Efficacy and safety of eszopiclone combined with drug therapy in the treatment of insomnia after stroke: A network meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of multi-drug therapy based on eszopiclone in the treatment of insomnia after stroke using a network meta-analysis method and to provide evidence for clinical practice. METHOD: Computer searches of PubMed, Excerpt Medica Database (Embase), Cochrane Library Central Register of Controlled Trials, APA PsycInfo, CNKI, WanFang, Sinomed and other databases were performed to search for clinical randomized controlled studies (RCTs) on multi-drug therapy based on eszopiclone in the treatment of insomnia patients after stroke. The search time was from the establishment of each database until July 2023. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included RCTs. Stata 14.0 was applied to perform network meta-analysis using Review Manager 5.3 software for traditional meta-analysis. RESULT: Eighteen RCTs and 1646 patients were ultimately included, involving 11 treatment options. The results of the network meta-analysis showed that the ranking of Pittsburgh Sleep Quality Index (PSQI) decline was eszopiclone combined with sweet dream oral liquid (ESZ+SDOL)>eszopiclone combined with a shugan jieyu capsule (ESZ+SGJYC)>eszopiclone combined with agomelatine (ESZ+AGO)>eszopiclone combined with flupentixol and melitracen tablets (ESZ+FMT)>eszopiclone combined with yangxue qingnao granules (ESZ+YXQNG)>eszopiclone combined with mirtazapine (ESZ+MIR)>ESZ>FMT; the modified Edinburgh Scandinavia Stroke Scale (MESSS) decline ranking was ESZ+SDOL>ESZ+AGO>ESZ; and the clinical total effective rate ranking was eszopiclone combined with a xuefu zhuyu capsule (ESZ+XFZYC)>ESZ+MIR>ESZ+SGJYC>ESZ+SDOL> ESZ+FMT>ESZ+YXQNG>ESZ>FMT. In terms of clinical adverse reactions, in addition to ESZ therapy, ESZ+ESC had the highest number of adverse reactions, with abdominal pain being the most common. ESZ+YXQNG had the most types of adverse reactions, with 8 types. CONCLUSION: Multi-drug therapy based on eszopiclone can effectively improve the sleep quality of patients with insomnia after stroke, and ESZ+SDOL has significant efficacy and safety. However, due to the limitations of this study, efficacy ranking cannot fully explain the superiority or inferiority of clinical efficacy. In the future, more multicentre, large sample, double-blind randomized controlled trials are needed to supplement and demonstrate the results of this study.

Efficacy of Zhumian Tang formula granules combined with eszopiclone for the treatment of poor sleep quality: a multi-center, randomized controlled, superiority trial.

OBJECTIVE: To evaluate the efficacy and safety of Zhumian Tang formula granules combined with eszopiclone for treating poor sleep quality. METHODS: This multi-center, dynamic block-randomized, parallel-group superiority clinical trial included 130 patients. The combined treatment group received Zhumian Tang formula granules combined with eszopiclone treatment, and the control group received eszopiclone treatment only. The group allocation ratio was 1∶1. The duration of treatment was 2 weeks. Participants were asked to complete questionnaires before treatment, after 1 week of the intervention, after 2 weeks of the intervention, and at the follow-up on week 3. The primary outcomes were the Pittsburgh Sleep Quality Index (PSQI) score and the total effective rate of treatment. The secondary outcome was the rate of adverse effects. RESULTS: Compared with the eszopiclone treatment group, the PSQI score of the combined treatment group was significantly lower after 2 weeks of the intervention (6.98 vs 8.26, P < 0.05). However, there was no significant difference in the mean PSQI score after 1 week of the intervention (9.89 vs 9.15, P = 0.124). After the follow-up on week 3, the PSQI score of the combined treatment group remained significantly lower than that of the eszopiclone treatment group (6.12 vs 8.31, P < 0.001). The total effective rates of treatment of the combined group and the eszopiclone group were 36.92% vs 35.38% (Z = 0.033, P = 0.855) after 1 week of the intervention, 83.08% vs 58.46% (Z = 9.519, P < 0.05) after 2 weeks of the intervention, and 83.08% vs 61.54% (Z = 7.530, P < 0.05) and after the follow-up on week 3, respectively. There was no significant difference in the overall rate of adverse reactions between the combined and eszopiclone treatment groups (21.53% vs 31.8%, P = 0.318). CONCLUSION: The combination of Zhumian Tang formula granules with eszopiclone was found to be safe and more effective in improving sleep quality than eszopiclone alone. Traditional Chinese medicine can enhance the effectiveness of Western medicine in the treatment of insomnia.

