Sleep Initiation and Maintenance Disorders: Roth T

Roehrs T, Bonahoom A, Pedrosi B, Zorick F, Roth T. · Henry Ford Hospital, Sleep Disorders and Research Center, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202, USA. · Psychopharmacology (Berl). · Pubmed #11981593 No free full text.

Abstract: RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study assessed whether insomniacs' self-administration of hypnotics extended to the daytime. METHODS: Forty-four healthy men and women, 21-55 years old, with ( n=22) and without ( n=22) insomnia volunteered. They were randomized to one of two triazolam dose groups (0.125 or 0.25 mg) and their preference for placebo versus triazolam was assessed at night (2300 hours) and day (0900 hours) over 7 consecutive days in each phase. In both night and day phases of the study, subjects received triazolam or placebo in color-coded capsules on two sampling days or nights and then were forced to choose their preferred capsule on 5 subsequent days or nights. The order of day and night study phases and the placebo and triazolam sampling days was counterbalanced. In the night phase subjects went to bed from 2330 to 0730 hours and in the day phase they were tested for level of sleepiness-alertness at 1000, 1200, 1400, and 1600 hours by the multiple sleep latency test (MSLT) and mood and performance at 1100 and 1500 hours. RESULTS: More triazolam was chosen at night than during the day. No dose differences in preferences at night versus day or between insomniacs and normals were found. Insomniacs did not differ in their triazolam preferences between night and day, while the normals chose triazolam less frequently during the day. Among insomniacs, 40% chose triazolam on >3 of the 5 days. On both screening and placebo sampling days, those with a high (>60%) daytime triazolam preference had greater average daily sleep latencies on the MSLT than those with a low (<50%) daytime triazolam preference (i.e. with a placebo preference). In the triazolam preference group, triazolam reduced daily MSLT latencies to the level of the placebo preference group. CONCLUSIONS: This study shows that the minority of insomniacs who self-administer hypnotics during the day are physiologically aroused and the drug reduces their arousal suggesting that their daytime self-administration, like their night-time self-administration, is more consistent with therapy-seeking than drug-seeking behavior, at least for the short-term.

Roehrs T, Bonahoom A, Pedrosi B, Rosenthal L, Roth T. · Henry Ford Hospital, Sleep Disorders and Research Center, 2799 West Grand Blvd, Detroit, MI 48202, USA. · Psychopharmacology (Berl). · Pubmed #11374329 No free full text.

Abstract: RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study determined whether prior experience with different treatment regimens (i.e., instructions and capsule availability) would alter the previously observed high hypnotic self-administration rates. METHODS: Sixty-four healthy men and women with (n = 32) and without (n = 32) insomnia, 21-55 years, self administered placebo or triazolam (0.25 mg) after different prior treatment regimens. They received one of three different treatment regimens enforced for 11 nights: a capsule each night, a capsule as needed, or a capsule every third night. On 14 subsequent nights they choose to self-administer a capsule or not, placebo during 1 week and triazolam (0.25 mg) the other (counterbalanced in order). RESULTS: Insomniacs self-administered more capsules than normals and triazolam was self-administered more than placebo. For both groups, treatment regimen had a minimal effect on capsule self-administration. During the treatment phase, triazolam improved self-ratings of sleep relative to placebo. During the choice phase, nightly variations in self-rated sleep predicted self-administration of a capsule on the following night, regardless of whether the capsule was active drug or placebo. CONCLUSIONS: The data of this study are consistent with the view that hypnotic self-administration by insomniacs is therapy-seeking behavior and not drug abuse.

Walsh JK, Roth T, Randazzo A, Erman M, Jamieson A, Scharf M, Schweitzer PK, Ware JC. · Sleep Medicine and Research Center, St. Luke's Hospital, St. Louis, Missouri, USA. · Sleep. · Pubmed #11145323 No free full text.

Abstract: CONTEXT: Intermittent use (i.e., a few nights per week) of hypnotic medication is often recommended for the treatment of chronic insomnia despite an absence of efficacy and safety data using this regimen. STUDY OBJECTIVES: To evaluate the clinical efficacy and safety of intermittent pharmacotherapy for chronic insomnia. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel groups, clinical trial at six sleep research sites. PATIENTS: One hundred-sixty-three (115 women, 48 men; mean age 44.1+ SE. 0.9 years), DSM-IV-defined primary insomnia patients were randomized, 134 patients completed the study. INTERVENTIONS: Eight weeks of treatment with either zolpidem 10 mg or placebo. Patients were instructed to take medication when they felt they needed it, but at least three and no more than five times per week. MAIN OUTCOME MEASURES: Investigator and Patient Global Ratings were the primary outcome variables. Secondary measures from daily questionnaires to assess efficacy, rebound insomnia and drug taking behavior. RESULTS: The Investigator's Global Rating indicated that intermittent use of zolpidem produced a significantly better therapeutic effect and significantly reduced insomnia severity throughout the 8-week study relative to placebo. Zolpidem was found to be effective in initiating and maintaining sleep on nights taken, as compared to placebo, based upon the Patient's Global Ratings and all subjective sleep variables. No evidence of rebound insomnia was found on nights that zolpidem was not taken. The number of nights a pill was taken did not differ between groups, nor did frequency of pill taking change in either group across the duration of the study. There were no significant effects of treatment upon quality of life or neurocognitive measures. CONCLUSIONS: Zolpidem 10 mg is effective in treating insomnia when used intermittently, without evidence of discontinuation effects or increased frequency of pill taking.

