Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Melatonin In Acute Mania Investigation (MIAMI-UK). A randomized controlled trial of add-on melatonin in bipolar disorder.

OBJECTIVES: Current options for treating emergent episodes of hypomania and mania in bipolar disorder are limited. Our objective was to compare the effectiveness and safety of add-on melatonin in hypomania or mania over 3 weeks as a well-tolerated therapy. METHODS: A randomized, double-blind, parallel-group, 3-week comparison of modified release melatonin (n = 21) vs placebo (n = 20) in adult bipolar patients aged 18-65 years. Permuted block randomization was used with participants and investigators masked to treatment allocation. Trial registration is ISRCTN28988273 and EUdraCT2008-000281-23. Approved by the South Central National Research Ethics Service (Oxford REC A) ref: 09/H0604/63. RESULTS: The trial was negative as there was no significant difference between melatonin and placebo on the primary outcome-mean Young Mania Rating Scale (YMRS) score at Day 21: (mean difference [MD] -1.77 ([95% CI: -6.39 to 2.85]; P = .447). Significantly fewer patients on melatonin scored 10 or more on the Altman Self Rating Mania Scale: (odds ratio [OR] 0.164 [95% CI: 0.0260-1.0002]; P = .05). Quick Inventory of Depression Symptomatology Clinician Version-16 (QIDS-C16) scores were not significantly different. (OR 1.77 [95% CI: 0.43-7.29]; P = .430). The proportion of patients scoring less than or equal to 5 on the self-report QIDS-SR16 at end-point was greater for the melatonin group (OR 8.35 [95% CI: 1.04-67.23]; P = .046). CONCLUSIONS: In this small trial, melatonin did not effectively treat emerging hypomania or mania as there was no significant difference on the primary outcome. The sample size limitation and secondary outcomes suggest further investigation of melatonin treatment in mood episodes is indicated.

Actigraphic features of bipolar disorder: A systematic review and meta-analysis.

Sleep disruptions represent a core feature of bipolar disorders and have been widely studied through the use of actigraphy, which is an objective measure of motor activity and sleep. Finding objective outcomes, which reliably measure sleep in bipolar disorders, is essential in developing better therapies and improving follow-up monitoring strategies. Our aim is to understand the role of actigraphy as an objective measure of sleep in bipolar disorder. We undertook a systematic review and meta-analysis on studies using actigraphy to detect changes in activity and sleep patterns in bipolar patients versus healthy controls. The primary outcome measures were the analyses of 'activity mean' and 'sleep duration'. As secondary outcomes we analysed 'sleep onset latency', 'sleep efficiency', and 'time awake after sleep onset'. Thirteen studies comprising 821 subjects met quality criteria for inclusion. The results show a decrease in activity mean and an altered pattern of sleep in bipolar patients. Further analyses suggest that the results might be generalized to a bipolar condition which underlies manic and depressed episodes as well as euthymic phases. This study highlights the role of actigraphy as an important objective tool for the ambulatory monitoring of sleep and activity in bipolar disorders.

A positron emission tomography study of the 5-HT1A receptor in schizophrenia and during clozapine treatment.

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

Is lateral bias anomalous in early-onset schizophrenia? Selected comparisons with normal populations.

The aim of this study was to investigate lateral bias in patients with early-onset schizophrenia. Hand, eye, and foot preferences and relative hand skill were examined in early-onset patients (n=44) and matched controls (n=39), and were compared with population estimates. Patients demonstrated a significant excess in mixed handedness (20.5% vs. 8.5%) relative to population estimates and reduced relative hand skill on a pegboard task compared with controls. Left eye preference was significantly less common in schizophrenic patients relative to population estimates. Crossed eye-hand and eye-foot preferences were not significantly increased in the patient group as a whole but were present, respectively, in four of nine and five of nine mixed-handed patients but in none of five mixed-handed controls. These findings are consistent with the view that lateralisation is anomalous in schizophrenia early in the course of illness.

Brain volume, asymmetry and intellectual impairment in relation to sex in early-onset schizophrenia.

BACKGROUND: Accumulating evidence suggests that early-onset schizophrenia arises from a disturbance in the normal trajectory of cerebral development. AIMS: To investigate brain structure, asymmetry and IQ in early-onset schizophrenia. METHOD: Volumes of left and right cerebral hemispheres and IQ were assessed in 33 participants with early-onset DSM-IV schizophrenia and 30 members of a matched, normal control group. RESULTS: Total brain volume was significantly smaller in the group with early-onset disease ('cases') relative to the control group (4.5%), especially for the left hemisphere in males (6.0%). A significant sex x diagnosis interaction in hemisphere asymmetry revealed that the female cases group had significantly reduced rightward asymmetry relative to the female control group and that the male cases tended to have reduced leftward asymmetry relative to the male control group. Decreased left hemisphere volume in males and decreased rightward hemispheric asymmetry in females correlated with reduced IQ. CONCLUSIONS: Sexually dimorphic alterations in asymmetry correlate with degree of intellectual impairment in early-onset schizophrenia.

Thought and Language Index: an instrument for assessing thought and language in schizophrenia.

BACKGROUND: Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown. AIMS: To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia. METHOD: Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared. RESULTS: The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlated with the prevalence of definite formal thought disorders. CONCLUSIONS: The TLI is reliable and capable of detecting subtle disorders. Some mild aberrations occurring in the speech of healthy individuals appear to be attenuated forms of the florid disorders characteristic of schizophrenia.