Milton K. Erman

Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder

BACKGROUND Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII–R primary insomnia

Trazodone is an antidepressant which is used at low doses as a hypnotic. The hypnotic efficacy of trazodone in non‐depressed insomniacs is unknown, especially in comparison to hypnotic medications such as zolpidem. Following a placebo screening week, DSM‐IIIR defined primary insomniacs were randomized into a parallel‐group, double‐blind, 14‐day comparison of trazodone 50 mg, zolpidem 10 mg and placebo. Patients completed daily morning questionnaires and weekly office visits. Self‐reported sleep latencies were compared by the Cox proportional hazards regression technique; self‐reported sleep duration by ANOVA. During treatment Week 1, both drugs produced significantly shorter self‐reported sleep latencies and longer self‐reported sleep durations than placebo. Self‐reported sleep latency was significantly shorter with zolpidem than with trazodone. During Week 2, only the zolpidem group maintained a significantly shorter sleep latency than the placebo group, and self‐reported sleep duration did not vary significantly among groups. The incidence of adverse events was low in all groups. Both trazodone and zolpidem improved self‐reported sleep latency and duration of non‐depressed, primary insomniacs; zolpidem was somewhat more efficacious at the doses studied.

A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia

Objective: To examine the hypnotic efficacy of zaleplon 10 mg, a selective benzodiazepine receptor agonist, over a period of 35 nights in primary insomniacs.Methods: A double-blind, parallel-group, placebo-controlled design was employed. Subjects were 113 men and women, ages 18 to 65 years. Polysomnographic and subjective sleep data were collected during baseline, on two nights during each of five treatment weeks, and on the first two nights after discontinuation of active medication.Results: Sleep latency was significantly shortened with zaleplon 10 mg for all 5 weeks of treatment as assessed by polysomnography and by subjective sleep measures. Total sleep time, whether evaluated with polysomnography or with subjective estimates, was inconsistently affected. Sleep architecture was similar with zaleplon and placebo. There was no evidence of tolerance to the sleep promoting effects of zaleplon during the five weeks of administration, and there was no rebound insomnia upon discontinuation. Adverse events occurred with equal frequency in the zaleplon and placebo groups.Conclusions: Zaleplon 10 mg is effective in the treatment of sleep onset insomnia over a period of 35 nights, with minimal evidence of undesired effects.

A polysomnography study of eszopiclone in elderly patients with insomnia

ABSTRACT Objective: To evaluate the safety and efficacy of eszopiclone 2 mg in elderly patients (aged 64-86 years) with chronic insomnia. Methods: This was a randomized, double-blind, placebo-controlled 2‐week study. Patients meeting DSM-IV criteria for primary insomnia and screening polysomnography criteria (wakefulness after sleep onset [WASO] ≥ 20 min and latency to persistent sleep ≥ 20 min) were randomized to 2 weeks of nightly treatment with eszopiclone 2 mg (n = 136) or placebo (n = 128). Efficacy was assessed using polysomnography (Nights 1, 2, 13, and 14) and patient reports (Nights 1–14); safety was assessed using adverse events, clinical labs, physical examination, and vital signs. The mean of all efficacy results during the double-blind period was used for the efficacy analysis. Results: Results indicated that eszopiclone was associated with significantly shorter sleep onset, less WASO, higher sleep efficiency, more total sleep time, and greater patient-reported quality and depth of sleep scores than placebo ( p < 0.05 for all) with a trend in patient-reported morning sleepiness ( p = 0.07). Other measures of daytime functioning (ability to function, daytime alertness, and sense of well-being) were not significantly different between the two treatment groups. Among patients who napped, eszopiclone patients reported fewer naps ( p = 0.03) and less cumulative naptime (median: 98 min placebo, 70 min eszopiclone, p = 0.07). Unpleasant taste, dry mouth, somnolence, and dizziness were higher in the eszopiclone group (12.5%, 8.8%, 6.6%, and 6.6%, respectively) than in the placebo group (0%, 1.6%, 5.5%, and 1.6%, respectively). Conclusion: In this study, eszopiclone was well tolerated and produced significant improvements in both polysomnographic and patient-reported measures of sleep maintenance, sleep induction, and sleep duration in elderly patients with chronic primary insomnia.

Efficacy and tolerability of armodafinil: effect on clinical condition late in the shift and overall functioning of patients with excessive sleepiness associated with shift work disorder.

