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The International Journal of... Feb 2024Cannabis use is a risk factor of psychiatric illness, such as bipolar disorder type-I (BDI). Indeed, cannabis use strongly influences the onset and clinical course of...
BACKGROUND
Cannabis use is a risk factor of psychiatric illness, such as bipolar disorder type-I (BDI). Indeed, cannabis use strongly influences the onset and clinical course of BDI, although the biological mechanisms underlying this interaction remain unknown. Therefore, we have reviewed the biological mechanisms affected by cannabis use that may trigger BD.
METHODS
A systematic review was carried out of articles in which gene expression was studied in cannabis users or human-derived cells exposed to tetrahydrocannabinol (THC) or cannabidiol (CBD). A second systematic review was then performed to identify articles in which gene expression was studied in BDI samples, highlighting those that described alterations to the same molecular and cellular mechanisms affected by cannabis/THC/CBD.
RESULTS
The initial search identified 82 studies on cannabis and 962 on BDI. After removing duplicates and applying the inclusion/exclusion criteria, 9 studies into cannabis and 228 on BDI were retained. The molecular and cellular mechanisms altered by cannabis use or THC/CBD exposure were then identified, including neural development and function, cytoskeletal function, cell adhesion, mitochondrial biology, inflammatory related pathways, lipid metabolism, the endocannabinoid system, the hypocretin/orexin system, and apoptosis. Alterations to those activities were also described in 19 of 228 focused on BDI.
CONCLUSIONS
The biological mechanisms described in this study may be good candidates to the search for diagnostic biomarkers and therapeutic targets for BDI. Because cannabis use can trigger the onset of BD, further studies would be of interest to determine whether they are involved in the early development of the disorder, prompting early treatment.
Topics: Humans; Cannabis; Bipolar Disorder; Cannabinoid Receptor Agonists; Cannabidiol; Hallucinogens; Risk Factors; Dronabinol
PubMed: 38175142
DOI: 10.1093/ijnp/pyae002 -
Sleep Medicine: X Dec 2023Insomnia is a common disease, and the application of various types of sleeping pills for cognitive impairment is controversial, especially as different doses can lead to... (Review)
Review
BACKGROUND
Insomnia is a common disease, and the application of various types of sleeping pills for cognitive impairment is controversial, especially as different doses can lead to different effects. Therefore, it is necessary to evaluate the cognitive impairment caused by different sleeping pills to provide a theoretical basis for guiding clinicians in the selection of medication regimens.
OBJECTIVE
To evaluate whether various different doses (low, medium and high) of anti-insomnia drugs, such as the dual-orexin receptor antagonist (DORA), zopiclone, eszopiclone and zolpidem, induce cognitive impairment.
METHODS
The PubMed, Embase, Scopus, Cochrane Library, and Google Scholar databases were searched from inception to September 20th, 2022 for keywords in randomized controlled trials (RCTs) to evaluate the therapeutic effects of DORA, eszopiclone, zopiclone and zolpidem on sleep and cognitive function. The primary outcomes were indicators related to cognitive characteristics, including scores on the Digit Symbol Substitution Test (DSST) and daytime alertness. The secondary outcomes were the indicators associated with sleep and adverse events. Continuous variables were expressed as the standard mean difference (SMD). Data were obtained through GetData 2.26 and analyzed by Stata v.15.0.
RESULTS
A total of 8702 subjects were included in 29 studies. Eszopiclone significantly increased the daytime alertness score (SMD = 3.00, 95 % CI: 1.86 to 4.13) compared with the placebo, and eszopiclone significantly increased the daytime alertness score (SMD = 4.21, 95 % CI: 1.65 to 6.77; SMD = 3.95, 95 % CI: 1.38 to 6.51; SMD = 3.26, 95 % CI: 0.38 to 6.15; and SMD = 3.23, 95 % CI: 0.34 to 6.11) compared with zolpidem, zolpidem, DORA, and eszopiclone, respectively. Compared with the placebo, zopiclone, zolpidem, and eszopiclone, DORA significantly increased the TST (SMD = 2.39, 95 % CI: 1.11 to 3.67; SMD = 6.00, 95 % CI: 2.73 to 9.27; SMD = 1.89, 95 % CI: 0.90 to 2.88; and SMD = 1.70, 95 % CI: 0.42 to 2.99, respectively).
CONCLUSION
We recommend DORA as the best intervention for insomnia because it was highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem had a more pronounced effect on sleep maintenance, this drug is better for short-term use. Eszopiclone and zopiclone improved sleep, but their cognitive effects have yet to be verified.
PubMed: 38149178
DOI: 10.1016/j.sleepx.2023.100094 -
Sleep Medicine Sep 2023Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been...
