Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled, active comparator crossover studies in healthy volunteers.
ABSTRACT 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.
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ABSTRACT: Although difficulty maintaining sleep (DMS) is the most common nighttime insomnia symptom among US adults, many FDA-approved hypnotics have indications only for sleep onset, stipulating bedtime administration to offset residual sedation. Given the well-known self-medication tendencies of insomniacs, concern arises that maintenance insomniacs might be prone to self-administer their prescribed hypnotics middle-of-the-night (MOTN) after nocturnal awakenings, despite little efficacy-safety data supporting such use. However, no US data characterize the actual population prevalence or correlates of MOTN hypnotic use. Telephone interviews assessed patterns of prescription hypnotic use in a national sample of 1,927 commercial health plan members (ages 18-64) receiving prescription hypnotics within 12 months of study. The Brief Insomnia Questionnaire assessed insomnia symptoms. 20.2% of respondents reported MOTN hypnotic use, including 9.0% who sometimes used twice-per-night (once at bedtime plus once MOTN) and another 11.2% who sometimes used MOTN, but never twice-per-night. The remaining 79.8% used exclusively at bedtime. Among exclusive MOTN users, only 14.0% used MOTN on the advice of their physician (52.6% of those seen by sleep medicine specialists and 42.6% by psychiatrists vs. 5.2% to 13.6% seen by other physicians). MOTN use predictors included DMS being the most bothersome sleep problem, long duration of hypnotic use, and low frequency of DMS. One-fifth of patients with prescription hypnotics used MOTN, only a minority on advice from their physicians. Since significant next-day cognitive and psychomotor impairment is documented with off-label MOTN hypnotic use, prescribing physicians should question patients about unsupervised MOTN dosing. Roth T; Berglund P; Shahly V; Shillington AC; Stephenson JJ; Kessler RC. Middle-of-the-night hypnotic use in a large national health plan. J Clin Sleep Med 2013;9(7):661-668.Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 01/2013; 9(7):661-8. DOI:10.5664/jcsm.2832 · 2.93 Impact Factor
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ABSTRACT: Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal’s state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (~65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders.PLoS ONE 11/2014; 9(11):e112068. DOI:10.1371/journal.pone.0112068 · 3.53 Impact Factor
Revista Brasileira de Psiquiatria 01/2010; 32(3):288-293. · 1.64 Impact Factor