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.

Assessment of Suvorexant and Eszopiclone as Alternatives to Benzodiazepines for Treating Insomnia in Patients With Major Depressive Disorder.

OBJECTIVES: We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study. METHODS: Patients with MDD who have insomnia symptoms (a score of >7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study. RESULTS: Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline. CONCLUSIONS: Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

Effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease and sleep disorder: A randomized controlled trial.

OBJECTIVE: To investigate the effects of eszopiclone on sleep quality and cognitive function in elderly patients with Alzheimer's disease (AD) and sleep disorders. METHODS: This study was a prospective study of 96 elderly patients with AD and sleep disturbance treated in our hospital from April 2019 to December 2020. All patients were divided into a control group (48 patients, given alprazolam tablets) and a study group (48 patients, given eszopiclone) according to the random number table method. RESULTS: After treatment, compared with the control group, the study group had lower sleep latency, daytime function, sleep disturbance, sleep efficiency, sleep quality, sleeping time, and hypnotic medication scores (p < .05). After treatment, sleep progression and sleep architecture improvement were more obvious in the study group compared with the control group (p < .05). After treatment, compared with the control group, the rhythm disturbance, psychotic disorder, hallucination, phobic anxiety, and disorder in the study group improved more significantly (p < .05). After treatment, compared with the control group, the scores of orientation, attention, memory, calculation, recall, and language ability in the study group improved more significantly (p < .05). After treatment, the scores of the physical life self-care scale and instrumental activities of daily living scale in the study group were improved more obviously compared with the control group, with significant differences (p < .05). CONCLUSION: Eszopiclone can effectively improve the quality of sleep and cognitive function in elderly patients with AD and sleep disorder.

Eszopiclone for the treatment of primary insomnia: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.

STUDY OBJECTIVE: In this study, we performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the efficacy and safety of eszopiclone for the treatment of primary insomnia. METHODS: We searched MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and PubMed from inception to June 2018. Additionally, we searched the ClinicalTrials.gov trials register for other relevant trials. According to participants, intervention, comparison, outcome (PICO) criteria, studies were included that focused on: adults diagnosed with primary insomnia, aged 18-65 and > 65 years; eszopiclone for the treatment of primary insomnia; comparison were made between eszopiclone and placebo; as well as primary outcomes, secondary outcomes, and adverse effects. RESULTS: A total of six randomized trials involving 2809 patients with primary insomnia were included in our analysis. Our analysis suggested that eszopiclone was associated with significant improvements in subjective sleep latency, wake after sleep onset, number of awakenings, total sleep time at one week, two weeks, one month, three months and six months. Meanwhile, eszopiclone was associated with increased quality of sleep, ability to function, daytime alertness and sense of physical well-being at one week, one month, three months and six months. Dizziness and unpleasant taste were the most common adverse effects in elderly subgroup. Alternately, non-elderly patients may be more prone to adverse effects such as infection, pharyngitis, somnolence, unpleasant taste and dry mouth. CONCLUSION: This meta-analysis showed that eszopiclone is an effective and safe therapy option for patients with primary insomnia, especially in elderly patients. However, due to the high clinical heterogeneity in some outcomes, further standardized preparation, large-scale and rigorously designed trials are needed.

Evaluation of the prescribing practices of nonbenzodiazepine, benzodiazepine receptor agonist hypnotics in adults at a federally qualified health center.