Roehrs T, Turner L, Roth T. · Henry Ford Hospital, Sleep Disorders and Research Center and Department of Psychiatry and Behavioral Neuroscience, Wayne State University, School of Medicine, Detroit MI 48202, USA. · Sleep. · Pubmed #11007446 No free full text.

Abstract: STUDY OBJECTIVES: To assess the effect of sleep loss and the effect of a sedating drug on waking actigraphy DESIGN: N/A SETTING: N/A PARTICIPANTS: Seventeen healthy volunteers, aged 19-35 yrs Interventions: Four night-day treatments presented in a Latin Square Design: placebo-8 hr time-in-bed (TIB), placebo-4 hr TIB, placebo-0 hr TIB, and diphenhydramine 50 mg-8 hr TIB. MEASUREMENTS AND RESULTS: After the appropriate TIB, medication was administered at 09:00 hr, the Multiple Sleep Latency Test at 09:30, 11:30, 13:30, 15:30, and 17:30 hr, and a 45 min performance battery at 10:30, 14:30, and 16:30 hr. Each day the volunteers wore actigraphs from 0700-1800 hrs. Decreasing TIB was associated with decreased daily mean sleep latency on the MSLT with 4 and 0 hrs differing from 8 hrs and each other. Daytime activity also was reduced by the reduced prior TIB. Increased inactivity relative to the 8 hr TIB developed between the 4 hr and 0 hr TIBs, with 4 hrs differing from 0 hrs, but not 8 hrs. Diphenhydramine 50 mg reduced mean daily sleep latency and increased percent inactive time relative to placebo. On the MSLT diphenhydramine was intermediate to 4 hr and 0 hr TIB and on actigraphy it was similar to 0 hr TIB. CONCLUSIONS: The difference in the effect of diphenhydramine on these actigraphy and MSLT may reflect the different sensitivities of the measures.

Roehrs T, Papineau K, Rosenthal L, Roth T. · Sleep Disorders & Research Center, Henry Ford Hospital, Detroit, Michigan, USA. · Neuropsychopharmacology. · Pubmed #10063488 links to  free full text

Abstract: The purpose of this study was to assess the effects of low ethanol doses on sleep and mood and to assess its reinforcing effects used as a hypnotic. Twenty healthy adults, aged 21-45 yrs, all moderate social drinkers, were studied: eleven subjects had insomnia and nine were normal sleepers, as documented by clinical polysomnography. On two sampling nights each, ethanol (0.5 g/kg) or placebo was administered before sleep in color-coded cups presented in three doses (0.2, 0.2, and 0.1 g/kg) separated by 15 min. On three subsequent nights subjects chose their preferred presleep beverage (0.2 g/kg ethanol or placebo) based on cup color and were given an opportunity for 3 additional refills (0.2 g/kg each) of the chosen beverage at 15 min intervals, yielding a total possible dose of 0.8 g/kg. Insomniacs chose ethanol 67% of nights and normals 22%. Insomniacs chose significantly more ethanol refills than normals for an average nightly dose of 0.45 g/kg and normals took significantly more placebo refills. On the sampling nights 0.5 g/kg ethanol reduced REM sleep for both groups for the 8-hr sleep period and in insomniacs increased stage 3-4 sleep and reduced stage 1 sleep during the first half of the night to the level seen in the normals. Other sleep variables were not altered in either group or halves of the night. Presleep improvements in the Profile of Mood States tension and concentration factors were also associated with ethanol administration. Thus, acutely, both sleep and mood effects appear to be associated with the reinforcing effects of ethanol as a hypnotic for insomniacs.

Scharf M, Rogowski R, Hull S, Cohn M, Mayleben D, Feldman N, Ereshefsky L, Lankford A, Roth T. · Tristate Sleep Disorders Center, 1275 East Kemper Rd., Cincinnati, OH 45246, USA. · J Clin Psychiatry. · Pubmed #19192438 No free full text.

