Sleep Initiation and Maintenance Disorders: McCall WV

Perlis ML, McCall WV, Jungquist CR, Pigeon WR, Matteson SE. · Sleep and Neurophysiology Research Laboratory, Department of Psychiatry, University of Rochester, 300 Crittenden Blvd. Rochester, NY 14642, USA. · Sleep Med Rev. · Pubmed #16109495 No free full text.

Abstract: Placebo effects are commonly observed in insomnia clinical trials. With the advent of longer-term trials, such effects appear to be remarkably robust and durable. In this paper we review the classic factors that are believed to contribute to placebo effects and how these factors operate in insomnia randomized clinical trials. Beyond this we suggest that the episodic nature of insomnia may interact with patient preferences for intermittent dosing in such a way as to sustain placebo effects in the long term. An appreciation of the latter phenomenon may provide increased power to detect therapeutic outcomes and may be used to potentiate clinical gains.

McCall WV. · Department of Psychiatry and Behavioral Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA. · J Am Geriatr Soc. · Pubmed #15982376 No free full text.

Abstract: Insomnia is a common but underrecognized problem in elderly patients. Five basic steps can help clinicians identify and treat insomnia. The first step is to ask a single question about sleep at every new patient visit, which goes a long way toward detection of patients with insomnia. The second step is to perform an initial evaluation of the problem, including symptoms, contributing factors, and effects on daytime function. Step three is to determine whether the patient is in crisis. True sleep emergencies are rare, and in most cases, treatment can be delayed until another appointment can be made for a full evaluation of the problem. A sleep evaluation constitutes the fourth step and focuses mainly on a thorough sleep history; blood tests and polysomnography rarely have a role. The final step is intervention. Nonpharmacological strategies are a mainstay of treatment for chronic insomnia, but hypnotics have a role in treating transient insomnia and chronic insomnia that does not improve with nonpharmacological treatment or treatment of associated primary conditions. Pharmacological therapy usually consists of benzodiazepines with short half-lives or nonbenzodiazepines such as zolpidem and zaleplon, although lack of demonstrated efficacy against sleep maintenance difficulties, one of the primary symptoms of insomnia among older people, limits use of these agents. Emerging nonbenzodiazepine agents such as indiplon and eszopiclone may specifically address sleep maintenance problems in elderly patients and are pending Food and Drug Administration (FDA) approval. (Editor's note: Since preparation of this manuscript, the FDA has approved eszopiclone for treatment of insomnia.).

Edinger JD, Bonnet MH, Bootzin RR, Doghramji K, Dorsey CM, Espie CA, Jamieson AO, McCall WV, Morin CM, Stepanski EJ, Anonymous00028. · VA Medical Center, Durham, NC, USA. · Sleep. · Pubmed #15683149 No free full text.

Abstract: Insomnia is a highly prevalent, often debilitating, and economically burdensome form of sleep disturbance caused by various situational, medical, emotional, environmental and behavioral factors. Although several consensually-derived nosologies have described numerous insomnia phenotypes, research concerning these phenotypes has been greatly hampered by a lack of widely accepted operational research diagnostic criteria (RDC) for their definition. The lack of RDC has, in turn, led to inconsistent research findings for most phenotypes largely due to the variable definitions used for their ascertainment. Given this problem, the American Academy of Sleep Medicine (AASM) commissioned a Work Group (WG) to review the literature and identify those insomnia phenotypes that appear most valid and tenable. In addition, this WG was asked to derive standardized RDC for these phenotypes and recommend assessment procedures for their ascertainment. This report outlines the WG's findings, the insomnia RDC derived, and research assessment procedures the WG recommends for identifying study participants who meet these RDC.

McCall WV. · Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. · J Clin Psychiatry. · Pubmed #11388587 No free full text.

Abstract: Insomnia is a cardinal symptom for many psychiatric disorders, especially depressive disorders. Treatment of the underlying psychiatric disorder may be sufficient to relieve the accompanying insomnia. If the insomnia fails to respond, then consideration should be given to the possibility of inadequate treatment of the primary psychiatric disorder, iatrogenic insomnia, insomnia related to a medical disorder, or learned/habit insomnia. Persistent insomnia should be aggressively pursued, since it has been associated with a variety of adverse outcomes in samples of depressed patients. The physician should always inquire about and encourage healthy sleeping behaviors, even if hypnotic medication is contemplated. Benzodiazepines and nonbenzodiazepine benzodiazepine receptor agonists (BzRAs) have the best evidence for efficacy as hypnotics, although sedating antidepressants are popularly prescribed. Although all benzodiazepine hypnotics and nonbenzodiazepine BzRAs are comparably efficacious in inducing sleep, they vary markedly in their potential for residual side effects.

Perlis ML, McCall WV, Krystal AD, Walsh JK. · Sleep and Neurophysiology Laboratory, Department of Psychiatry, University of Rochester, and the University of Rochester Medical Center, Neurosciences Program, Rochester, NY 14642, USA. · J Clin Psychiatry. · Pubmed #15323600 No free full text.

Abstract: INTRODUCTION: While it is common practice that hypnotics are used on a non-nightly basis, few investigations have been undertaken to evaluate the efficacy of the intermittent dosing strategy. The present study was designed to further evaluate this issue within a large scale, double-blind, placebo-controlled, long-term trial. METHOD: Patients who met DSM-IV criteria for primary insomnia participated in the study from January 2000 through October 2001. Patients were randomly assigned to 1 of 2 treatment groups (zolpidem 10 mg or placebo) for a period of 12 weeks. Ten pills were provided in foil packs on an every-other-week basis, and patients were instructed to take no fewer than 3 and no more than 5 pills per week. Sleep was evaluated daily with sleep diaries. Pill use was recorded in the sleep diaries. RESULTS: 199 patients (mean +/- SD age = 41.0 +/- 12.8 years; 71% female) were randomly assigned to treatment. On mean, patients receiving zolpidem exhibited (vs. baseline) a 42% decrease in sleep latency, a 52% reduction in number of awakenings, a 55% decrease in wake time after sleep onset, and a 27% increase in total sleep time. These positive clinical gains did not diminish with time and were not associated with dose escalation. There was also no evidence of rebound insomnia. CONCLUSIONS: Over a period of 12 weeks of intermittent treatment with zolpidem, sleep continuity was significantly improved, the clinical gains were sustained, and there was no evidence of subjective rebound insomnia between doses or increases in the amount of medication used during the study interval.

Brenes GA, Miller ME, Stanley MA, Williamson JD, Knudson M, McCall WV. · Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. · Am J Geriatr Psychiatry. · Pubmed #19472436 No free full text.

Abstract: OBJECTIVES: The purposes of this study are to determine the frequency and severity of insomnia symptoms and related complaints experienced by older adults with Generalized Anxiety Disorder (GAD) and compare them with older adults without GAD; compare insomnia symptoms among older adults with GAD with and without comorbid depression; determine if there are age differences in insomnia severity among people with GAD; and determine if there are differences in insomnia severity between older adults with GAD and older adults diagnosed with insomnia. DESIGN: Cross-sectional. SETTING: Participants were recruited through primary care clinics, advertisements, and mass mailings. PARTICIPANTS: One hundred ten older adults; 31 with GAD, 25 with GAD and depression, 33 worried well, and 21 with no psychiatric diagnosis. MEASUREMENTS: Psychiatric diagnosis, sleep disturbance, and health. RESULTS: Participants with GAD with and without comorbid depression reported significantly greater sleep disturbance severity than participants with no psychiatric diagnosis and the worried well. There were no differences in sleep disturbances between older adults with GAD only and older adults with comorbid GAD and depression. The severity of sleep disturbance reported by older participants with GAD was greater than reports by young and middle-aged participants with GAD, and comparable with reports by older adults with a diagnosis of insomnia. CONCLUSIONS: Ninety percent of older adults with GAD report dissatisfaction with sleep and the majority report moderate to severe insomnia. These findings support the assessment of sleep disturbances within the context of late-life GAD.

Pollack M, Kinrys G, Krystal A, McCall WV, Roth T, Schaefer K, Rubens R, Roach J, Huang H, Krishnan R. · Massachusetts General Hospital, Simches Research Bldg, 185 Cambridge St, Ste 2200, 2nd Floor, Boston, MA 02114, USA. · Arch Gen Psychiatry. · Pubmed #18458207 links to  free full text

Abstract: CONTEXT: Insomnia and generalized anxiety disorder (GAD) are prevalent disorders that may coexist. OBJECTIVE: To determine the efficacy of eszopiclone combined with escitalopram oxalate in treating insomnia comorbid with GAD. DESIGN: Double-blind, randomized, placebo-controlled, parallel-group, add-on therapy 10-week study. SETTING: Multicenter outpatient study from July 2005 to April 2006. PATIENTS: Adults aged 18 to 64 years meeting DSM-IV-TR criteria for GAD and insomnia. INTERVENTIONS: Patients received 10 mg of escitalopram oxolate for 10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo (n = 301) nightly for 8 weeks. For the last 2 weeks, eszopiclone was replaced with a single-blind placebo. MAIN OUTCOME MEASURES: Sleep, daytime functioning, psychiatric measures, and adverse events. RESULTS: Compared with treatment with placebo and escitalopram, treatment with eszopiclone and escitalopram resulted in significantly improved sleep and daytime functioning (P < .05), with no evidence of tolerance. Patients taking eszopiclone and escitalopram had greater improvements in total Hamilton Anxiety Scale (HAM-A) scores at each week (P < .05) and at weeks 4 through 10 with the insomnia item removed. Clinical Global Impressions (CGI) of Improvement scores were improved with eszopiclone and escitalopram at every point (P < .02), while CGI of Severity of Illness scores were not significantly different after week 1. The HAM-A response (63% vs 49%, respectively, P = .001) and remission (42% vs 36%, respectively, P = .09) rates at week 8 were higher in patients treated with eszopiclone and escitalopram than those treated with placebo and escitalopram, and median time to onset of anxiolytic response was significantly reduced (P < or = .05). After eszopiclone discontinuation, there was no evidence of rebound insomnia, and while treatment differences in anxiety measures were maintained, differences in sleep outcomes were not. Overall adverse event rates were 77.6% with cotherapy and 67.9% with monotherapy. The most common adverse events with cotherapy were unpleasant taste, headache, dry mouth, and somnolence. CONCLUSIONS: Coadministration of eszopiclone and escitalopram was well tolerated and associated with significantly improved sleep, daytime functioning, anxiety, and mood in patients with insomnia and GAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235508.

Krystal A, Fava M, Rubens R, Wessel T, Caron J, Wilson P, Roth T, McCall WV. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · J Clin Sleep Med. · Pubmed #17557453 No free full text.

