 1.9u2009min for placebo (u2009p < 0.01 for all three comparisons). Mean late-day MWT latency (1500–1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8u2009min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGI-C rating from baseline to final visit in the armodafinil 150‐mg, 250‐mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (u2009p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (u2009p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness. Conclusions: Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.

A new questionnaire to detect sleep disorders

OBJECTIVESnSleep disorders remain largely undiagnosed in the general population. The current study assessed whether the Global Sleep Assessment Questionnaire (GSAQ) could: (1), distinguish between sleep disorders (including no sleep disorder); (2), be a reliable and valid sleep disorder screener; and (3), serve as a practical, user-friendly screening tool for primary care and sleep centers.nnnMETHODSnTwo hundred and twelve adults from five sleep centers and two primary care clinics completed the GSAQ and received confirmed diagnoses from a sleep specialist. Of the 212 patients, 139 (65.6%) had at least one sleep disorder, 60 (28.3%) had two or more sleep disorders, and 13 (6.1%) had no confirmed sleep disorder. Ninety-one (43%) individuals completed the GSAQ a second time for reliability testing. Scores for each sleep disorder including, but not limited to, primary insomnia (I), insomnia associated with a mental disorder (IME), obstructive sleep apnea (OSA), periodic limb movement (PLM), and parasomnia (P) were computed. The sensitivity and specificity were estimated using comprehensive clinical diagnosis as the gold standard and mean domain scores as a cutpoint.nnnRESULTSnThe mean participant age was 45 years, 52% were female. Observed frequencies were: 36 (I), 14 (IME), 31 (OSA), 7 (PLM) and 4% (P). Test-retest reliability ranged from 0.51 to 0.92. Pearson correlation coefficients suggested that the GSAQ discriminated between diagnoses. The sensitivities and specificities were 79/57, 83/51, 93/58, 93/52, and 100/49 for I, IME, OSA, PLM, and P, respectively.nnnCONCLUSIONSnOur findings suggest that the GSAQ can aid in recognizing sleep disorders. Future studies should focus on characterizing its predictive values in primary care settings.

Nocturnal Rapid Eye Movement Sleep Latency for Identifying Patients With Narcolepsy/Hypocretin Deficiency

IMPORTANCEnNarcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.nnnOBJECTIVEnTo determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.nnnDESIGN, SETTING, AND PARTICIPANTSnObservational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.nnnMAIN OUTCOME AND MEASURESnSensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.nnnRESULTSnShort REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).nnnCONCLUSIONS AND RELEVANCEnAmong patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.

Psychometric evaluation of daytime sleepiness and nocturnal sleep onset scales in a representative community sample

BACKGROUNDnThe public health importance of daytime sleepiness as a risk factor for accidents, interpersonal problems, and decreased productivity has been recognized. However, epidemiologic research on this topic has been limited by the reliance on laboratory measures (i.e., the Multiple Sleep Latency Test-MSLT). Two scales, daytime sleepiness and nocturnal sleep onset, have been identified from the self-report Sleep-Wake Activity Inventory (SWAI) in a clinic sample and validated against the MSLT. This study evaluates the replicability of the two scales in a population sample and assesses potential thresholds in scale scores that distinguish normal from pathologic levels of daytime sleepiness and difficulty falling asleep.nnnMETHODSnThe sample consisted of 2181 subjects 18-45 years old in the Detroit metropolitan area. All sleep characteristic information covered the 2 weeks prior to interview. Split-half sample factor analyses were conducted to assess replicability of the results. Distribution of scale scores and their relation to construct validity variables were used to evaluate possible thresholds.nnnRESULTSnA two-factor model appeared to best account for the variation among the 12 items from the SWAI. The two factors accounted for 50% of the variance in both split-half sample analyses. The revised eight-item daytime sleepiness and two-item nocturnal sleep onset scales showed good and fair internal consistency respectively across both split-half samples. There appeared to be a natural break in daytime sleepiness scale scores that was associated with a substantial and consistent change in number of hours slept. No breaks appeared in nocturnal sleep onset scores.nnnCONCLUSIONSnThis study replicated the results of the clinic-based study and suggested a potentially useful diagnostic threshold for self-report excessive daytime sleepiness. Epidemiology of sleep depends on the ability to move from the laboratory to population surveys in reliable and valid ways. Development of self-report is a step in that direction.