Abstract: OBJECTIVES: Evaluate efficacy and safety of the histamine-H1 antagonist doxepin at doses of 1 mg, 3 mg, and 6 mg in elderly adults with primary insomnia. DESIGN: A randomized, double-blind, placebo-controlled, crossover design was used in this population of elderly adults with primary insomnia (DSM-IV). Each treatment period consisted of 2 polysomnographic (PSG) assessment nights with a 5- or 12-day drug-free interval between periods. The study was conducted from September 2004 to January 2005. SETTING: Sleep laboratories in 11 sleep centers in the United States. PARTICIPANTS: Elderly adults with primary insomnia. INTERVENTION: Doxepin 1 mg, 3 mg, and 6 mg. MEASUREMENTS: Efficacy was assessed using PSG and patient-reported measures. RESULTS: Seventy-six patients were randomly assigned. All 3 doxepin doses produced dose-related significant improvements in PSG-determined wake time during sleep (p < .0001), wake time after sleep onset (p < .0001), total sleep time (p < .0001), and overall sleep efficiency (p < .0001) versus placebo. At the 3-mg and 6-mg doses, sleep efficiency was significantly improved during all thirds of the night (p < .05). There was a dose-related decrease in patient-reported sleep latency, with the 6-mg dose achieving statistical significance in latency to sleep onset (p = .0181). The pattern of the remaining subjective efficacy results was consistent with PSG. All 3 doxepin doses had side effect profiles comparable to placebo, with no spontaneously reported anticholinergic effects, no memory impairment, and no significant next-day residual effects. CONCLUSIONS: In this 2-night study of elderly adults with primary insomnia, doxepin doses of 1 mg, 3 mg, and 6 mg were well tolerated and produced significant improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. Positive effects on patient-reported sleep onset were observed at the highest dose. All 3 doxepin doses had a safety profile comparable to placebo. These data demonstrate that doxepin was efficacious in improving sleep in elderly adults.

Rosenberg R, Seiden DJ, Hull SG, Erman M, Schwartz H, Anderson C, Prosser W, Shanahan W, Sanchez M, Chuang E, Roth T. · NeuroTrials Research and Atlanta School of Sleep Medicine, Atlanta 30342, USA. · Sleep. · Pubmed #19090322 links to  free full text

Abstract: INTRODUCTION: Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT(2A) receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated. METHODOLOGY: Adult subjects (n=173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period. RESULTS: APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs. placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests. CONCLUSIONS: APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia.

Roth T, Hull SG, Lankford DA, Rosenberg R, Scharf MB, Anonymous00088. · Henry Ford Hospital Sleep Disorders and Research, Detroit, MI 48202, USA. · Sleep. · Pubmed #18788653 links to  free full text

Abstract: STUDY OBJECTIVES: To evaluate the efficacy and safety of low-dose, sublingual zolpidem tartrate when taken during a scheduled middle-of-the-night (MOTN) awakening in subjects with insomnia characterized by difficulty returning to sleep following MOTN awakenings. DESIGN: Randomized, double-blind, placebo-controlled, 3-way crossover study. METHODS: Each treatment period consisted of 2 consecutive nights of dosing separated by a washout of 5 to 12 days. Subjects were awakened 4 h after lights out, dosed with sublingual zolpidem tartrate (3.5 mg or 1.75 mg) or placebo, kept awake for 30 min, and then returned to bed for an additional 4 h. Sleep parameters were assessed by polysomnography (PSG) and post-sleep questionnaires. SETTING: Five sleep laboratories. PARTICIPANTS: Adults (24 males, 58 females, mean age 45.9 y) with a diagnosis of DSM-IV primary insomnia and a history of prolonged MOTN awakenings. Baseline difficulties with MOTN awakenings were confirmed by a 10-day screening sleep diary and PSG screening. RESULTS: Low-dose sublingual zolpidem tartrate demonstrated significant dose-related decreases in latency to persistent sleep and total sleep time (P < 0.001) compared to placebo after MOTN dosing. All subject reports paralleled PSG observations. Neither dose showed next-morning impairment on the DSST or ratings of sleepiness. The 3.5-mg dose produced improvements in reports of sleep quality (P < 0.001), ability to function, and level of refreshed sleep (P < 0.05 for both dosages) compared to placebo. Sublingual zolpidem tartrate lozenges were generally safe and well tolerated. CONCLUSIONS: Low-dose sublingual zolpidem tartrate may be suitable for treatment of patients who have difficulty resuming sleep after MOTN awakenings.

