indiplon and Sleep-Initiation-and-Maintenance-Disorders

Topics: Animals; Azabicyclo Compounds; Benzodiazepines; Diphenhydramine; Drug Design; Fluorobenzenes; GABA-A Receptor Agonists; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Indenes; Orexin Receptors; Phenols; Piperazines; Pyridines; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Serotonin 5-HT2 Receptor Antagonists; Sleep Initiation and Maintenance Disorders; Thiophenes; Zolpidem

Indiplon is a novel non-benzodiazepine sedative-hypnotic that modulates the GABAA receptor complex. It appears to be more selective for the alpha1-receptor subunit, associated with sedation, than other hypnotics. Two different formulations of indiplon have been developed: an immediate release (IR) version targeting sleep onset insomnia and a modified release (MR) version addressing sleep maintenance insomnia. Early results from clinical trials indicate that both formulations are well tolerated and effective at improving both objective and subjective measures of sleep. As of May 2006 indiplon-IR has been provisionally approved for use in the US market and discussions are continuing with the FDA regarding the MR formulation.

Topics: Adult; Benzodiazepines; Delayed-Action Preparations; Drug Interactions; Female; Humans; Hypnotics and Sedatives; Male; Sleep Initiation and Maintenance Disorders; Thiophenes; Treatment Outcome

Insomnia is a prevalent problem in late life. Sleep problems in the elderly are often mistakenly considered a normal part of aging. Insomnia, the most common sleep disorder, is a subjective report of insufficient or nonrestorative sleep despite adequate opportunity to sleep. Despite the fact that more than 50% of elderly people have insomnia, it is typically undertreated, and nonpharmacologic interventions are underused by health care practitioners. This article will review the causes of insomnia in the elderly, the approach to patient evaluation, and the nonpharmacologic and pharmacologic treatment of insomnia.

Topics: Acetamides; Aged; Aging; Antidepressive Agents; Azabicyclo Compounds; Behavior Therapy; Benzodiazepines; Humans; Hypnotics and Sedatives; Nonprescription Drugs; Piperazines; Pyridines; Pyrimidines; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Sleep; Sleep Initiation and Maintenance Disorders; Sleep, REM; Thiophenes; Trazodone; Zolpidem

Indiplon is a short-acting hypnotic that is currently being developed as a treatment for insomnia by Neurocrine Biosciences and Pfizer, and is expected to be marketed in mid-2006. It is a high-affinity allosteric potentiator of GABAA responses that demonstrates preference for alpha1 subunit-containing GABAA receptors. Indiplon will be an addition to the general category of newer-generation hypnotics that now includes zaleplon, zolpidem, zopiclone and eszopiclone. Clinical trials were carried out with an immediate-release capsule and a modified-release tablet and demonstrate very positive efficacy and safety profiles. The major challenge will be developing a commercial success in the crowded insomnia treatment marketplace.

Topics: Animals; Benzodiazepines; Drugs, Investigational; Humans; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Thiophenes