Objective: This study examined the effect of armodafinil on late-in-shift clinical condition, wakefulness, and overall functioning of patients with shift work disorder. Methods: Patients with clinically diagnosed shift work disorder received armodafinil or placebo on nights worked for 6 weeks. Patients included in the study experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale ≥6) and were functionally impaired (Global Assessment of Functioning <70). Efficacy was determined by improvements in clinical condition (Clinical Global Impression-Change), late-in-the-shift Karolinska Sleepiness Scale score, and overall Global Assessment of Functioning score. Tolerability was assessed. Results: Patients receiving armodafinil showed significant improvements in late-in-shift clinical condition, wakefulness, and global functioning, compared to placebo at final visit. Armodafinil was generally well tolerated. Conclusions: Armodafinil improved clinical condition and wakefulness late in the night shift of patients with shift work disorder. Overall patient functioning was also improved.

Extrapyramidal reactions: Neuropsychiatric mimics in patients with AIDs

The use of neuroleptic medication as antiemetics, or in the treatment of neuropsychiatric disorders in patients with AIDS, may be associated with extrapyramidal side effects and lead to difficulty with diagnosis and management. Two cases are presented that describe severe extrapyramidal syndromes occurring in two patients with AIDS, one treated with prochlorperazine and the other with prochlorperazine and metoclopropramide. It is possible that the neuropathologic lesions found in patients with the AIDS dementia complex may pre-dispose to extrapyramidal side effects of neuroleptic medication. The differential diagnosis and treatment of delirium, dementia, depression, and extrapyramidal reactions in patients with AIDS is discussed.

The Effect of Armodafinil on Patient-Reported Functioning and Quality of Life in Patients With Excessive Sleepiness Associated With Shift Work Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To examine whether treatment with armodafinil for 6 weeks affected patient-reported overall functioning and daily quality of life compared with placebo in patients with excessive sleepiness associated with shift work disorder. METHOD This 6-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 45 sleep centers across the United States between February and October 2010. Patients included in the study were 18 to 65 years of age and diagnosed with excessive sleepiness associated with shift work disorder on the basis of the International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition and DSM-IV-TR criteria. These patients also experienced late-in-shift sleepiness between 4 AM and 8 AM (Karolinska Sleepiness Scale score ≥ 6) and were functionally impaired (Global Assessment of Functioning score < 70). Patients were administered 150 mg of armodafinil or placebo on nights worked, and efficacy measures included changes in patient-reported overall functioning (modified Sheehan Disability Scale [SDS-M]) and daily quality of life (10-question Functional Outcomes of Sleep Questionnaire [FOSQ-10]). RESULTS Patients treated with armodafinil had significantly greater improvement in SDS-M composite scores at final visit (last observation carried forward) (-6.8 vs -4.5, respectively, P = .0027) than those receiving placebo. Although the armodafinil group, compared to the placebo group, showed a greater improvement in total FOSQ-10 score from baseline to final visit (+3.4 vs +2.7, respectively, P = .0775), a statistically significant improvement was observed only at week 6 (+3.6 vs +2.7, respectively, P = .0351). CONCLUSIONS These findings are consistent with our previous report on clinician-rated measures of efficacy by demonstrating that armodafinil improves patient-rated functioning in patients with shift work disorder. Additionally, the current findings show for the first time that armodafinil may have benefits on quality of life after 6 weeks of treatment. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01080807.

Effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance and sleep architecture in a model of transient insomnia

ABSTRACT To compare the effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance during the last third of the night (last 160 min) and on sleep architecture throughout the night. Research design and methods: This was a retrospective analysis of a previously reported double-blind, randomized, uncontrolled, parallel-group, multicenter study. Healthy subjects with previous but no current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the ‘first night’ effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic measures of sleep were evaluated for 1 night. The primary, prospectively-defined analysis of this study showed that 7.5-mg and 15-mg doses of temazepam had equivalent effects on latency to persistent sleep, total sleep time, and the number of sleep interruptions recorded over an 8-h period. Both doses were well tolerated. The post hoc analysis reported here compared these 2 doses for their effects on sleep maintenance and architecture. Sleep efficiency during the last third of the night was designated as the primary endpoint. The methodology for this analysis was fully defined and documented prior to re-analysis of the database for these parameters. Results: Sixty-five subjects received temazepam 7.5 mg and 66 received temazepam 15 mg. No statistically significant differences between doses were detected for sleep efficiency or number of sleep interruptions during the last third of the night. Sleep architecture (measured over 8 h) did not differ significantly between groups. Conclusions: The 7.5-mg and 15-mg doses of temazepam were equally effective for maintaining sleep during the last third of the night. Continuity of sleep throughout the night, as reflected by sleep architecture, was also similar regardless of dose. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should begin with the 7.5 mg dose.

Perioperative complications in obstructive sleep apnea patients.

