Hypnotic and Melatonin/Melatonin-Receptor Agonist Treatment in Bipolar Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Bipolar disorder (BD) is a chronic relapsing-remitting psychiatric disorder. Sleep and circadian rhythm disturbances persist during acute mood episodes of the disorder and during euthymia. However, the treatment potential of hypnotic agents that might be used to manage sleep disturbance in BD is not well understood. Similarly, melatonin and medications with a melatonin-receptor agonist mechanism of action may have chronotherapeutic potential for treating people with the disorder, but the impact of these substances on sleep and circadian rhythms and core symptoms in BD is unclear. OBJECTIVE: Our aim was to conduct a systematic review and meta-analysis evaluating the current evidence for hypnotic and melatonin/melatonin-receptor agonist pharmacotherapy for symptoms of sleep disturbance, mania, and depression in patients with BD. METHODS: AMED, Embase, MEDLINE and PsychINFO databases were searched for studies published in English from the date of inception to 31 October 2021. Studies included in this review were randomised controlled trials (RCTs) and non-controlled/non-randomised studies for BD that examined hypnotic medications selected based on a common pattern of usage for treating insomnia (i.e. chloral, clomethiazole, diphenhydramine, doxepin, doxylamine, promethazine, suvorexant, zaleplon, zolpidem, zopiclone, and eszopiclone) and melatonin and the melatonin-receptor agonist drugs ramelteon and agomelatine. Risk of bias was assessed using the RoB2 and AXIS tools. Pooled effect sizes for RCT outcomes were estimated using random-effects models. RESULTS: A total of eleven studies (six RCTs and five experimental feasibility studies) involving 1279 participants were included. Each study examined melatonin or melatonin-receptor agonists. No studies of hypnotics were found that fulfilled the review inclusion criteria. Pilot feasibility studies suggested beneficial treatment effects for symptoms of sleep disturbance, depression, and mania. However, the pooled effect of the two available RCT studies assessing sleep quality via Pittsburgh Sleep Quality Index scores was not statistically significant (g = - 0.04 [95% CI - 0.81 to 0.73]) and neither was the pooled effect for depressive symptoms (four studies; g = - 0.10 [95% CI - 0.27 to 0.08]). Some RCT evidence suggests ramelteon might prevent relapse into depression in BD. The largest efficacy signal detected was for manic symptoms (four studies; g = - 0.44 [95% CI - 1.03 to 0.14]) but there was substantial heterogeneity between studies and patient characteristics. In the two RCTs assessing manic symptoms during acute mania, adjunctive melatonin demonstrated superior treatment effects versus placebo. CONCLUSIONS: There is a paucity of studies examining pharmacological interventions for sleep and circadian rhythm disturbance in BD. Few studies assessed sleep-related symptoms, and none quantitatively examined endogenous melatonin patterns or other circadian rhythms. Melatonin may be a promising candidate for the adjunctive treatment of bipolar mania. However, dose-finding studies and studies with larger sample sizes are needed to confirm its efficacy. We recommend parallel monitoring of sleep and circadian rhythms in future trials. Chronobiology-informed trial designs are needed to improve the quality of future studies. PROTOCOL REGISTRATION: PROSPERO (CRD42020167528).

Psychological and behavioural interventions in bipolar disorder that target sleep and circadian rhythms: A systematic review of randomised controlled trials.

Sleep and circadian disruptions are prominent symptoms of bipolar disorder (BD) and potential targets for adjunctive interventions. The aim of this review was to appraise the effectiveness of psychological and behavioural interventions in BD that target sleep and circadian rhythms, as reported by randomised controlled trials. Nineteen studies met the inclusion/exclusion criteria. They were summarised via narrative synthesis and meta-analysis wherever appropriate. Six studies delivered bright light therapy, five interpersonal and social rhythm therapy, two blue-light blocking glasses, one cognitive behavioural therapy for insomnia, one total sleep deprivation, and four combination treatments. More than half of the studies (N = 10, 52 %) did not measure sleep or circadian rhythms despite being the principal target of the intervention. Overall, the evidence base for the effectiveness of these interventions was limited. There was a small number of studies for each intervention, and a lack of consistency in protocols and outcomes. Meta-analysis was possible for the effect of bright light therapy on depression, revealing a medium-to-large post-treatment effect (Nc = 6; g=-0.74 [95 % CI=-1.05 to -0.42], p < 0.001).

The acute effects of sleep restriction therapy for insomnia on circadian timing and vigilance.