Zammit G, Schwartz H, Roth T, Wang-Weigand S, Sainati S, Zhang J. · Clinilabs Sleep Disorder Institute, 423 West 55th Street, New York, NY 10019, USA. · Sleep Med. · Pubmed #18691937 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of ramelteon, a highly selective MT(1)/MT(2) melatonin receptor agonist, for the treatment of transient insomnia in adults. METHODS: In a randomized, double-blind, placebo-controlled, multi-center study, 289 adults naive to a sleep laboratory environment were randomized to receive a single nighttime dose of ramelteon 8 mg, 16 mg, or placebo. The primary variable was latency to persistent sleep measured by polysomnography. Additional objective and subjective sleep parameters as well as next-morning residual effects were assessed. RESULTS: Ramelteon 8 mg treatment significantly reduced latency to persistent sleep compared with placebo (12.2 min vs. 19.7 min, P=0.004). Total sleep time was significantly increased with both ramelteon 8 mg (436.8 min, P=0.009) and ramelteon 16 mg (433.1 min, P=0.043) compared with placebo (419.7 min). Ramelteon did not alter sleep architecture, and no significant next-morning residual effects were detected. The incidence of adverse events was similar for the ramelteon and placebo groups and most were considered mild or moderate. CONCLUSION: Ramelteon 8 mg significantly decreased latency to persistent sleep and increased total sleep time, with no significant next-morning psychomotor, memory, or cognitive effects in this first-night model of transient insomnia.

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.

Roth T, Zammit GK, Scharf MB, Farber R. · Sleep Disorders and Research Center, Department of Psychiatry and Behavioral Neurosciences Henry Ford Hospital, 2799 West Grand Blvd, CEP-3, Detroit, MI 48202, USA. · Sleep. · Pubmed #18246982 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and tolerability of immediate release indiplon capsules in patients with chronic insomnia using an "as-needed" dosing strategy in response to difficulty falling back to sleep following a middle of the night, nocturnal awakening. METHODS: Adult outpatients (N=264; 71% female; age, 46 years) who met DSM-IV criteria for primary insomnia, with average total sleep time (TST) < 6.5 hours and >8 nights in the past month with nocturnal awakenings, were randomized to 4 weeks of double-blind treatment with 10 mg or 20 mg indiplon capsules, or placebo. The primary endpoint was latency to sleep onset post-dosing after a middle of the night awakening (LSOpd). Secondary endpoints included patients' subjective assessment of total sleep time (sTSTpd). Next day residual effects were evaluated by a 100 mm Visual Analog Scale (VAS) rating of sleepiness. RESULTS: Both doses of indiplon significantly reduced LSOpd at all time-points. Compared to placebo (45.2 min), the 4-week least squares (LS) mean LSOpd was 36.5 min in the indiplon 10 mg group (P = 0.0023) and 34.4 min in the indiplon 20mg group (P < 0.0001). The 4-week LS mean sTSTpd was higher in the indiplon 10 mg group (253 min) and 20mg group (278 min) compared to placebo (229 min; P < 0.01 for both comparisons). There was no increase observed in VAS ratings of next-day sleepiness for either dose of indiplon when compared to placebo. Indiplon was well-tolerated at both doses. CONCLUSIONS: Patients with chronic insomnia with nocturnal awakenings achieved significant and sustained improvement in sleep parameters while utilizing an as-needed post bedtime dosing strategy with indiplon capsules. Indiplon was well-tolerated, with no self-rated, next-day residual effects.

Krystal AD, Erman M, Zammit GK, Soubrane C, Roth T, Anonymous00063. · Duke University Medical Center, Durham, NC 27710, USA. · Sleep. · Pubmed #18220081 links to  free full text

Abstract: STUDY OBJECTIVES: To evaluate long-term efficacy and safety of zolpidem extended-release 3 to 7 nights/week for chronic primary insomnia. DESIGN: Multicenter, 25-week, phase IIIb, randomized, double-blind, placebo-controlled, parallel-group. SETTING: Outpatient; visits every 4 weeks. PATIENTS: Aged 18 to 64 years; DSM-IV criteria for chronic primary insomnia; > or =3 months of difficulty initiating or maintaining sleep or experiencing nonrestorative sleep. INTERVENTIONS: Single-dose zolpidem extended-release 12.5 mg (n = 669) or placebo (n = 349), self-administered from a minimum of 3 nights/week to a maximum of 7 nights/week. MEASUREMENTS AND RESULTS: Patient's Global Impression (PGI) and Clinical Global Impression-Improvement (CGI-I) were assessed every 4 weeks up to week 24. Patient Morning Questionnaire (PMQ), recorded daily, assessed subjective sleep measures-sleep onset latency (SOL), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and quality of sleep (QOS)-and next-day functioning. At week 12, PGI, Item 1 (aid to sleep), the primary endpoint, was scored as favorable (i.e., "helped me sleep") by 89.8% of zolpidem patients vs. 51.4% of placebo patients (P < 0.0001, based on rank score) and at week 24 by 92.3% of zolpidem extended-release patients vs. 59.7% of placebo patients. Zolpidem extended-release also was statistically significantly superior to placebo at every time point for PGI (Items 1-4) and CGI-I (P < 0.0001, rank score), TST, WASO, QOS (P < 0.0001), and SOL (P < or = 0.0014); NAW (Months 2-6; P < 0.0001). Sustained improvement (P < 0.0001, all time points) was observed in morning sleepiness and ability to concentrate (P = 0.0014, month 6) with zolpidem extended-release compared with placebo. Most frequent adverse events for zolpidem extended-release were headache, anxiety and somnolence. No rebound effect was observed during the first 3 nights of discontinuation. CONCLUSIONS: These findings establish the efficacy of 3 to 7 nights per week dosing of zolpidem extended-release 12.5 mg for up to 6 months. Treatment provided sustained and significant improvements in sleep onset and maintenance and also improved next-day concentration and morning sleepiness.

