Antidepressants for insomnia in adults

Background Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments. Objectives To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults. Search methods This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review. Selection criteria Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual. Data collection and analysis Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction. Main results The search identified 23 RCTs (2806 participants). Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence). There were either no adverse events or they were not reported (very low quality evidence). Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants). There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence). 'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence). There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst). Authors' conclusions We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a 2-week randomized outpatient trial

BACKGROUND: Esmirtazapine (Org 50081), a high-affinity antagonist at 5-HT2A and H1 receptors, was assessed for its hypnotic efficacy. METHODS: In this double-blind, randomized study, non-elderly patients with primary insomnia (but otherwise healthy) were treated with esmirtazapine (1.5, 3.0, or 4.5 mg) or placebo for two weeks. The primary end point was patient-reported total sleep time (TST); other patient-reported end points included sleep latency (SL), wake time after sleep onset (WASO), number of awakenings, sleep quality, and satisfaction with sleep duration. Measures to assess the potential adverse effects of treatment included morning alertness, daytime function/napping, and rebound insomnia during a single-blind placebo run-out week after treatment ended. Adverse events (AEs) were also assessed. RESULTS: Overall, 526 patients were randomized and 463 (88%) completed treatment. All esmirtazapine doses significantly improved TST, SL, sleep quality, and satisfaction with sleep duration versus placebo. Relative to placebo, TST was increased by 30-40 min and SL decreased by ~12 min for all doses. The highest dose (4.5 mg) also significantly reduced WASO and number of awakenings. Across doses, AEs occurred in 25.5-32.8% of patients, compared with 20.7% with placebo. The most common AE was somnolence (~10% for esmirtazapine and 2% for placebo). The incidence of AEs leading to discontinuation was low (≤7%), and there were no serious drug-related AEs. Finally, there was no evidence of a rebound insomnia after discontinuation of esmirtazapine. CONCLUSIONS: Two weeks of treatment with esmirtazapine consistently and significantly improved patient-reported sleep parameters, and it was well tolerated in patients with primary insomnia

Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial

OBJECTIVE: Esmirtazapine (Org 50081), a medication that binds with high affinity to serotonin 5-HT2A and histamine-1 receptors, was evaluated as a potential treatment for insomnia. METHODS: Adults with primary insomnia were treated with esmirtazapine (3.0 or 4.5 mg) or placebo in this 6-week, double-blind, randomized, polysomnography (PSG) study. The end points included wake time after sleep onset (WASO) (primary), latency to persistent sleep, and total sleep time. Patient-reported parameters were also evaluated, including sleep quality and satisfaction with sleep duration. Residual daytime effects and rebound insomnia (sleep parameters during the single-blind placebo run-out week after treatment ended) were also assessed. RESULTS: Overall, 419 patients were randomized and 366 (87%) completed treatment. The median decrease in PSG WASO (double-blind average) was 20.5 min for placebo, and 52.0 min and 53.6 min for the 3.0- and 4.5-mg esmirtazapine groups, respectively (P \u3c 0.0001 vs. placebo for both doses). Changes in the other PSG parameters and in all patient-reported parameters were also statistically significant with both doses versus placebo. Overall, 35-42% of esmirtazapine-treated patients had adverse events (AEs) versus 29% in the placebo group. AEs were mild or moderate in most esmirtazapine-treated patients. Furthermore, the incidence of AEs leading to discontinuation was low (\u3c8%). CONCLUSIONS: Six weeks of treatment with esmirtazapine was associated with consistent improvements in objective and patient-reported parameters of sleep onset, maintenance, and duration. It was generally well tolerated, and residual daytime effects were minimal and no rebound insomnia was observed

A Phase 2 Randomized Dose-Finding Study With Esmirtazapine in Patients With Primary Insomnia

The antidepressant mirtazapine is an alternative to classical hypnotics, and this study investigated the efficacy and safety of esmirtazapine (Org 50081, the maleic acid salt of S-mirtazapine) in patients given a diagnosis of primary insomnia after acute (2-day) treatment. Patients aged 18 to 65 years with primary insomnia were randomized to receive placebo or 1.5-, 3.0-, or 4.5-mg esmirtazapine in a balanced 4-way crossover study; 2 sleep laboratory nights with polysomnography were separated by 5-day, single-blind placebo washout periods. Polysomnography-determined total sleep time (primary end point) and patient-reported total sleep time improved by at least 25 minutes with all 3 doses of esmirtazapine (P ≤ 0.001 vs placebo). Polysomnography-measured wake time after sleep onset (P ≤ 0.0001) and latency to persistent sleep also improved vs placebo (P ≤ 0.01, 3.0 and 4.5 mg). Patient-reported sleep quality improved with 3.0- and 4.5-mg esmirtazapine (P ≤ 0.01 and P ≤ 0.05, respectively, vs placebo). Morning alertness and contentment were not altered after esmirtazapine, and calmness increased with 4.5-mg esmirtazapine vs placebo. Evening questionnaires showed no difference in duration of daytime naps but reduced energy and ability to work/function after esmirtazapine treatment periods vs placebo (P \u3c 0.05), although this effect was limited to the first night of each 2-night period. There were few adverse events, no serious adverse events, or clinically relevant treatment differences in vital signs, laboratory values, or electrocardiogram. Esmirtazapine doses of 1.5 to 4.5 mg/day significantly improved quantity and quality of sleep and were generally well tolerated, with no evidence of safety concerns or consistent pattern of residual effects

Efficacy and safety of esmirtazapine in adult outpatients with chronic primary insomnia: a randomized, double-blind placebo-controlled study, and open-label extension

STUDY OBJECTIVES: Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in non-elderly outpatients with chronic insomnia. This Phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia. METHODS: Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then re-randomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine versus placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively. RESULTS: Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n=342; placebo, n=115) and 184 participants (prior esmirtazapine, n=136; prior placebo, n=48) received esmirtazapine in the extension. In the double-blind study, a 48.7-min increase in average nightly total sleep time was observed for esmirtazapine versus placebo (95% confidence interval 35.0, 62.5; P\u3c.0001) at Months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning, and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events. CONCLUSIONS: Esmirtazapine improved sleep duration versus placebo over at least 6 months. There was no evidence of next-day residual effects, or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation

Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials

BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2. RESULTS: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated