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and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials.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

New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world

New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world

Elm1 kinase activates the spindle position checkpoint kinase Kin4

Elm1 phosphorylates a conserved residue within the Kin4 kinase domain to coordinate spindle position with cell cycle progression

Evidence for an association of serum melatonin concentrations with recognition and circadian preferences in patients with schizophrenia

Melatonin, a neuro-differentiation factor, may play a role in the neurodevelopmental origins of schizophrenia. Cognitive impairment and decreased melatonin are reported in schizophrenia; however, the relationship between them remains unclear. We hypothesised that patients with schizophrenia would have lower concentrations of circulating melatonin than healthy controls and that melatonin levels would be associated with cognitive impairment. This study included 47 patients with schizophrenia and 40 healthy controls (HC). Serum melatonin concentrations were measured using the enzyme-linked immunosorbent assay. Positive and Negative Syndrome Scales (PANSS), The Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI), the Stroop and Oktem verbal memory processes (VMPT) tests were applied. Patients with schizophrenia had lower levels of melatonin compared to the HC group (p=0.016), also after controlling for age, sex, and body mass index (BMI) (p=0.024). In patients with schizophrenia, melatonin concentrations were associated with higher BMI (rho=0.34, p=0.01) and lower MEQ score (rho=-0.29, p=0.035). The patient sample was split into low and high melatonin categories by using the median melatonin concentration in HC as the cut-off. Patients in the low melatonin group had poorer performance in VMPT-Recognition (p=0.026) and Stroop-Colour Error (p=0.032). Notwithstanding its limitations, the findings of this exploratory study suggest that decreased serum melatonin concentrations observed in schizophrenia might also be associated with cognitive impairment and circadian preferences. Future studies are required to investigate the role of melatonergic pathways in patients with schizophrenia

Evidence for an association of serum melatonin concentrations with recognition and circadian preferences in patients with schizophrenia

Melatonin, a neuro-differentiation factor, may play a role in the neurodevelopmental origins of schizophrenia. Cognitive impairment and decreased melatonin are reported in schizophrenia; however, the relationship between them remains unclear. We hypothesised that patients with schizophrenia would have lower concentrations of circulating melatonin than healthy controls and that melatonin levels would be associated with cognitive impairment. This study included 47 patients with schizophrenia and 40 healthy controls (HC). Serum melatonin concentrations were measured using the enzyme-linked immunosorbent assay. Positive and Negative Syndrome Scales (PANSS), The Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI), the Stroop and Oktem verbal memory processes (VMPT) tests were applied. Patients with schizophrenia had lower levels of melatonin compared to the HC group (p=0.016), also after controlling for age, sex, and body mass index (BMI) (p=0.024). In patients with schizophrenia, melatonin concentrations were associated with higher BMI (rho=0.34, p=0.01) and lower MEQ score (rho=-0.29, p=0.035). The patient sample was split into low and high melatonin categories by using the median melatonin concentration in HC as the cut-off. Patients in the low melatonin group had poorer performance in VMPT-Recognition (p=0.026) and Stroop-Colour Error (p=0.032). Notwithstanding its limitations, the findings of this exploratory study suggest that decreased serum melatonin concentrations observed in schizophrenia might also be associated with cognitive impairment and circadian preferences. Future studies are required to investigate the role of melatonergic pathways in patients with schizophrenia

Reduced regulatory T cells with increased proinflammatory response in patients with schizophrenia

Aim To investigate whether circulating T cells including regulatory T cells (Treg) and derived cytokines contribute to the immune imbalance observed in schizophrenia. Methods Forty patients with schizophrenia and 40 age, sex, body mass index, education, and smoking status-matched healthy controls (HC) are included in the study. We stained cells with anti-CD14, anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD20, and anti-CD16/56. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with the human FoxP3 kit containing anti-CD4/anti-CD25 and intracellular anti-Foxp3. PBMCs were cultured for 72 h and stimulated with anti-CD3/anti-CD28. Cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma, TNF-alpha, and IL-17A) were measured from the culture supernatant and plasma using the Th1/Th2/Th17 cytokine bead array kit. Results In comparison with HC, Treg percentages in schizophrenia were higher (1.17 +/- 0.63 vs 0.81 +/- 0.53, P = 0.005) in unstimulated but lower in the stimulated condition (0.73 +/- 0.69 vs 0.97 +/- 0.55, P = 0.011). Activated T cell percentages were higher in schizophrenia than HC in unstimulated (2.22 +/- 0.78 vs 1.64 +/- 0.89, P = 0.001) and stimulated (2.25 +/- 1.01 vs 1.72 +/- 1.00, P = 0.010) conditions. The culture supernatant levels of IL-6 (7505.17 +/- 5170.07 vs 1787.81 +/- 1363.32, P <0.001), IL-17A (191.73 +/- 212.49 vs 46.43 +/- 23.99, P <0.001), TNF-alpha (1557 +/- 1059.69 vs 426.57 +/- 174.62, P = 0.023), and IFN-gamma (3204.13 +/- 1397.06 vs 447.79 +/- 270.13, P <0.001); and plasma levels of IL-6 (3.83 +/- 3.41vs 1.89 +/- 1.14, P = 0.003) and IL-17A (1.20 +/- 0.84 vs 0.83 +/- 0.53, P = 0.033) were higher in patients with schizophrenia than HC. Conclusion Our explorative study shows reduced level of Foxp3 expressing Treg in a stimulated condition with induced levels of proinflammatory cytokines in patients with schizophrenia