Walsh JK, Soubrane C, Roth T. · Sleep Medicine and Research Center, St. John's Mercy and St. Luke's Hospitals, 232 S. Woods Hill Road, Chesterfield, MO 63017, USA. · Am J Geriatr Psychiatry. · Pubmed #18165461 No free full text.

Abstract: OBJECTIVES: To evaluate the clinical efficacy and safety of zolpidem extended release for the treatment of primary insomnia in elderly patients. METHODS: A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 +/- 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined primary insomnia patients were randomized to 3 weeks of nightly treatment with either zolpidem extended release 6.25 mg or placebo; 198 patients completed the study. RESULTS: Relative to placebo, zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups. CONCLUSIONS: Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly primary insomnia patients during three weeks of administration.

Roth T, Rogowski R, Hull S, Schwartz H, Koshorek G, Corser B, Seiden D, Lankford A. · Henri Ford Hospital, Detroit, MI 48202, USA. · Sleep. · Pubmed #18041488 links to  free full text

Abstract: STUDY OBJECTIVES: To evaluate the efficacy and safety of doxepin 1, 3, and 6 mg in insomnia patients. DESIGN: Adults (18-64 y) with chronic primary insomnia (DSM-IV) were randomly assigned to one of four sequences of 1 mg, 3 mg, and 6 mg of doxepin, and placebo in a crossover study. Treatment periods consisted of 2 polysomnographic assessment nights with a 5-day or 12-day drug-free interval between periods. Efficacy was assessed using polysomnography (PSG) and patient-reported measures. Safety analyses included measures of residual sedation and adverse events. MEASUREMENTS AND RESULTS: Sixty-seven patients were randomized. Wake time during sleep, the a priori defined primary endpoint, was statistically significantly improved at the doxepin 3 mg and 6 mg doses versus placebo. All three doses had statistically significant improvements versus placebo for PSG-defined wake after sleep onset, total sleep time, and overall sleep efficiency (SE). SE in the final third-of-the-night also demonstrated statistically significant improvement at all doses. The doxepin 6 mg dose significantly reduced subjective latency to sleep onset. All three doxepin doses had a safety profile comparable to placebo. There were no statistically significant differences in next-day residual sedation, and sleep architecture was generally clinically preserved. ConclusionS: In adults with primary insomnia, doxepin 1 mg, 3 mg, and 6 mg was well-tolerated and produced improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. The side-effect profile was comparable to placebo, with no reported anticholinergic effects, no memory impairment, and no significant hangover/next-day residual effects. These data demonstrate that doxepin 1 mg, 3 mg, and 6 mg is efficacious in improving the sleep of patients with chronic primary insomnia.

Walsh JK, Moscovitch A, Burke J, Farber R, Roth T. · Sleep Medicine and Research Center, St. John's/St. Luke's Hospitals, 232 S. Woods Mill Road, Chesterfield, St. Louis, MO 63017, USA. · Sleep Med. · Pubmed #17825616 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of indiplon in elderly patients with primary insomnia. PATIENTS AND METHODS: Elderly patients, 65-80 years (N=358; 55% female; mean age, 71 years) who met the criteria for primary insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) for three months were randomized to two weeks of double-blind nightly treatment with 5 mg or 10 mg indiplon or placebo. Daily self-assessments by the patients included latency to sleep onset (LSO), total sleep time (TST), number of awakenings (NAW), wake time after sleep onset (WASO), and sleep quality. Data were collected between July, 2002, and October, 2003, at 52 clinical research sites in North America. RESULTS: Treatment with indiplon was associated with significant reduction in LSO at Week 1 for the 5 mg (34.6+/-1.8 min) and 10 mg doses (30.4+/-1.6 min) relative to placebo (47.4+/-2.5 min; p<0.0001 for both comparisons). During Week 2, LSO remained shorter on both indiplon doses compared to placebo (5 mg, p=0.016; and 10 mg, p=0.0028). During both study weeks, treatment with indiplon was also associated with significant improvement, relative to placebo, in TST, NAW, WASO, and sleep quality. The frequency of adverse events was similar in the indiplon 5 mg and placebo groups; somnolence, nausea, depression and decreased appetite were slightly more common in the indiplon 10 mg group. CONCLUSION: In elderly patients with primary insomnia, indiplon 5 mg and 10 mg were efficacious in inducing and maintaining sleep and improving sleep quality during the two weeks of treatment. Indiplon 5mg was well-tolerated, with no serious adverse events and no significant changes in electrocardiogram (ECG) or routine clinical laboratory evaluations; the 10mg dose produced slightly greater efficacy as well as somewhat increased adverse events.