Efficacy and safety of doxepin 6 mg in a four-week outpatient trial of elderly adults with chronic primary insomnia

INTRODUCTIONnThe efficacy and safety of doxepin (DXP), a histamine H(1) receptor antagonist, was evaluated in elderly adults with sleep maintenance insomnia.nnnMETHODSnThis was a randomized, double-blind, placebo-controlled outpatient trial. Elderly adults meeting DSM-IV-TR criteria for primary insomnia were randomized to four weeks of nightly treatment with either DXP 6 mg (N=130) or placebo (PBO; N=124). Efficacy was assessed using patient self-report instruments and clinician ratings. Patient-reported endpoints included subjective total sleep time (sTST), subjective wake after sleep onset (sWASO), latency to sleep onset (LSO), sleep quality, and a Patient Global Impression scale (PGI). The primary endpoint was sTST at week 1.nnnRESULTSnDXP 6 mg produced significantly more sTST and less sWASO at week 1 (both p-values <0.0001) than PBO. These significant improvements versus placebo were maintained at weeks 2-4 (all p-values <0.05). There were no significant differences in LSO for DXP 6 mg versus PBO. DXP 6 mg significantly improved sleep quality (weeks 1, 3, and 4, p<0.05) and several outcome-related parameters, including several items on the PGI, the severity and improvement items of the Clinician Global Impression scale (CGI; weeks 1 and 2) and the Insomnia Severity Index (ISI; weeks 1-4), all versus PBO. There were no reports of anticholinergic effects (e.g., dry mouth) or memory impairment. The safety profile of DXP 6 mg was comparable to that of PBO.nnnCONCLUSIONSnIn elderly adults with insomnia, DXP 6 mg produced significant improvements in sleep maintenance, sleep duration, and sleep quality endpoints that were sustained throughout the trial. These data suggest that DXP 6 mg is effective for treating sleep maintenance insomnia and is well-tolerated in elderly adults with chronic primary insomnia.

The effect of eszopiclone in patients with insomnia and coexisting rheumatoid arthritis: a pilot study.

OBJECTIVEnTo evaluate the efficacy and safety of eszopiclone 3 mg, a nonbenzodiazepine medication/hypnotic indicated for the treatment of insomnia with comorbid rheumatoid arthritis (RA).nnnMETHODnThis multicenter, double-blind, placebo-controlled pilot study was conducted in 153 patients aged 25-64 years with American College of Rheumatology-defined RA who met DSM-IV criteria for insomnia. The data were collected from February to November of 2004. Patients were randomly assigned to either eszopiclone or placebo nightly for 4 weeks, followed by a 2-week placebo run out. Efficacy was evaluated using patient reports of sleep (wake time after sleep onset [WASO], sleep latency [SL], and total sleep time [TST]), daytime function, pain, and RA assessments. Insomnia severity was evaluated using the Insomnia Severity Index. Safety was also evaluated.nnnRESULTSnEszopiclone significantly improved all patient-reported sleep measures (WASO, SL, and TST), sleep quality, depth of sleep, and daytime function (P < .05 vs placebo). At week 4, 48% of eszopiclone-treated patients had no clinically meaningful insomnia as assessed by ISI score (versus 30% of placebo-treated patients, P = .03). Eszopiclone was significantly better than placebo on some RA-associated pain measures: (1) overall (P = .05), pain (P = .006), and pain and other symptoms (P = .02) scores of the Arthritis Self-Efficacy Scale, (2) tender joint counts (P = .03) and pain severity scores (P = .023), (3) the activities domain of the Health Assessment Questionnaire-Disability Index (P = .04), and (4) the role physical (P = .03) and bodily pain (P = .01) scales of the 36-item Medical Outcomes Study Short-Form General Health Survey. The most commonly reported adverse events with eszopiclone were unpleasant taste and transient increases in RA symptoms.nnnCONCLUSIONSnIn this pilot study of patients with insomnia comorbid with RA, eszopiclone 3 mg improved all assessed sleep and daytime function measures over the treatment period, as well as some measures of RA-associated pain, disability, and quality of life.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00367965.