OBJECTIVE: To assess the change in prescribing of nonbenzodiazepine and benzodiazepine receptor agonist hypnotics (Z-drugs) prescribed to adults after U.S. Food and Drug Administration safety warnings. SETTING: Five clinical sites as part of a Federally Qualified Health Center (FQHC). PRACTICE DESCRIPTION: Virginia Garcia Memorial Health Center is an FQHC consisting of 5 patient centered medical homes. PRACTICE INNOVATION: Examine Z-drug use in a vulnerable adult population to confirm appropriate prescribing and quality care. EVALUATION: The primary measure was to determine the percentage of Z-drugs prescribed to patients age 18 years or older during the study period of September 1, 2016, to August 31, 2017. Patients were identified using the electronic health record. Z-drugs included zolpidem, zaleplon, and eszopiclone. Secondary measures included percentage of Z-drug prescribing to adults age 65 years and older, percentage of female patients prescribed zolpidem doses greater than 5 mg, prior behavioral health encounter, and prior pharmacotherapy for insomnia. RESULTS: Of 22,733 adults age 18 years and older, 282 patients (1.3%) received a Z-drug prescription during the study period. Forty-nine (28.9%) female patients received 10 mg of zolpidem nightly, a zolpidem dose higher than the recommended 5 mg nightly. In addition, of 2239 patients age 65 years and older, 34 patients (1.5%) received a prescription for a Z-drug. CONCLUSION: Prescribing rates of zolpidem in 10-mg doses to female patients were high, indicating that providers could benefit from further education on this topic. In the population, and in adults age 65 years and older, Z-drug prescribing in an FQHC was low compared with available prescribing rates.

Treatment Options for Insomnia in Schizophrenia: A Systematic Review.

BACKGROUND: Insomnia is a common feature of schizophrenia. Although several studies have been published about the influence of certain drugs on schizophrenia patients' sleep, there are no well-grounded recommendations about insomnia treatment in this clinical setting. The present review aimed to identify relevant empirical evidence on available treatments of insomnia in patients with schizophrenia, assessing their safety and efficacy. METHODS: This is a systematic review of clinical trials investigating the effect of treatments for insomnia in patients with a diagnosis of schizophrenia. Data were obtained from Medline/PubMed, Embase, PsycInfo, and the Cochrane Library. Risk of bias was assessed in individual studies for selection, performance, detection, attrition, and reporting bias. RESULTS: Four studies met inclusion criteria; 2 using melatonin, 1 using paliperidone, and 1 with eszopiclone. All reported positive results: melatonin increased sleep efficiency and total duration of sleep; paliperidone decreased sleep latency onset and increased total sleep time and sleep efficiency; eszopiclone decreased insomnia severity index. CONCLUSIONS: Despite a very limited number of specific studies on this matter, all 4 studies have shown good benefit/risk ratios and reviewed options-melatonin, paliperidone, and eszopiclone-might represent valid options for residual insomnia in schizophrenia.

Eszopiclone for insomnia.