OBJECTIVE
Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study.
METHODS
We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported.
RESULTS
The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7).
CONCLUSIONS
Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.
Topics: Humans; Cataplexy; Analgesics, Opioid; Orexins; Oxycodone; Narcolepsy; Disorders of Excessive Somnolence; Surveys and Questionnaires
PubMed: 37437491
DOI: 10.1016/j.sleep.2023.06.008 -
Complex Psychiatry 2023Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and... (Review)
Review
INTRODUCTION
Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrated brain-specific molecular findings of PTSD from humans and animals.
METHODS
A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal-stress paradigms.
RESULTS
Gene- and pathway-level convergence analyses revealed PTSD-dysregulated genes and biological pathways across brain regions and species. A total of 243 genes converged across species, with 17 of them significantly enriched for PTSD. Chemical synaptic transmission and signaling by G-protein-coupled receptors were consistently enriched across omics and species.
DISCUSSION
Our findings point out dysregulated genes highly replicated across PTSD studies in humans and animal models and suggest a potential role for the corticotropin-releasing hormone/orexin pathway in PTSD's pathophysiology. Further, we highlight current knowledge gaps and limitations and recommend future directions to address them.
PubMed: 37404872
DOI: 10.1159/000529536 -
Frontiers in Pharmacology 2023Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited....
Systematic comparisons of the doses of the Food and Drug Administration (FDA)-approved dual orexin receptor antagonists (DORAs) for people with insomnia are limited. PubMed, Embase, Cochrane Library, and Clinicaltrials. gov were systematically searched to identify relevant studies published before 31 October 2022. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. We pooled 7257 participants from 9 randomized controlled trials (RCTs). Moderate to high certainty evidence demonstrated suvorexant (20 and 40 mg) and daridorexant (10 and 50 mg) as the most effective in latency to persistent sleep (LPS) reduction. Lemborexant at 5 and 10 mg was the most effective in subjective sleep onset time (sTSO) reduction. For wake time after sleep onset (WASO), all drugs except daridorexant 5 mg were more effective than placebo. Lemborexant 5 mg was among the best in subjective WASO (sWASO) (moderate to high certainty) and had the highest surface under the curve ranking area (SUCRA) values for sWASO (100%). For total sleep time (TST), suvorexant and daridorexant, except the respective minimum doses, were more effective than placebo, while suvorexant 40 mg and lemborexant 10 mg may have been the most effective for subjective TST (sTST) (low to very low certainty). Suvorexant 40 mg (RR 1.09), suvorexant 80 mg (RR 1.65), and daridorexant 25 mg (RR 1.16) showed a higher safety risk than placebo. Suvorexant 20 mg, lemborexant 5 mg, lemborexant 10 mg, and daridorexant 50 mg represent suitable approaches for insomnia. clinicaltrials.gov, PROSPERO (CRD42022362655).
PubMed: 37261282
DOI: 10.3389/fphar.2023.1175372 -
Arquivos de Neuro-psiquiatria May 2023Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear.
OBJECTIVE
To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia.
METHODS
The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs).
RESULTS
We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes (standardized mean difference [SMD] = -25.40; 95% confidence interval [95%CI] = -40.02--10.78), followed by suvorexant 20/15mg (SMD = -25.29; 95%CI = -36.42--14.15), which also appeared to provide the largest decrease in long-term WASO (SMD = -23.70; 95%CI = -35.89--11.51). The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%.
CONCLUSION
Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Orexin Receptor Antagonists; Network Meta-Analysis; Sleep; Wakefulness
PubMed: 37257468
DOI: 10.1055/s-0043-1768667 -
International Journal of Molecular... Apr 2023The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine,... (Review)
Review
The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.
Topics: Adolescent; Humans; Child; Sleep; Sleep Initiation and Maintenance Disorders; Histamine; Histamine Antagonists; Neurotransmitter Agents; Sleep Wake Disorders
PubMed: 37175525
DOI: 10.3390/ijms24097821 -
Medicine Feb 2023Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy and safety of daridorexant for treatment of insomnia disorder has not been characterized comprehensively in the literature. Therefore, we performed a meta-analysis of available studies. We performed a meta-analysis to systematically evaluate the efficacy and safety of daridorexant for treatment of insomnia disorder.
METHODS
MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials were systematically searched up to February 2022. Relative risk and standard mean difference were used to evaluate clinical outcomes.
RESULTS
We pooled 2271 patients from 4 randomized clinical trials, and evaluated efficacy endpoints. We found that 50 mg of daridorexant was superior to placebo for 4 efficacy outcomes including wake time after sleep onset, latency to persistent sleep, subjective total sleep time, and Insomnia Daytime Symptoms and Impacts Questionnaire domain score (P < .05). In addition, there were no significant differences (P > .05) in adverse events between daridorexant and placebo.