Drake CL, Scofield H, Roth T. · Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Blvd, CFP3, Detroit, MI 48202, USA. · Sleep Med. · Pubmed #17825612 links to  free full text

Abstract: BACKGROUND: The goal of this study was to determine the degree of familial aggregation in vulnerability to stress-related sleep disturbance among siblings. One approach to investigating a potential "familial" predisposition to sleep disturbance is to examine the relationship between siblings on a standard measure of vulnerability to stress-related sleep disturbance. DESIGN: Cross-sectional data on insomnia, vulnerability to stress-related sleep disturbance, sleepiness, habitual sleep, and additional demographic variables was collected separately from pairs of biological siblings. Data were collected during a 15-20min phone assessment. PARTICIPANTS: Interviews on a total of 62 individuals (31 sibling pairs) were completed. A total of 8 individuals and their respective siblings were excluded after meeting conservative criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV)-based insomnia. The mean age of the sample was 51.1+/-12.1 years (range 18-70) and habitual nightly total sleep time averaged 6.91+/-1.42h/night. RESULTS: Individuals completed the Ford Insomnia Response to Stress Test (FIRST), a standardized measure of individual vulnerability to stress-induced sleep disturbance. The intraclass correlation coefficient (ICC) was r =0.61, df=23, p =0.001 for the relationship between siblings in FIRST scores. This indicated that 37.2% of the variance in vulnerability to stress-related sleep disturbance can be accounted for by familial aggregation. This relationship remained after controlling for potential confounds including age, gender, shift schedule, and psychiatric history. CONCLUSIONS: Our data support the notion that vulnerability to stress-related sleep disturbance has a strong familial aggregation. Additional studies are needed to determine the genetic or environmental origins of this relationship and its underlying biological substrates.

Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T. · Clinilabs Sleep Disorders Institute, New York, NY 10025, USA. · J Clin Sleep Med. · Pubmed #17803013 links to  free full text

Abstract: OBJECTIVE: To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor [corrected] agonist) in subjects with chronic primary insomnia. METHODS: Randomized, multicenter, double-blind, placebo-controlled trial of nightly ramelteon treatment (8 mg or 16 mg) in adults (N=405) with primary chronic insomnia (DSM-IV-TR). Latency to persistent sleep (LPS), TST, sleep efficiency, wake time after sleep onset, and number of awakenings were measured by polysomnography. Subject-reported measures were also assessed. RESULTS: LPS at Week 1 (primary measure) was significantly shorter with ramelteon 8 mg (32.2 min) or 16 mg (28.9 min) vs placebo (47.9 min; p <0.001). Significant improvements in LPS were maintained at Weeks 3 and 5. TST was significantly longer with both doses of ramelteon at Week 1 (p <0.001) vs placebo. Subject-reported sleep latency was significantly shorter with ramelteon 8 mg at Weeks 1, 3, and 5 (p <0.001) and ramelteon 16 mg at Weeks 1 and 3 (p < or =0.050) vs placebo. Wake time after sleep onset and number of awakenings were not significantly different with ramelteon 8 mg or 16 mg treatment vs placebo. Subjective TST was significantly longer with ramelteon 8 mg at Weeks 1, 3, and 5 (p < or =0.050) and ramelteon 16 mg at Week 1 (p = 0.003) vs placebo. Ramelteon had no clinically meaningful effect on sleep architecture, next-morning psychomotor tasks, alertness, or ability to concentrate. No withdrawal or rebound effects were observed. CONCLUSIONS: Ramelteon reduced LPS over 5 weeks of treatment in subjects with chronic insomnia, with no clinically meaningful sleep architecture alterations, next-morning residual pharmacologic effects, and no evidence of rebound insomnia or withdrawal. No numerical differences were observed between the 2 doses of ramelteon.