A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Armodafinil for Excessive Sleepiness Associated With Jet Lag Disorder

OBJECTIVEnTo assess the effect of armodafinil, the longer-lasting isomer of modafinil, on jet lag disorder.nnnPARTICIPANTS AND METHODSnThis double-blind, randomized, parallel-group, multicenter study was conducted between September 18, 2008, and February 9, 2009. Adults with a history of jet lag symptoms on previous flights through multiple time zones flew from the United States to France (a 6-hour time zone change) for a 3-day laboratory-based study period. Participants received armodafinil (50 or 150 mg/d) or placebo each morning. Wakefulness was assessed by the coprimary outcomes, mean sleep latency on the Multiple Sleep Latency Test (MSLT) (average of all MSLT sessions across days 1 and 2) and Patient Global Impression of Severity in relation to jet lag symptoms (averaged across days 1 and 2).nnnRESULTSnA total of 427 participants received armodafinil at 50 mg/d (n=142), armodafinil at 150 mg/d (n=143), or placebo (n=142). Armodafinil at 150 mg/d provided a significant benefit in sleep latency on the MSLT (days 1-2: mean, 11.7 minutes vs 4.8 minutes for placebo; P<.001) and participants perception of their overall condition in relation to jet lag symptoms (Patient Global Impression of Severity, days 1-2: mean, 1.6 vs 1.9 for placebo; P<.05). The most frequently reported adverse events for armodafinil at 150 mg/d were headache (27%), nausea (13%), diarrhea (5%), circadian rhythm sleep disorder (5%), and palpitations (5%).nnnCONCLUSIONnArmodafinil increased wakefulness after eastward travel through 6 time zones.nnnTRIAL REGISTRATIONnclinicaltrials.gov identifier: NCT00758498.

Efficacy and safety of doxepin 6 mg in a model of transient insomnia

INTRODUCTIONnThe efficacy and safety of doxepin (DXP) 6mg tablets were evaluated in healthy adults in a model of transient insomnia.nnnMETHODSnThis was a randomized, double-blind, parallel-group, placebo-controlled study in healthy adults using a model of transient insomnia. A first-night effect combined with a 3-h phase advance was implemented to induce transient insomnia in healthy adults. Subjects received a single night time dose of placebo (PBO; N=282) or DXP 6mg (N=283) in a sleep laboratory. Efficacy was evaluated objectively (polysomnography; PSG) and subjectively (morning questionnaire). Consistent with the model utilized, the primary endpoint was latency to persistent sleep (LPS); secondary PSG endpoints included wake after sleep onset (WASO; key secondary endpoint), total sleep time (TST), wake time after sleep (WTAS) and sleep efficiency (SE; overall, by quarter of the night and hourly); secondary subjective endpoints included latency to sleep onset (LSO), subjective WASO (sWASO), subjective TST (sTST) and sleep quality.nnnRESULTSnDXP 6mg demonstrated statistically significant improvements in LPS (13min decrease versus PBO; p<0.0001), WASO (39min less than PBO; p<0.0001), TST (51min more than PBO; p<0.0001), WTAS (p<0.0001), overall SE (p<0.0001), SE in each quarter of the night (p<0.0001) and SE in each of the 8h (p⩽0.0003), all versus PBO. Additionally, DXP 6mg significantly improved subjective variables including LSO (p<0.0001), sWASO (p=0.0063), sTST (p<0.0001), and sleep quality (p=0.0004), versus PBO. There was no consistent evidence of next-day residual sedation and also minor sleep stages alterations. The incidence of adverse events was comparable to placebo.nnnCONCLUSIONSnIn this model of transient insomnia, DXP 6mg demonstrated significant improvements in sleep onset, sleep maintenance, sleep duration and sleep quality, and also appeared to reduce early morning awakenings. These data suggest that DXP 6mg may be effective and well tolerated in adults experiencing transient insomnia.