CONCLUSIONS
Different dosages of daridorexant were tested for treatment of insomnia; however, 5 and 10 mg are not available because of issues of suboptimal effectiveness. Daridorexant showed better efficacy and safety for treatment of insomnia disorder at doses of 25 and 50 mg.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Randomized Controlled Trials as Topic; Imidazoles; Pyrrolidines
PubMed: 36800596
DOI: 10.1097/MD.0000000000032754 -
Life (Basel, Switzerland) Jan 2023Background and objective: Obstructive sleep apnea (OSA) can be related to changes in the levels of adipokines and neuropeptides, which in turn may affect the energy... (Review)
Review
Background and objective: Obstructive sleep apnea (OSA) can be related to changes in the levels of adipokines and neuropeptides, which in turn may affect the energy balance components of neuronal cells. Herein, a systematic review and meta-analysis checked the changes in serum/plasma levels of omentin-1 (OM-1: an adipokine) and orexin-A (OXA: a neuropeptide) in adults (age > 18 years old) with OSA (aOSA) compared to controls. Materials and methods: Four databases (Cochrane Library, PubMed, Web of Science, and Scopus) were systematically searched until 14 November 2022, without any restrictions. The Joanna Briggs Institute (JBI) critical appraisal checklist adapted for case−control studies was used to assess the quality of the papers. The effect sizes were extracted using the Review Manager 5.3 software for the blood levels of OM-1 and OXA in aOSA compared with controls. Results: Thirteen articles, with six studies for OM-1 levels and eight for OXA levels, were included. The pooled standardized mean differences were −0.85 (95% confidence interval (CI): −2.19, 0.48; p = 0.21; I2 = 98%) and −0.20 (95%CI: −1.16, 0.76; p = 0.68; I2 = 96%) for OM-1 and OXA levels, respectively. Among the studies reporting OM-1, five were high and one was moderate quality. Among the studies reporting OXA, six were moderate, one was high, and one was low quality. Based on the trial sequential analysis, more participants are needed to confirm the pooled results of the analyses of blood levels of OM-1 and OXA. In addition, the radial plot showed outliers as significant factors for high heterogeneity. Conclusions: The main findings indicated a lack of association between the blood levels of OM-1 and OXA and OSA risk. Therefore, OM-1 and OXA did not appear to be suitable biomarkers for the diagnosis and development of OSA.
PubMed: 36676194
DOI: 10.3390/life13010245 -
Frontiers in Psychiatry 2022Recent treatment guidelines for chronic insomnia recommend pharmacological and non-pharmacological therapies. One of the contemporary drug options for insomnia includes...
Dual orexin receptor antagonists for treatment of insomnia: A systematic review and meta-analysis on randomized, double-blind, placebo-controlled trials of suvorexant and lemborexant.
STUDY OBJECTIVES
Recent treatment guidelines for chronic insomnia recommend pharmacological and non-pharmacological therapies. One of the contemporary drug options for insomnia includes dual orexin receptor antagonist (DORA), such as suvorexant and lemborexant. We conducted a systematic review and meta-analysis for the treatment of insomnia with suvorexant and lemborexant based on randomized, double-blind, placebo-controlled Trials.
METHODS
We conducted a comprehensive search on three databases (PubMed/Medline, Web of Science, and Cochrane Library) till August 14, 2021, without any restrictions to retrieve the relevant articles. The effect sizes were computed presenting the pooled mean difference or risk ratio along with 95% confidence interval of each outcome.
RESULTS
Our search showed eight articles (five for suvorexant and three for lemborexant). Results of diary measures, rating scales, polysomnography results, treatment discontinuation, and adverse events were measured. All efficacy outcome measures favorably and significantly differed in the suvorexant compared to placebo. Safety profile did not differ significantly except for somnolence, excessive daytime sleepiness/sedation, fatigue, back pain, dry mouth, and abnormal dreams. Important adverse events including hallucinations, suicidal ideation/behavior and motor vehicle accidents did not differ between suvorexant and placebo. All the efficacy outcomes significantly differed between lemborexant 5 and lemborexant 10 compared to placebo. Somnolence rate for lemborexant 5 and lemborexant 10 and nightmare for lemborexant 10 were significantly higher than placebo.
CONCLUSION
The present meta-analysis reported that suvorexant and lemborexant are efficacious and safe agents for the patients with insomnia. Further data in patients with insomnia and various comorbid conditions are needed.
PubMed: 36578296
DOI: 10.3389/fpsyt.2022.1070522