Walsh JK, Krystal AD, Amato DA, Rubens R, Caron J, Wessel TC, Schaefer K, Roach J, Wallenstein G, Roth T. · Sleep Medicine and Research Center, St. John's/St. Luke's Hospitals and the Department of Psychology, Saint Louis University, St. Louis, MO 63017, USA. · Sleep. · Pubmed #17702264 links to  free full text

Abstract: STUDY OBJECTIVES: To evaluate 6 months' eszopiclone treatment upon patient-reported sleep, fatigue and sleepiness, insomnia severity, quality of life, and work limitations. DESIGN: Randomized, double blind, controlled clinical trial. SETTING: 54 research sites in the U.S. PATIENTS: 830 primary insomnia patients who reported mean nightly total sleep time (TST) < or = 6.5 hours/night and/or mean nightly sleep latency (SL) >30 min. INTERVENTION: Eszopiclone 3 mg or matching placebo. MEASUREMENTS: Patient-reported sleep measures, Insomnia Severity Index, Medical Outcomes Study Short-Form Health Survey (SF-36), Work Limitations Questionnaire, and other assessments measured during baseline, treatment Months 1-6, and 2 weeks following discontinuation of treatment. RESULTS: Patient-reported sleep and daytime function were improved more with eszopiclone than with placebo at all months (P <0.001). Eszopiclone reduced Insomnia Severity Index scores to below clinically meaningful levels for 50% of patients (vs 19% with placebo; P <0.05) at Month 6. SF-36 domains of Physical Functioning, Vitality, and Social Functioning were improved with eszopiclone vs placebo for the Month 1-6 average (P < 0.05). Similarly, improvements were observed for all domains of the Work Limitations Questionnaire with eszopiclone vs placebo for the Month 1-6 average (P <0.05). CONCLUSIONS: This is the first placebo-controlled investigation to demonstrate that long-term nightly pharmacologic treatment of primary insomnia with any hypnotic enhanced quality of life, reduced work limitations, and reduced global insomnia severity, in addition to improving patient-reported sleep variables.

Rosenberg R, Roth T, Scharf MB, Lankford DA, Farber R. · Atlanta Sleep Institute, Atlanta, GA 30342, USA. · J Clin Sleep Med. · Pubmed #17694726 links to  free full text

Abstract: OBJECTIVE: The efficacy of indiplon was evaluated by polysomnography (PSG) in an experimental model of transient insomnia consisting of the first night effect combined with a 2-hour phase advance. METHODS: Healthy volunteers age 21-64 years (N=593; 62% female; mean +/- SEM) years, 32 +/- 0.39) were randomized to double-blind treatment with a single nighttime dose of indiplon (10 mg or 20 mg) or placebo. PSG assessments included latency to persistent sleep (LPS, primary endpoint) and total sleep time (TST); self-report assessments included sleep quality (SQ); next day residual effects were evaluated by the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), and a Visual Analog Scale of sleepiness (VAS). RESULTS: LPS mean (+/- SEM) values were significantly reduced on indiplon 10 mg (21.2 +/- 1.5 minutes) and indiplon 20 mg (16.8 +/- 1.1 minutes) compared to placebo (33.1 +/- 2.5 minutes; p < 0.0001 for both comparisons to placebo). TST mean (+/- SEM) values were significantly increased on indiplon 10 mg (414.5 +/- 3.9 minutes) and indiplon 20 mg (423.5 +/- 3.1 minutes) compared to placebo (402.9 +/- 3.9 minutes; p <0.005 for the 10 mg dose; p < 0.0001 for the 20 mg dose). SQ was also significantly improved on both doses. There were no differences between indiplon and placebo on next day DSST, SCT, or VAS. CONCLUSIONS: Indiplon was effective in inducing sleep, increasing sleep duration, and improving overall sleep quality without next day residual effects in healthy volunteers in a model of transient insomnia.

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.

Roth T. · Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, MI 48202, USA. · J Clin Psychiatry. · Pubmed #17539702 No free full text.

This publication has no abstract.

Roth T, Seiden D, Wang-Weigand S, Zhang J. · Sleep Disorders and Research Center, Detroit, MI 48202, USA. · Curr Med Res Opin. · Pubmed #17519067 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of ramelteon, a selective melatonin MT1/MT2-receptor agonist, for insomnia treatment in older adults. METHODS: In a randomized, 9-week, 3-period crossover trial conducted at 17 sleep centers, older adults (N = 100) with chronic primary insomnia (37 men, 63 women; mean age [range], 70.7 [65-83] years) were administered placebo, ramelteon 4 mg, and ramelteon 8 mg in three treatment phases for two consecutive nights. Each phase was separated by 5- to 12-day washout periods. Sleep was monitored via polysomnography. Subjective sleep parameters, using a Postsleep Questionnaire, were recorded, and residual pharmacologic effects were assessed. RESULTS: Statistically significant reductions in latency to persistent sleep were observed with both ramelteon 4 mg and 8 mg compared to placebo (28.7 min vs. 38.4 min, p < 0.001; 30.8 min vs. 38.4 min, p = 0.005, respectively). Total sleep time (p = 0.036 and p = 0.007, respectively) and sleep efficiency (p = 0.037 and p = 0.007, respectively) were also significantly improved with ramelteon 4 mg and 8 mg compared to placebo. Statistically significant reductions in subjective sleep latency on a Postsleep Questionnaire were reported with ramelteon 4 mg versus placebo (p = 0.037), but not ramelteon 8 mg (p = 0.120); no significant differences on other subjective sleep assessments were reported. A lack of power limits interpretation of self-reported sleep parameters. Incidences of adverse events considered treatment related were placebo (7%), ramelteon 4 mg (11%), and ramelteon 8 mg (5%). No residual pharmacologic effects were observed via Digit Symbol Substitution Test, memory recall tests (immediate and delayed), visual analog scales (feelings and mood), and Postsleep Questionnaire (level of alertness and ability to concentrate). CONCLUSIONS: In older adults with chronic primary insomnia, ramelteon produced significant reductions in latency to persistent sleep and increases in total sleep time and sleep efficacy, and showed no evidence of adverse next-day psychomotor or cognitive effects.