Reduced regulatory T cells with increased proinflammatory response in patients with schizophrenia

Aim To investigate whether circulating T cells including regulatory T cells (Treg) and derived cytokines contribute to the immune imbalance observed in schizophrenia. Methods Forty patients with schizophrenia and 40 age, sex, body mass index, education, and smoking status-matched healthy controls (HC) are included in the study. We stained cells with anti-CD14, anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD20, and anti-CD16/56. Peripheral blood mononuclear cells (PBMCs) were isolated and stained with the human FoxP3 kit containing anti-CD4/anti-CD25 and intracellular anti-Foxp3. PBMCs were cultured for 72 h and stimulated with anti-CD3/anti-CD28. Cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma, TNF-alpha, and IL-17A) were measured from the culture supernatant and plasma using the Th1/Th2/Th17 cytokine bead array kit. Results In comparison with HC, Treg percentages in schizophrenia were higher (1.17 +/- 0.63 vs 0.81 +/- 0.53, P = 0.005) in unstimulated but lower in the stimulated condition (0.73 +/- 0.69 vs 0.97 +/- 0.55, P = 0.011). Activated T cell percentages were higher in schizophrenia than HC in unstimulated (2.22 +/- 0.78 vs 1.64 +/- 0.89, P = 0.001) and stimulated (2.25 +/- 1.01 vs 1.72 +/- 1.00, P = 0.010) conditions. The culture supernatant levels of IL-6 (7505.17 +/- 5170.07 vs 1787.81 +/- 1363.32, P <0.001), IL-17A (191.73 +/- 212.49 vs 46.43 +/- 23.99, P <0.001), TNF-alpha (1557 +/- 1059.69 vs 426.57 +/- 174.62, P = 0.023), and IFN-gamma (3204.13 +/- 1397.06 vs 447.79 +/- 270.13, P <0.001); and plasma levels of IL-6 (3.83 +/- 3.41vs 1.89 +/- 1.14, P = 0.003) and IL-17A (1.20 +/- 0.84 vs 0.83 +/- 0.53, P = 0.033) were higher in patients with schizophrenia than HC. Conclusion Our explorative study shows reduced level of Foxp3 expressing Treg in a stimulated condition with induced levels of proinflammatory cytokines in patients with schizophrenia

The effects of focused ultrasound pulsation of nucleus accumbens in opioid-dependent rats

Background: Deep Brain Stimulation (DBS) is the only modality proven to be effective on selective stimulation of the deep brain structures. It was previously reported that, by using DBS, stimulation of nucleus accumbens (NA), a region that plays a pivotal role in the pathogenesis of substance addiction, is effective for the treatment of substance addiction. Objective: The purpose of the current study was to observe how the morphine-conditioned place preference changed in rats by stimulating NA with a non-invasive method, focused ultrasound (US) and to detect whether there would be any tissue damage caused by US waves. Methods: We used low-intensity focused ultrasound (LIFU), a noninvasive modality, in a place conditioning model to stimulate NA in rats. Results: At the initial stage of our study, we used morphine to induce place preference. As expected, morphine administration caused significant place preference. After the place preference was obtained by morphine, we divided the rats into two groups. One group received LIFU waves to NA and the other group received only sham, that is, no stimulation with US waves. Rats in both groups were continued to receive morphine. Then, we investigated whether LIFU and sham will reduce morphine-induced place preference or not. We observed that morphine-induced place preference had an ongoing raise in the sham group while no raise was detected in the ultrasound group. Although LIFU prevented the rats from the raise, it did not cause a significant reduction of morphine preference. Conclusion: We state that there is a need for future studies to investigate the effects of low-intensity focused ultrasound as an alternative treatment modality in addiction