To assess the effects of post-bedtime dosing with indiplon on next-day function in adults and the elderly.. Two randomized, double-blind, placebo-controlled crossover studies were conducted in two groups of healthy volunteers: an adult study (18-45 years) and an elderly study (65-80 years). In adults, a single post-bedtime dose of indiplon 10 mg and 20 mg was compared to placebo, with zolpidem 10 mg and zopiclone 7.5 mg included as controls. In the elderly, a single post-bedtime dose of indiplon 5 mg and 10 mg was compared to placebo, with zopiclone 3.75 mg included as a control. Next-day residual effects were evaluated in the morning at 4 and 6 h post-dose in adults, and 4, 6, and 8 h in the elderly, by a Visual Analog Scale of sleepiness (VAS-sleepiness), Digit Symbol Substitution Test (DSST), and the Symbol Copying Test (SCT).. In adults, there were no statistically significant differences between indiplon and placebo on the VAS-sleepiness, DSST, or SCT at any time-point for either dose. In contrast, a significant increase versus placebo in VAS-sleepiness was observed for both zopiclone (at 4 and 6 h post-dose; p < 0.0001 and p = 0.002, respectively) and zolpidem (at 4 h post-dose; p = 0.042). In the elderly, there were no statistically significant differences between indiplon 5 mg and placebo on the VAS-sleepiness, DSST, or SCT at any time-point. DSST was significantly reduced for indiplon 10 mg versus placebo at 4 h only (p = 0.022), compared with a significant reduction in DSST for zopiclone at both 4 and 8 h post-dose (p = 0.002 and p = 0.003, respectively). In adults, the overall incidence of adverse events was higher on zopiclone compared to indiplon, zolpidem, and placebo. In the elderly, the incidence of adverse events was similar for indiplon, zopiclone, and placebo. Potential limitations of the current study include recruitment of healthy volunteers and the use of a limited pharmacodynamic battery.. Indiplon, at doses of 10 mg in adults and 5 mg in the elderly, was not associated with next day residual sedation or impairment in simple cognitive and psychomotor tasks when administered during the night 4 h prior to awakening.

Topics: Adult; Aged; Aged, 80 and over; Azabicyclo Compounds; Benzodiazepines; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Pain Measurement; Piperazines; Psychological Tests; Psychometrics; Pyridines; Reference Values; Sleep Initiation and Maintenance Disorders; Thiophenes; Time Factors; Zolpidem

To evaluate the efficacy and safety of indiplon in primary insomnia.. Randomized, double-blind, placebo-controlled, 3-month study.. Multi-center outpatient setting.. N=702 (61% female; mean age 46 years) who met DSM-IV criteria for primary insomnia of at least 3 months' duration.. Indiplon 10 mg (n=236), indiplon 20 mg (n=233), or placebo (n=233).. Subjective assessment of each of the following: latency to sleep onset (sLSO), total sleep time (sTST), number of awakenings after sleep onset (sNAASO), wake time after sleep onset (sWASO), sleep quality, Insomnia Severity Index (ISI), and global improvement.. Treatment with indiplon resulted in significant improvement relative to placebo at all time points for the primary endpoint, sLSO. Mean sLSO at Month 1 for each treatment group was: 10 mg (34.0 +/- 1.3 mins), 20 mg (33.0 +/- 1.3 mins), and placebo (48.7 +/- 1.9 mins; P <0.0001 for both comparisons); efficacy was sustained through Month 3. Both doses of indiplon resulted in significant improvement in sleep maintenance and duration endpoints, sTST and sWASO, as well as sleep quality, ISI, and global improvement at all assessment time points.. In patients with chronic insomnia, long-term nightly treatment with 10 mg and 20 mg doses of indiplon resulted in significant and sustained efficacy in sleep onset, maintenance, and duration, and significant associated improvement in both daytime functioning and quality of life.

Topics: Adult; Benzodiazepines; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Polysomnography; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Thiophenes; Time Factors

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.. 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).. 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.. 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.

Topics: Adult; Analysis of Variance; Benzodiazepines; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Polysomnography; Reference Values; Self Disclosure; Sleep Initiation and Maintenance Disorders; Thiophenes; Time Factors; Treatment Outcome

To evaluate the efficacy and safety of indiplon in elderly patients with primary insomnia.. 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.. 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.. 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.