Kryger M, Wang-Weigand S, Roth T. · Gaylord Hospital, Sleep Research and Education, 400 Gaylord Farm Road, Wallingford, CT 06492, USA. · Sleep Breath. · Pubmed #17294232 No free full text.

Abstract: Ramelteon is a selective MT(1)/MT(2)-receptor agonist indicated for insomnia treatment. Because it has no depressant effects on the nervous system, it is not expected to affect the control of breathing. The potential effects of ramelteon on apneic and hypopneic events and arterial oxygen saturation (SaO(2)) in individuals with obstructive sleep apnea were assessed. In this double-blind, randomized, crossover study, 26 adults with mild to moderate obstructive sleep apnea received ramelteon 16 mg and placebo for one night each, with a 5- to 12-day washout period between treatments. Treatments were administered 30 min before habitual bedtime. Respiratory effort was monitored using respiratory inductance plethysmography, SaO(2) was measured by pulse oximetry, and sleep onset and duration were measured by polysomnography and post-sleep questionnaire. Post-sleep questionnaire also measured next-day residual effects. The primary measure was apnea-hypopnea index. Apnea-hypopnea index was similar in ramelteon and placebo groups (11.4 vs 11.1, respectively; CI = -2.1, 2.6, P = 0.812). Ramelteon had no effect on the number of central, obstructive, or mixed apnea episodes. No significant differences were observed in SaO(2) for the entire night between ramelteon and placebo (95.1 vs 94.7%; P = 0.070). Ramelteon did not meaningfully affect sleep when evaluated by polysomnography and post-sleep questionnaire. Compared with placebo, ramelteon had no significant effect on next-day residual effects. Adverse events were reported by three subjects in the ramelteon group: headache (n = 2) and urinary tract infection (n = 1). No adverse events were reported with placebo. Ramelteon was well-tolerated and, as expected, did not worsen sleep apnea when administered to subjects with mild to moderate obstructive sleep apnea.

Soares CN, Joffe H, Rubens R, Caron J, Roth T, Cohen L. · Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, Canada, and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. · Obstet Gynecol. · Pubmed #17138773 No free full text.

Abstract: OBJECTIVE: To evaluate eszopiclone 3 mg for treatment of insomnia in perimenopausal and early postmenopausal women, as well as the impact of insomnia treatment on mood, menopause-related symptoms, and quality of life. METHODS: This was a double-blind, placebo-controlled study with 410 women (aged 40-60; perimenopausal or early postmenopausal) who reported insomnia defined as sleep latency of at least 45 minutes and total sleep time less than or equal to 6 hours per night for at least 3 nights per week over the previous month. Patients were randomly assigned to eszopiclone 3 mg or placebo nightly for 4 weeks. Sleep data were collected once a day. Physician global assessments of menopause, menopause-specific questionnaire, Greene Climacteric Scale, the Montgomery Asberg Depression Rating Scale, and the Sheehan Disability Scale were collected at baseline and end of treatment. RESULTS: Patients receiving eszopiclone reported improvements in sleep induction, sleep maintenance, sleep duration, sleep quality, and next-day functioning relative to placebo (P<.05). Patients receiving eszopiclone reported fewer total awakenings and awakenings due to hot flushes (P<.05). Eszopiclone use led to greater improvement in Montgomery Asberg Depression Rating Scale scores (P<.05) and physician global assessments of menopause scores (P<.001); total Greene Climacteric Scale score and the vasomotor and psychological sub-scores (P<.05); vasomotor and physical domains of the menopause-specific questionnaire (P<.05); and family life/home domain of the Sheehan Disability Scale (P<.05). CONCLUSION: In this study, eszopiclone provided significant improvements in sleep and positively impacted mood, quality of life, and menopause-related symptoms in perimenopausal and early postmenopausal women with insomnia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00366093 LEVEL OF EVIDENCE: I.