BACKGROUND: Insomnia is a major public health issue affecting between 6% to 10% of the adult population in Western countries. Eszopiclone is a hypnotic drug belonging to a newer group of hypnotic agents, known as new generation hypnotics, which was marketed as being just as effective as benzodiazepines for this condition, while being safer and having a lower risk for abuse and dependence. It is the aim of the review to integrate evidence from randomised controlled trials and to draw conclusions on eszopiclone's efficacy and safety profile, while taking methodological features and bias risks into consideration. OBJECTIVES: To assess the efficacy and safety of eszopiclone for the treatment of insomnia compared to placebo or active control. SEARCH METHODS: We searched the Cochrane Central Register of Controlled trials (CENTRAL), MEDLINE, Embase, PsycINFO, PSYNDEX and registry databases (WHO trials portal, ClinicalTrials.gov) with results incorporated from searches to 10 February 2016. To identify trials not registered in electronic databases, we contacted key informants and searched reference lists of identified studies. We ran an update search (21 February 2018) and have placed studies of interest in awaiting classification/ongoing studies. These will be incorporated into the next version of the review, as appropriate. SELECTION CRITERIA: Parallel group randomised controlled trials (RCTs) comparing eszopiclone with either placebo or active control were included in the review. Participants were adults with insomnia, as diagnosed with a standardised diagnostic system, including primary insomnia and comorbid insomnia. DATA COLLECTION AND ANALYSIS: Two authors independently extracted outcome data; one reviewer assessed trial quality and the second author cross-checked it. MAIN RESULTS: A total of 14 RCTs, with 4732 participants, were included in this review covering short-term (≤ 4 weeks; 6 studies), medium-term (> 4 weeks ≤ 6 months; 6 studies) and long-term treatment (> 6 months; 2 studies) with eszopiclone. Most RCTs included in the review included participants aged between 18 and 64 years, three RCTs only included elderly participants (64 to 85 years) and one RCT included participants with a broader age range (35 to 85 years). Seven studies considered primary insomnia; the remaining studies considered secondary insomnia comorbid with depression (2), generalised anxiety (1), back pain (1), Parkinson's disease (1), rheumatoid arthritis (1) and menopausal transition (1).Meta-analytic integrations of participant-reported data on sleep efficacy outcomes demonstrated better results for eszopiclone compared to placebo: a 12-minute decrease of sleep onset latency (mean difference (MD) -11.94 min, 95% confidence interval (CI) -16.03 to -7.86; 9 studies, 2890 participants, moderate quality evidence), a 17-minute decrease of wake time after sleep onset (MD -17.02 min, 95% CI -24.89 to -9.15; 8 studies, 2295 participants, moderate quality evidence) and a 28-minute increase of total sleep time (MD 27.70 min, 95% CI 20.30 to 35.09; 10 studies, 2965 participants, moderate quality evidence). There were no significant changes from baseline to the first three nights after drug discontinuation for sleep onset latency (MD 17.00 min, 95% CI -4.29 to 38.29; 1 study, 291 participants, low quality evidence) and wake time after sleep onset (MD -6.71 min, 95% CI -21.25 to 7.83; 1 study, 291 participants, low quality evidence). Adverse events during treatment that were documented more frequently under eszopiclone compared to placebo included unpleasant taste (risk difference (RD) 0.18, 95% CI 0.14 to 0.21; 9 studies, 3787 participants), dry mouth (RD 0.04, 95% CI 0.02 to 0.06; 6 studies, 2802 participants), somnolence (RD 0.04, 95% CI 0.02 to 0.06; 8 studies, 3532 participants) and dizziness (RD 0.03, 95% CI 0.01 to 0.05; 7 studies, 2933 participants). According to the GRADE criteria, evidence was rated as being of moderate quality for sleep efficacy outcomes and adverse events and of low quality for rebound effects and next-day functioning. AUTHORS' CONCLUSIONS: Eszopiclone appears to be an efficient drug with moderate effects on sleep onset and maintenance. There was no or little evidence of harm if taken as recommended. However, as certain patient subgroups were underrepresented in RCTs included in the review, findings might not have displayed the entire spectrum of possible adverse events. Further, increased caution is required in elderly individuals with cognitive and motor impairments and individuals who are at increased risk of using eszopiclone in a non-recommended way.

Zolpidem and Eszopiclone Pre-medication for PSG: Effects on Staging, Titration, and Adherence.

Introduction: The non-benzodiazepine sedative hypnotic (NBSH) eszopiclone improves polysomnography (PSG) quality and continuous positive airway pressure (CPAP) adherence. It is unclear whether zolpidem has the same effect and neither NBSH has been studied in populations with milder forms of obstructive sleep apnea. Materials and Methods: We performed a retrospective analysis on patients undergoing level I PSG at our institution. Patients are pre-medicated with NBSHs at the discretion of the sleep physician. We compared PSG/CPAP titration quality and subsequent CPAP adherence for patients receiving NBSHs or no pre-study medication. We adjusted for obstructive sleep apnea pre-test probability (PTP), arousal threshold, and other factors showing differences at baseline. Results: Data on 560 patients were analyzed. Mean age and body mass index were 42.2 ± 10.1 and 28.8 ± 4.5, respectively. Median apnea hypopnea index was 12.9 (6.4-25.3), 100 (18.0%) patients had normal studies, 97 (17.3%) were split, and 457 (81.6%) had a respiratory low-arousal threshold. After adjusting for differences at baseline, neither NBSH was associated with sleep efficiency, wake after sleep onset, or total sleep time on PSG. After adjustment, patients receiving eszopiclone had a higher apnea hypopnea index at the final CPAP pressure (ß = 14.2; 95% confidence intervals (CI) 7.2-21.2; p < 0.001) and were more likely to have an unacceptable titration (odds ratio (OR) = 6.6; 95% CI 2.0-21.0; p = 0.002). When only split-night studies were examined, there were no differences in any adherence variables across or between categories. Conclusions: In a population with predominantly mild obstructive sleep apnea, NBSHs did not improve PSG or CPAP titration quality and did not increase CPAP adherence. There was no difference in effect between eszopiclone and zolpidem.