Sleep-restriction therapy (SRT) has been shown to improve insomnia symptoms by restricting sleep opportunity. Curtailment of time in bed affects the duration and consolidation of sleep, but also its timing. While recent work suggests that people with insomnia are characterised by misalignment between circadian and behavioural timing of sleep, no study has investigated if SRT modifies this relationship. The primary aim of the present study was to examine change in phase angle after 2 weeks of SRT. As a secondary aim, we also sought to assess the effect of SRT on psychomotor vigilance. Following a 1-week baseline phase, participants implemented SRT for 2 consecutive weeks. Phase angle was derived from the difference between the decimal clock time of dim light melatonin onset (DLMO) and attempted sleep time. Secondary outcomes included vigilance (assessed via hourly measurement during the DLMO laboratory protocol), sleep continuity (assessed via sleep diary and actigraphy), and insomnia severity. Eighteen participants meeting insomnia criteria (mean [SD] age 37.06 [8.99] years) took part in the study. Consistent with previous research, participants showed robust improvements in subjective and objective sleep continuity, as well as reductions in insomnia severity. The primary outcome (phase angle) was measurable in 15 participants and revealed an increase of 34.8 min (~0.58 hr; 95% confidence interval [CI] 0.01-1.15) from baseline to post-treatment (mean [SD] 2.27 [0.94] versus 2.85 [1.25] hr). DLMO remained relatively stable (20:49 versus 21:01 hours), while attempted sleep was 46.8 min later (~0.78 hr; 95%CI 0.41-1.15; 23:05 versus 23:52 hours). For psychomotor vigilance, reaction time was delayed (by 52.71 ms, 95% CI 34.44-70.97) and number of lapses increased (by 5.84, 95% CI 3.93-7.75) after SRT. We show that SRT increases phase angle during treatment, principally by delaying the timing of sleep attempt. Future studies are needed to test if an increase in phase angle is linked to clinical improvement. Finally, reduction in vigilance after SRT appears to be of similar magnitude to normal sleepers undergoing experimental sleep restriction, reinforcing the importance of appropriate safety advice during implementation.

The effects of digital cognitive behavioral therapy for insomnia on cognitive function: a randomized controlled trial.

STUDY OBJECTIVES: We sought to examine the impact of digital cognitive behavioral therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance. METHODS: The Defining the Impact of Sleep improvement on Cognitive Outcomes (DISCO) trial was an online, two-arm, single-blind, randomized clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder, and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomization. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression, and anxiety. RESULTS: Four hundred and ten participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomization the estimated adjusted mean difference for the BC-CCI was -3.03 (95% CI: -3.60, -2.47; p < 0.0001, d = -0.86), indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = -0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favor of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences in objective tests of cognitive performance. CONCLUSIONS: Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months.

Cognitive behavioral therapy for insomnia: A meta-analysis of long-term effects in controlled studies.

Cognitive behavioral therapy for insomnia (CBT-I) is a treatment with moderate to large effects. These effects are believed to be sustained long-term, but no systematic meta-analyses of recent evidence exist. In this present meta-analysis, we investigate long-term effects in 30 randomized controlled trials (RCTs) comparing CBT-I to non-active control groups. The primary analyses (n = 29 after excluding one study which was an outlier) showed that CBT-I is effective at 3-, 6- and 12-mo compared to non-active controls: Hedges g for Insomnia severity index: 0.64 (3 m), 0.40 (6 m) and 0.25 (12 m); sleep onset latency: 0.38 (3 m), 0.29 (6 m) and 0.40 (12 m); sleep efficiency: 0.51 (3 m), 0.32 (6 m) and 0.35 (12 m). We demonstrate that although effects decline over time, CBT-I produces clinically significant effects that last up to a year after therapy.

The impact of cognitive behavioural therapy for insomnia on objective sleep parameters: A meta-analysis and systematic review.

It is well-established that cognitive behavioural therapy for insomnia (CBT-I) improves self-reported sleep disturbance, however the impact on objective sleep is less clear. This meta-analysis aimed to quantify the impact of multi-component CBT-I on objective measures of sleep, indexed via polysomnography (PSG) and actigraphy. Fifteen studies met inclusion criteria. Following appraisal for risk of bias, extracted data were meta-analysed using random-effects models. The quality of the literature was generally high, although reporting of methodological detail varied markedly between studies. Meta-analyses found no evidence that CBT-I reliably improves PSG-defined sleep parameters. Actigraphy evidence was more mixed; with a small effect for reduction in sleep onset latency (Hedge's g = -0.28 [95% confidence interval (CI) -0.51 to -0.05], p = 0.018) and a moderate effect for reduction in total sleep time (TST) (Hedge's g = -0.51 [95% CI -0.75 to -0.26], p < 0.001). In contrast, and consistent with recent meta-analyses, CBT-I was associated with robust improvements in diary measures of sleep initiation and maintenance (Hedge's g range = 0.50 to 0.79) but not TST. While the literature is small and still developing, the sleep benefits of CBT-I are more clearly expressed in the subjective versus objective domain.