Abstract: BACKGROUND: Insomnia and major depressive disorder (MDD) may coexist. This study evaluated hypnotic discontinuation effects following an 8-week placebo-controlled study of eszopiclone/fluoxetine cotherapy in patients with insomnia and comorbid MDD. METHODS: Patients meeting DSM-IV criteria for MDD and insomnia received fluoxetine each morning for 8 weeks and were randomized to concomitant treatment with nightly eszopiclone 3 mg (cotherapy) or placebo (monotherapy). Thereafter, patients received 2 weeks of continued fluoxetine plus single-blind placebo. RESULTS: Incidence rates of central nervous system (CNS) and potentially CNS-related adverse events (AEs) during the run-out period were similar between treatment groups (8.8% with monotherapy vs 9.8% with cotherapy), and there was no evidence of benzodiazepine withdrawal AEs. Physician-assessed Clinical Global Impression improvements in depressive symptoms were maintained after eszopiclone discontinuation. Improvements in 17-item Hamilton-Depression Rating Scale (HAMD-17) scores with cotherapy versus monotherapy seen at Week 8 (p = .0004) were maintained at Week 10 (p < .0001) and significantly higher depression response and remission rates were observed after cotherapy at Week 10 (p < .02). Patients discontinued from eszopiclone maintained improvements in SL (sleep latency), WASO (wake after sleep onset), and TST (total sleep time) during the 2 weeks following discontinuation (p < .05). CONCLUSIONS: In this study, eszopiclone discontinuation did not result in significant CNS or benzodiazepine withdrawal AEs, rebound insomnia, or rebound depression; and improvements in sleep and depressive symptoms were maintained.

McCall WV, Erman M, Krystal AD, Rosenberg R, Scharf M, Zammit GK, Wessel T. · Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA. · Curr Med Res Opin. · Pubmed #16968566 No free full text.

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] >or= 20 min and latency to persistent sleep >or= 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.

Fava M, McCall WV, Krystal A, Wessel T, Rubens R, Caron J, Amato D, Roth T. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Biol Psychiatry. · Pubmed #16581036 No free full text.

Abstract: BACKGROUND: Insomnia and major depressive disorder (MDD) can coexist. This study evaluated the effect of adding eszopiclone to fluoxetine. METHODS: Patients who met DSM-IV criteria for both MDD and insomnia (n = 545) received morning fluoxetine and were randomized to nightly eszopiclone 3 mg (ESZ+FLX) or placebo (PBO+FLX) for 8 weeks. Subjective sleep and daytime function were assessed weekly. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Impression Improvement (CGI-I) and Severity items (CGI-S). RESULTS: Patients in the ESZ+FLX group had significantly decreased sleep latency, wake time after sleep onset (WASO), increased total sleep time (TST), sleep quality, and depth of sleep at all double-blind time points (all p < .05). Eszopiclone co-therapy also resulted in: significantly greater changes in HAM-D-17 scores at Week 4 (p = .01) with progressive improvement at Week 8 (p = .002); significantly improved CGI-I and CGI-S scores at all time points beyond Week 1 (p < .05); and significantly more responders (59% vs. 48%; p = .009) and remitters (42% vs. 33%; p = .03) at Week 8. Treatment was well tolerated, with similar adverse event and dropout rates. CONCLUSIONS: In this study, eszopiclone/fluoxetine co-therapy was relatively well tolerated and associated with rapid, substantial, and sustained sleep improvement, a faster onset of antidepressant response on the basis of CGI, and a greater magnitude of the antidepressant effect.

Scharf M, Erman M, Rosenberg R, Seiden D, McCall WV, Amato D, Wessel TC. · Tri-State Sleep Disorders Center, Cincinnati, OH 45246, USA. · Sleep. · Pubmed #16477959 No free full text.