Eszopiclone for persistent negative symptoms in schizophrenia - An unintended N-of-1 study.

Persistent negative and cognitive symptoms in patients with schizophrenia pose a significant challenge to clinicians. Being a heterogeneous cluster of symptoms with potentially distinct underlying pathogenesis, it is important to examine novel therapies based on emerging neurobiological evidence. Eszopiclone is known to enhance the deficient sleep spindles that are related to impairments in learning and memory in schizophrenia. In this report we highlight the potential utility of eszopiclone in treating persistent negative symptoms in a patient with chronic schizophrenia. The unintended N-of-1 design that spanned out over a period of 24weeks demonstrated improvements in negative symptoms while the patient was on eszopiclone and worsening of these symptoms while unintentionally being off eszopiclone treatment. These observations suggest a reasonable degree of specificity of our patient's response to eszopiclone, thus warranting future sleep-EEG guided systematic studies.

Una revisión de los trastornos del sueño en la esquizofrenia / Sleep disorders in schizophrenia: a review

La esquizofrenia se acompaña hasta en un 80% de los pacientes de trastornos del sueño, que son normalmente infradiagnosticados e infratratados debido a su falta de consideración en el manejo de esta enfermedad. Los principales trastornos son el insomnio, el síndrome de piernas inquietas, el síndrome de apnea obstructiva del sueño, la hipersomnia, las parasomnias y los trastornos del ritmo circadiano. Destaca en su importancia el insomnio, ya que puede ser un signo prodrómico de la enfermedad, así como un signo de alarma temprano de una descompensación psicótica incipiente. En pacientes con esquizofrenia se han encontrado alteraciones polisomnográficas en la arquitectura del sueño que se correlacionan tanto con la clínica subjetiva de insomnio como con las manifestaciones clínicas predominantes de la esquizofrenia. Los antipsicóticos pueden alterar la estructura del sueño, pero también tienen un papel importante en el tratamiento de las alteraciones del sueño en la esquizofrenia. Han demostrado una mejoría clínica del insomnio y la corrección polisomnográfica de las alteraciones de la arquitectura del sueño, mejorando la calidad de vida y la capacidad funcional de los pacientes. Sin embargo, pueden también exacerbar otros trastornos comórbidos del sueño, como el síndrome de piernas inquietas o el síndrome de apnea obstructiva del sueño, o provocar hipersomnia u obesidad. Existe evidencia de que los trastornos del sueño en esquizofrenia afectan de forma relevante la calidad de vida y de que influyen en la sintomatología de los pacientes con esquizofrenia, por lo que es muy importante reconocerlos y tratarlos de forma adecuada (AU)

Up to 80% of patients with schizophrenia suffer from sleep disorders, and are usually under-diagnosed and under-treated due to a lack of being taken into account in the management of this illness. The main disorders are insomnia, restless legs syndrome, obstructive sleep apnoea syndrome, hypersomnia, the parasomnias, and circadian rhythm disorders. The importance of insomnia is highlighted, as it can be a prodromic sign of the illness, as well as an early alarm sign of an incipient psychotic decompensation. Polysomnographic changes that correlate with subjective clinical insomnia and with the predominant clinical manifestations of schizophrenia. Antipsychotic drugs can alter the structure of sleep, but they also have an important role in the treatment of sleep alterations in schizophrenia. They have demonstrated a clinical improvement of the insomnia and the polysomnographic correction of the changes in sleep architecture, with an improvement in the quality of life and functional capacity of the patients. However, they can also exacerbate other comorbid sleep disorders such as restless legs syndrome and obstructive sleep apnoea syndrome, or trigger hypersomnia or obesity. There is evidence that sleep disorders in schizophrenia has a significant effect on the quality of life and has an influence on the symptoms of patients with schizophrenia, thus it is very important to recognise them and treat them accordingly (AU)

Z-drug for schizophrenia: A systematic review and meta-analysis.

No systematic reviews and meta-analyses on the use of Z-drug for schizophrenia are available. Randomized, placebo-controlled, or non-pharmacological intervention-controlled trials published before 03/20/2017 were retrieved from major healthcare databases and clinical trial registries. A meta-analysis including only randomized, placebo-controlled trials was performed. Efficacy outcomes were measured as improvement in overall schizophrenia symptoms, total sleep time, and wake after sleep onset. Safety/acceptability outcomes were discontinuation rate and individual adverse events. Four trials [1 alpidem placebo-controlled study (n=66), 2 eszopiclone placebo-controlled studies (n=60), and 1 eszopiclone, shallow needling-controlled study (n=96)] were identified. The meta-analysis showed no significant differences in any outcome between pooled Z-drug and placebo treatment groups. For individual studies, alpidem was superior to placebo in improving the overall schizophrenia symptoms. One of the eszopiclone studies showed that eszopiclone was superior to placebo in improving the Insomnia Severity Index scores. Another eszopiclone study showed that eszopiclone did not differ from shallow needling therapy in improving both schizophrenia- and insomnia-related symptoms. Although this study failed to show significant benefits for the use of Z-drug in the treatment of schizophrenia, it showed that short-term use of eszopiclone is an acceptable method for treating persistent insomnia among these patients.

Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment.

OBJECTIVE: A large proportion of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) have associated sleep problems which not only affect the child's wellbeing but also impact family functioning. Management of sleep problems is consequently an important aspect of overall ADHD management in paediatric patients. Although some drugs are being used off-label for the management of paediatric insomnia, there is scant clinical evidence supporting their use. Our aim was to identify and assess the quality of published studies reporting the safety, tolerability and efficacy of drugs used for treating behavioural insomnia in children with ADHD. METHODS: After an initial screen to determine which drugs were most commonly used, we conducted a systematic review of English-language publications from searches of PubMed, EMBASE, PsycINFO and two trial register databases to February 2017, using keywords 'clonidine', 'melatonin', 'zolpidem', 'eszopiclone', 'L-theanine', 'guanfacine', 'ADHD', 'sleep disorder' and 'children'. For quality assessment of included studies, we used the CONSORT checklist for randomised control trials (RCTs) and the Downs and Black checklist for non-RCTs. RESULTS: Twelve studies were included. Two case series for clonidine, two RCTs and four observational studies for melatonin and one RCT each for zolpidem, eszopiclone, L-theanine and guanfacine. Of the 12 included studies, only one on eszopiclone scored excellent for quality. The quality of the rest of the studies varied from moderate to low. For clonidine, melatonin and L-theanine, improvements in sleep-onset latency and total sleep duration were reported; however, zolpidem, eszopiclone and guanfacine failed to show any improvement when compared with placebo. Clonidine, melatonin, L-theanine, eszopiclone and guanfacine were well tolerated with mild to moderate adverse events; zolpidem was associated with neuropsychiatric adverse effects. CONCLUSION: There is generally poor evidence for prescribing drugs for behavioural insomnia in children with ADHD. Further controlled studies are warranted.

Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement.

BACKGROUND AND OBJECTIVE: Upper airway collapsibility predicts the response to several non-continuous positive airway pressure (CPAP) interventions for obstructive sleep apnoea (OSA). Measures of upper airway collapsibility cannot be easily performed in a clinical context; however, a patient's therapeutic CPAP requirement may serve as a surrogate measure of collapsibility. The present work aimed to compare the predictive use of CPAP level with detailed physiological measures of collapsibility. METHODS: Therapeutic CPAP levels and gold-standard pharyngeal collapsibility measures (passive pharyngeal critical closing pressure (Pcrit ) and ventilation at CPAP level of 0 cmH2 O (Vpassive )) were retrospectively analysed from a randomized controlled trial (n = 20) comparing the combination of oxygen and eszopiclone (treatment) versus placebo/air control. Responders (9/20) to treatment were defined as those who exhibited a 50% reduction in apnoea/hypopnoea index (AHI) plus an AHI<15 events/h on-therapy. RESULTS: Responders to treatment had a lower therapeutic CPAP requirement compared with non-responders (6.6 (5.4-8.1) cmH2 O vs 8.9 (8.4-10.4) cmH2 O, P = 0.007), consistent with their reduced collapsibility (lower Pcrit , P = 0.017, higher Vpassive P = 0.025). Therapeutic CPAP level provided the highest predictive accuracy for differentiating responders from non-responders (area under the curve (AUC) = 0.86 ± 0.9, 95% CI: 0.68-1.00, P = 0.007). However, both Pcrit (AUC = 0.83 ± 0.11, 95% CI: 0.62-1.00, P = 0.017) and Vpassive (AUC = 0.77 ± 0.12, 95% CI: 0.53-1.00, P = 0.44) performed well, and the difference in AUC for these three metrics was not statistically different. A therapeutic CPAP level ≤8 cmH2 O provided 78% sensitivity and 82% specificity (positive predictive value = 78%, negative predictive value = 82%) for predicting a response to these therapies. CONCLUSION: Therapeutic CPAP requirement, as a surrogate measure of pharyngeal collapsibility, predicts the response to non-anatomical therapy (oxygen and eszopiclone) for OSA.

