Sleep Initiation and Maintenance Disorders: Krystal A

Asnis GM, Chakraburtty A, DuBoff EA, Krystal A, Londborg PD, Rosenberg R, Roth-Schechter B, Scharf MB, Walsh JK. · Department of Psychiatry, Montefiore Medical Center, Bronx, NY 10467, USA. · J Clin Psychiatry. · Pubmed #10549683 No free full text.

Abstract: BACKGROUND: Depressed individuals effectively treated with selective serotonin reuptake inhibitors (SSRIs) often report persistent insomnia and require adjunctive sleep-promoting therapy. METHOD: Men (N = 40) and women (N = 150) with a mean age of 41.6 years who had persistent insomnia in the presence of effective and stable treatment (at least 2 weeks) with fluoxetine (< or =40 mg/day), sertraline (< or =100 mg/day), or paroxetine (< or =40 mg/day) for DSM-IV major depressive disorder, dysthymic disorder, or minor depressive disorder of mild-to-moderate severity (and score of < or =2 on item 3 of the Hamilton Rating Scale for Depression [HAM-D]) participated in this randomized, double-blind, parallel-group study. At study entry, patients were required to score < or =12 on the HAM-D. During a 1-week single-blind placebo period, patients had to report on at least 3 nights a latency of > or =30 minutes or a sleep time of <6.5 hours and clinically significant daytime impairment. Patients received either placebo (N = 96) or zolpidem, 10 mg (N = 94) nightly, for 4 weeks and single-blind placebo for 1 week thereafter. Sleep was measured with daily questionnaires and during weekly physician visits. RESULTS: Compared with placebo, zolpidem was associated with improved sleep: longer sleep times (weeks 1 through 4, p<.05), greater sleep quality (weeks 1 through 4, p<.01), and reduced number of awakenings (weeks 1, 2, and 4; p<.05), together with feeling significantly more refreshed, less sleepy, and more able to concentrate. After placebo substitution, the zolpidem group showed significant worsening relative to pretreatment sleep on the first posttreatment night in total sleep time and sleep quality, reverted to pretreatment insomnia levels on the other hypnotic efficacy measures, or maintained improvement (fewer number of awakenings). There was no evidence of dependence or withdrawal from zolpidem (DSM-IV criteria). Incidence rates of adverse events were similar in both treatment groups (74% and 83% for placebo and zolpidem, respectively), but 7 zolpidem patients discontinued compared with 2 placebo patients. CONCLUSION: In this defined patient population, zolpidem, 10 mg, was effectively and safely co-administered with an SSRI, resulting in improved self-rated sleep, daytime functioning, and well-being.

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.

Walsh JK, Perlis M, Rosenthal M, Krystal A, Jiang J, Roth T. · Sleep Medicine and Research Center, St. Johnś/St. Lukeś Hospitals, St. Louis, MO 63017, USA. · J Clin Sleep Med. · Pubmed #17557435 No free full text.

Abstract: INTRODUCTION: This study evaluated dose-response effects of tiagabine on sleep in adults with primary insomnia. METHODS: Men and women with primary insomnia (DSM-IV-TR) were randomly assigned to receive tiagabine 4, 6, 8, 10 mg or placebo in a randomized, double-blind, parallel-group study. Efficacy was assessed using polysomnography and self-report measures. Safety analyses included measures of residual sedation and adverse events. RESULTS: A total of 232 patients (31% men; mean age 44.3 years) received study drug. No significant differences were observed between tiagabine and placebo in wake after sleep onset, latency to persistent sleep, or total sleep time. Significantly greater increases from baseline in slow-wave sleep (stages 3 and 4) were found with the 3 highest doses of tiagabine compared with placebo (p < .01). Stage 1 sleep showed a significantly greater decrease from baseline for all doses of tiagabine than for placebo (p < .01). Self-report measures of sleep and daytime function did not differ from placebo, except for poorer ratings on the 10-mg dose. Similarly, psychomotor performance on the 10-mg dose was worsened compared with placebo. Tiagabine was generally well tolerated; dizziness and nausea were the most common adverse events, particularly at the 2 higher doses. CONCLUSIONS: In adults with primary insomnia, tiagabine significantly increased slow-wave sleep in a dose-dependent manner with a corresponding significant decrease in Stage 1 sleep, whereas no significant differences were observed in wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo.

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.

Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA. · Henry Ford Hospital Sleep Center, 2799 West Grand Blvd, CFP-3, Detroit, MI 48202, USA. · Sleep Med. · Pubmed #16230048 No free full text.

Abstract: BACKGROUND AND PURPOSE: A double-blind placebo-controlled study of eszopiclone found significant, sustained improvement in sleep and daytime function. The 6-month open-label extension phase is described herein. PATIENTS AND METHODS: Adults (21-64) with primary insomnia who reported sleep duration <6.5 h/night or sleep latency >30 min/night were included. Patient-reported endpoints included sleep and daytime function. Safety and compliance were assessed at monthly clinic visits. The final double-blind month was used as the baseline for efficacy analyses of the open-label period. RESULTS: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (n=111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P<or=0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects (n=360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by >5% of patients. CONCLUSIONS: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double-blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3mg was well tolerated; tolerance was not observed.

Mccall WV, Perlis ML, Tu X, Groman AE, Krystal A, Walsh JK. · Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1071, USA. · Int J Clin Pharmacol Ther. · Pubmed #16119510 No free full text.

Abstract: OBJECTIVE: Sleep parameters commonly improve during placebo treatment in insomnia clinical trials. We examined whether the improvement seen with placebo was related to taking pills or other non-specific factors. METHOD: 95 insomniacs took either a placebo pill (pill+) or no pill (pill-) on nights of their choosing over 12 weeks. RESULTS: Pills were consumed on about half of the nights. Consistent improvement was seen with reduced reported sleep latency, wakefulness after sleep onset, number of awakenings, and total sleep time over the 12 weeks for both the pill+ and pill condition. A difference between pill+ and pill- was detected only for total sleep time, and this difference favored pill+. CONCLUSIONS: This study suggests that improvement seen during placebo treatment is more related to non-specific factors of participating in clinical trial than to pill taking behavior.