Abstract: STUDY OBJECTIVES: Evaluate the efficacy of eszopiclone in primary insomnia. DESIGN/SETTING: Randomized, double-blind, placebo-controlled multicenter in outpatient setting with weekly visits. PARTICIPANTS: Two-hundred thirty one men and women aged 65 to 85 years (mean age 72.3 years) with primary insomnia, as defined by the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. INTERVENTIONS: Eszopiclone 1 mg (n = 72), eszopiclone 2 mg (n = 79), or placebo (n = 80) nightly for 2 weeks. MEASUREMENTS/RESULTS: Efficacy was assessed using an interactive voice response system. Following the predefined hierarchical testing strategy, the eszopiclone 2-mg group had a significantly shorter sleep latency compared with placebo over the double-blind period (P = .0034). The eszopiclone 2-mg group had significantly longer total sleep time (P = .0003) and eszopiclone 1-mg group had significantly shorter sleep latency (P < or = .012) compared with placebo. The eszopiclone 1-mg group was not significantly different from placebo on total sleep time or any other secondary efficacy endpoint. Secondary analyses indicated that the eszopiclone 2-mg group had significantly less wake after sleep onset; significantly fewer and shorter in duration daytime naps; and significantly higher ratings of sleep quality and depth, daytime alertness, and sense of physical well-being compared with placebo (P < .05). Eszopiclone was well tolerated. The most frequent treatment-related adverse event was unpleasant taste. CONCLUSION: Nightly treatment with eszopiclone 1 mg effectively induced sleep, while the 2-mg dose was effective in inducing and maintaining sleep. Eszopiclone was well tolerated in elderly patients with primary insomnia, and the sleep efficacy was accompanied by significantly less napping and significantly higher ratings of daytime alertness, sense of physical well-being, and several quality-of-life parameters at the higher dose.

McCall WV, D'Agostino R, Dunn A. · Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USA. · Sleep Med. · Pubmed #14592361 No free full text.

Abstract: OBJECTIVES: The effects associated with placebo (EAP) have been incompletely described in clinical trials of insomnia treatment. We conducted a meta-analysis of insomnia medication trials for the purpose of estimating the magnitude of sleep EAP. METHOD: We reviewed Medline for 1966 through 2000 for the meta-analysis. The subject heading of insomnia restricted to the subheading of drug therapy was crossed against the results of a search on the subjects heading placebo and text word placebo. We selected only papers that examined primary insomnia, incorporating both placebo and active medication therapies in a randomized, double-blind, parallel-group design. We required that results be reported for 1, 2, 3, or 4 weeks of treatment, and that outcomes be reported in hours/minutes. RESULTS: Five papers satisfied our requirements for eligibility, comprising 213 patients receiving placebo for a 2-week interval. Subjective sleep latency demonstrated a significant reduction (mean+/-S.E.) of 13.1+/-2.0 min (95% confidence interval (CI) 9.2, 17.0) for the placebo group after combining the data across studies. Subjective total sleep time demonstrated a significant increase of 13.5+/-5.4 min (95% CI 2.9, 24.0). Polysomnographic (PSG) sleep latency demonstrated a non-significant reduction of 2.5+/-4.3 min (95% CI -5.9, 10.9). CONCLUSIONS: The confirmation of EAP in insomnia clinical trials argues for the retention of a placebo control in future insomnia clinical trials.

McCall WV, Reboussin BA, Cohen W. · Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston- Salem, NC 27157, USA. · J Sleep Res. · Pubmed #10733688 No free full text.

Abstract: Insomnia and major depressive episodes (MDE) have each been associated with quality of life (QOL) deficits. In this study we examined insomnia as an independent predictor of QOL deficits during MDE, and used a secondary analysis of cross-sectional data. The study was based at the inpatient psychiatric ward and included 88 adults (mean age 53; 78% women). We assessed insomnia severity with the 21-item Hamilton Rating Scale for Depression (HRSD) and the Beck Depression Inventory (BDI). Measurements of QOL in the week prior to admission included activities of daily living (ADLs), instrumental ADLs (IADLs), daily living and role functioning, and relation to self and colleagues (the last two both subscales of the Basis 32). Linear regression models used the insomnia items as independent variables and the QOL measures as the dependent variables, after adjusting for age and nonsleep related depression severity. The results showed that 93% of patients endorsed insomnia on the observer-rated HRSD, and 97% endorsed sleep disturbance in the self-rated BDI. However, the insomnia items on the HRSD and BDI showed poor concurrent validity. Increasing severity of insomnia on the HDRS was associated with better QOL, while increasing severity of insomnia on the BDI was associated with worse QOL. We conclude that the BDI and HRSD do not produce equivalent measures of insomnia severity in depressed inpatients, and each insomnia measure has a unique relationship with QOL.