The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) results from the interaction of several physiological traits; specifically a compromised upper airway anatomy and muscle function, and two key non-anatomical deficits: elevated loop gain and a low arousal threshold. Although continuous positive airway pressure (CPAP) is an efficacious treatment, it is often poorly tolerated. An alternative approach could involve administering therapies targeting the non-anatomic causes. However, therapies (oxygen or hypnotics) targeting these traits in isolation typically improve, but rarely resolve OSA. Therefore, our aim was to determine how the combination of oxygen and eszopiclone alters the phenotypic traits and OSA severity and to assess the baseline phenotypic characteristics of responders/nonresponders to combination therapy. METHODS: In a single-blinded randomized crossover study, 20 OSA patients received combination therapy (3 mg eszopiclone and 40% oxygen) versus placebo/sham air, with 1 w between conditions. Under each condition, we assessed the effects on OSA severity (clinical polysomnography) and the phenotypic traits causing OSA using CPAP manipulations (research polysomnography). RESULTS: Combination therapy reduced the apnea-hypopnea index (51.9 ± 6.2 vs. 29.5 ± 5.3 events/h; P < 0.001), lowered both the ventilation associated with arousal (5.7 ± 0.3 vs. 5.2 ± 0.3 L/min; P = 0.05) and loop gain (3.3 ± 0.5 vs. 2.2 ± 0.3; P = 0.025). Responders to therapy (apnea-hypopnea index reduced by > 50% to below 15 events/h; n = 9/20) had less severe OSA (P = 0.001), a less collapsible upper airway (P = 0.01) and greater upper airway muscle effectiveness (P = 0.002). CONCLUSIONS: The combination of lowering loop gain and raising the arousal threshold is an effective therapy in patients whose anatomy is not severely compromised. Our work demonstrates that combining therapies that target multiple traits can resolve OSA in selected individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01633827.

Nonbenzodiazepine Sedative Hypnotics and Risk of Fall-Related Injury.

STUDY OBJECTIVES: The objective of this study was to test the hypothesis that use of zolpidem, eszopiclone, and zaleplon would be associated with increased risk of traumatic brain injury (TBI) and hip fracture. METHODS: We conducted a case-crossover study on a 5% random sample of Medicare beneficiaries age 65 y or older hospitalized with either TBI (n = 15,031) or hip fracture (n = 37,833) during 2007-2009. Use of zolpidem, eszopiclone, or zaleplon during the 30-day period prior to injury hospitalization was compared to use during four control periods at 3, 6, 9, and 12 mo prior to injury. The primary outcome was hospitalization for TBI or hip fracture. RESULTS: Zolpidem use during the month prior to injury was associated with increased risk of TBI (odds ratio [OR] 1.87; 95% confidence interval [CI] 1.56, 2.25); however, eszopiclone use during the same period was not associated with increased risk (OR 0.67; 95% CI 0.40, 1.13). Zolpidem use during the month prior to injury was associated with increased risk of hip fracture (OR 1.59; 95% CI 1.41, 1.79); however, eszopiclone use during the same period was not associated with increased risk (OR 1.12; 95% CI 0.83, 1.50). Analysis of zaleplon use in the month prior to injury was limited by low drug utilization but was not associated with increased risk of TBI (OR 0.85; 95% CI 0.21, 3.34) or hip fracture (OR 0.92; 95% CI 0.40, 2.13) in this study. CONCLUSIONS: For the treatment of insomnia in older adults, eszopiclone may present a safer alternative to zolpidem, in terms of fall-related injuries.