Topics: Aged; Aged, 80 and over; Benzodiazepines; Diagnostic and Statistical Manual of Mental Disorders; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Electrocardiography; Female; Humans; Hypnotics and Sedatives; Male; Single-Blind Method; Sleep Initiation and Maintenance Disorders; Thiophenes; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Attention; Benzodiazepines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Pain Measurement; Patient Satisfaction; Sleep Initiation and Maintenance Disorders; Thiophenes; Treatment Outcome; Wakefulness

Indiplon is a nonbenzodiazepine GABA potentiator, which exhibits pharmacologic selectivity for GABA(A) receptors containing the alpha1 subunit. The aim of the present study was to evaluate the efficacy and safety of a 15-mg nightly dose of modified-release indiplon tablets in elderly patients with primary insomnia characterized by sleep-maintenance difficulties.. Two hundred twenty-nine elderly patients, aged 65 to 85 years, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for primary insomnia were randomly assigned to 2 weeks of nightly treatment with either indiplon, 15 mg, or placebo in a double-blind, parallel-group design. Daily sleep diaries were completed to collect patient reports of subjective total sleep time, wake time after sleep onset, number of awakenings after sleep-onset, latency to sleep onset, and sleep quality. Patient global impression ratings of various parameters of sleep were assessed on a weekly basis.. The least square mean total sleep time was significantly improved with indiplon versus placebo at week 1 (377 +/- 4 min vs. 328 +/- 4 min; p < .0001) and week 2 (373 +/- 5 min vs. 337 +/- 5 min; p < .0001). Indiplon also significantly improved subjective wake after sleep onset, subjective number of awakenings after sleep onset, subjective sleep-onset latency, sleep quality, and patient global impression ratings of sleep at both weeks 1 and 2. The number and severity of adverse events and rates of discontinuation due to adverse effects were comparable in the indiplon and placebo groups.. In elderly patients with primary insomnia characterized by sleep-maintenance difficulty, indiplon, 15 mg, was well tolerated and significantly improved all patient-reported measures of sleep during 2 weeks of treatment.

Topics: Aged; Benzodiazepines; Chronic Disease; Delayed-Action Preparations; Double-Blind Method; Drug Tolerance; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Sleep Initiation and Maintenance Disorders; Thiophenes

To review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and adverse effects of indiplon in the treatment of transient and chronic insomnia in adult and geriatric patients.. A literature search was conducted using MEDLINE (1966-May 2008), International Pharmaceutical Abstracts (1970-May 2008), and Cochrane database (2007) for the key words indiplon or NBI-34060. References cited in the articles were reviewed for additional information. Abstract data were included only in the absence of significant published data.. English-language literature reporting animal and human clinical studies was reviewed to evaluate data on the pharmacology, pharmacokinetics, pharmacodynamics, efficacy, and adverse effects of indiplon. Clinical trials selected for inclusion were limited to those with human subjects, with the accepted inclusion of pharmacology data in animals.. Indiplon is a nonbenzodiazepine sedative-hypnotic that exhibits its sedating activity through its interaction with the gamma-aminobutyric acid alpha receptor complex. Indiplon immediate-release (IR) as well as modified-release (MR) forms have shown improvement compared with placebo in patients with DSM-IV-TR primary insomnia in various areas of subjective and objective sleep measurements. Specifically, improvements in total sleep time, latency to persistent sleep, latency to sleep onset, wake after sleep onset, and sleep quality have been noted in clinical trials. Trials evaluating both indiplon IR and MR have so far not identified any major serious adverse effects.. Limited clinical trial data exist on use of indiplon in a "true" transient insomnia patient population. Based on recent Food and Drug Administration requests, clinical trial data assessing direct comparisons of indiplon IR with other approved nonbenzodiazepine sedative-hypnotics are needed to clearly define the differences among these agents.

Topics: Adult; Aged; Animals; Benzodiazepines; Humans; Hypnotics and Sedatives; Receptors, GABA-A; Sleep; Sleep Initiation and Maintenance Disorders; Thiophenes

Topics: Benzodiazepines; Central Nervous System; Clinical Trials as Topic; Delayed-Action Preparations; Humans; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Thiophenes

Topics: Benzodiazepines; Clinical Trials as Topic; Delayed-Action Preparations; Drug Industry; Hypnotics and Sedatives; Sleep Initiation and Maintenance Disorders; Thiophenes