BackgroundPerioperative complications in obstructive sleep apnea (OSA) patients are described in a small series of case reports. No study to date systematically evaluates perioperative complications in a large number of OSA patients receiving surgeries other than those involving the pharynx.MethodsNames of the 860 OSA patients seen in a hospital-based sleep disorders center was cross-referenced with a list of the names of the 2,350 patients receiving surgeries in hospital during an 18 month period. In-patient and sleep center records of the 57 OSA patients receiving surgery were reviewed.ResultsNine perioperative complications occurred in eight of 48 OSA patients (17%) receiving general anesthesia. All of these complications were related to difficulties with airway management both pre- and postoperatively. Clinical characteristics including body mass index and Polysomnographie measurements of OSA severity did not prove to be useful predictors of perioperative complications.ConclusionsThe incidence of respiratory complications related to difficulties in airway management in OSA patients was higher than that reported in a recent study for all patients receiving general anesthesia (4%). The perioperative complications observed in these OSA patients are consistent with the underlying pathogenesis of OSA, pharyngeal obstruction. The absence of observed perioperative arrhythmias and myocardial ischemia is consistent with previous findings that sleep-related cardiac ischemia is uncommon in OSA patients. Our results suggest it is prudent to cautiously manage all OSA patients receiving surgeries involving general anesthesia.ZusammenfassungBackgroundKomplikationen vor, während und nach Operationen von Schlafapnoe-patienten sind in einer kleinen Zahl von Fallberichten beschrieben. Bisher gab es keine Studie, die anhand einer großen Zahl von OSA-Patienten systematisch die Komplikationen im Zusammenhang mit chirurgischen Eingriffen außer solchen am Pharynx ausgewertet hätte.MethodenDie Namen von 860 Schlafapnoe-patienten im Zentrum für Schlafstörungen des Krankenhauses wurden im Cross-Reference-Verfahren mit einer Liste von 2350 Patienten verglichen, die innerhalb von 18 Monaten im Krankenhaus operiert worden waren. Die Stationsberichte des Krankenhauses und die Aufzeichnungen des Zentrums für Schlafstörungen von 57 OSA-Patienten, die operiert worden waren, kamen zur Auswertung.Ergebnisse:Bei 8 von 48 OSA-Patienten (17%), die unter Vollnarkose operiert worden waren, hatten sich 9 Komplikationen eingestellt. Alle diese Komplikationen waren mit Atemwegproblemen prä- und postoperativ korreliert. Die klinischen Charakteristiken einschließlich Body-Mass-Index und der poly-somnographischen Bedingungen des Schweregrads des Schlafapnoesyndroms erwiesen sich nicht als nützliche Parameter für die Vorhersage von prä-, intra- oder postoperativen Komplikationen.SchlußfolgerungenDas Vorkommen respiratorischer Komplikationen im Zusammenhang mit Schwierigkeiten der Luftzuführung bei OSA-Patienten war höher, als in einer kürzlichen Studie über Patienten berichtet wurde, die unter Vollnarkose operiert worden waren (4%). Die von uns bei den 8 operierten OSA-Patienten gefundenen Komplikationen stimmen mit der dem obstruktiven Schlafapnoesyndrom zu Grunde liegenden Behinderung überein: der Obstruktion des Pharynx. Es wurden im Zusammenhang mit den Operationen weder Arrhythmien noch Myokardischämien beobachtet, und das steht wiederum im Einklang mit früheren Feststellungen, daß Ischämie des Herzmuskels bei OSA-Patienten höchst ungewöhnlich ist.

Comparison of temazepam 7.5 mg with temazepam 15 mg for the treatment of transient insomnia

SUMMARY Objective: To demonstrate the equivalent efficacy of temazepam 7.5 mg and temazepam 15 mg for the treatment of transient insomnia. Research design and methods: This was a double-blind, parallel group, multicenter study. Healthy male and female subjects with previous but not current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the ‘first night’ effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic (PSG) measures of sleep were evaluated for one night. Latency to persistent sleep (LPS) and total sleep time (TST) were designated as the primary efficacy endpoints. Results: One hundred and thirty-one subjects completed the study: 65 received the 7.5-mg dose, and 66 received the 15-mg dose. Treatment groups were well matched based on background demographics. No statistically significant differences between doses were detected for LPS, TST, or any other objective (PSG) measure of sleep. Furthermore, both doses were found to be clinically equivalent for LPS and TST based on predetermined criteria. Temazepam was well tolerated, and no significant differences between doses were found for adverse event (AE) incidence, mean score on the Digit Symbol Substitution Task, or mean scores on questions related to tolerability from the Leeds Sleep Evaluation Questionnaire. Conclusions: The 7.5-mg and 15-mg doses of temazepam were equally effective for the treatment of transient insomnia. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should begin with the lowest effective dose, i.e., 7.5 mg.