-
Neurobiology and Symptomatology of Post-Acute Alcohol Withdrawal: A Mixed-Studies Systematic Review.Journal of Studies on Alcohol and Drugs Jul 2022This study aims to review the neurobiology and symptomatology of post-acute alcohol withdrawal syndrome (PAWS).
OBJECTIVE
This study aims to review the neurobiology and symptomatology of post-acute alcohol withdrawal syndrome (PAWS).
METHOD
We conducted a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-guided systematic review of articles from two databases for English-language randomized and nonrandomized studies involving PAWS published between database inception and December 2020.
RESULTS
Twenty-seven studies met inclusion criteria. PAWS involves predominantly negative affect, which develops in early abstinence and can persist for 4-6 months or longer. Symptoms include anxiety, dysphoria, anhedonia, sleep disturbance, cognitive impairment, cravings, and irritability. PAWS symptoms appear to be risk factors for recurrent alcohol consumption. They have been associated with reported neurobiological differences in evoked potentials; measures of orexins, cortisol, serotonin, and pancreatic polypeptides; and neuroadaptation changes in the nucleus accumbens and the prefrontal cortex.
CONCLUSIONS
There is credible evidence to support the concept of PAWS based on this review's findings. There remains a need to develop and test specific criteria for PAWS. High-quality treatment studies involving agents addressing its neurobiological underpinnings are also recommended.
Topics: Humans; Alcohol Drinking; Alcoholism; Craving; Neurobiology; Substance Withdrawal Syndrome
PubMed: 35838422
DOI: 10.15288/jsad.2022.83.461 -
Journal of Experimental Pharmacology 2021Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the... (Review)
Review
Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I-III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.
PubMed: 33889031
DOI: 10.2147/JEP.S261403 -
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 -
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 -
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 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 -
Clinical Neurology and Neurosurgery Jul 2024Parkinson's disease (PD) is a progressive neurological condition that affects movement and coordination. Orexin-A (OXA) is an excitatory neuropeptide that is found... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Parkinson's disease (PD) is a progressive neurological condition that affects movement and coordination. Orexin-A (OXA) is an excitatory neuropeptide that is found throughout the central nervous system. There is growing interest in investigating the potential diagnostic and therapeutic utility of OXA in PD. To date, studies have reported a wide range of OXA concentrations in patients with PD. In this review, we discuss the current understanding of the dysregulation of OXA in PD and analyze its levels in the CSF.
METHODS
We searched six databases (PubMed, Scopus, Web of Science, EMBASE, ProQuest, and EBSCOHost) and preprint servers using a predetermined search strategy through 4th March 4, 2023. The search keywords included "Parkinson's disease", "Orexin-A", "Hypocretin-1", "cerebrospinal fluid", and "CSF". Studies that reported OXA/Hypocretin-1 levels in the CSF of patients with PD were included. Two researchers independently reviewed the records and extracted data.
FINDINGS
Eighteen studies involving 244 patients were analyzed. CSF Orexin-A concentrations were lower in patients with Parkinson's disease than in controls, with a mean difference of -59.21 (95 % CI: -89.10 to -29.32). The mean OXA levels were 281.52 (95 % CI: 226.65-336.40).
CONCLUSION
Our analysis reveals lower concentrations of orexin-A in the cerebrospinal fluid of Parkinson's disease patients compared to controls, but within the normal range. These findings suggest a potential, but not significant, disruption in the orexinergic system associated with the disease.
Topics: Orexins; Humans; Parkinson Disease
PubMed: 38781804
DOI: 10.1016/j.clineuro.2024.108320 -
Neurological Sciences : Official... May 2023Insomnia is a common condition that may be caused by or coexist with other medical or psychological illnesses. Nearly a quarter of a billion people across the globe... (Review)
Review
INTRODUCTION
Insomnia is a common condition that may be caused by or coexist with other medical or psychological illnesses. Nearly a quarter of a billion people across the globe suffer from insomnia frequently. Lemborexant, a dual orexin receptor antagonist, is a recently authorized hypnotic-based medication for insomnia. The purpose of this systematic review is to further investigate its efficacy and safety profile, with the primary goal of comparing the effects of two FDA-approved doses of lemborexant, 5 mg and 10 mg (LEM5 and LEM10, respectively).
MATERIALS AND METHODS
PubMed, Google Scholar, ClinicalTrials.gov, and Cochrane Central were searched for relevant literature, and studies were considered if they compared the efficacy and safety of lemborexant 5 mg to lemborexant 10 mg. This study comprised clinical trials.
RESULTS
A total of 6 studies were evaluated for efficacy and safety of lemborexant therapy. They reported a significant betterment in values pertaining to sleep efficacy, sleep onset latency, wake after sleep onset, total sleep time, sleep quality, ISI score, and morning alertness. The results presented a dose-dependent pattern and showed slight variation with the different dosages. The most prevalent side effects noted were somnolence, headaches, and dizziness, with infections like UTIs and upper respiratory tract infections also being commonly reported. The incidence is rather ambiguous and not sincerely dose-dependent. The differences between results for LEM5 and LEM10 do not exhibit a wide variation, although slight dose-dependent alterations are noted.
CONCLUSION
Lemborexant is well integrated with the amelioration of sleep disturbances in insomniac patients, as shown by a decrease in eSOL and sWASO and a rise in sSE, sTST, quality of sleep, and morning alertness. Effects last 12 months after therapy.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Pyridines; Pyrimidines; Hypnotics and Sedatives; Orexin Receptor Antagonists
PubMed: 36633778
DOI: 10.1007/s10072-023-06601-6 -
International Clinical... Jan 2023Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We... (Meta-Analysis)
Meta-Analysis
Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We assess the safety and efficacy of this novel drug in the treatment of insomnia. We performed a systematic search for electronic databases in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized controlled trials were included in this review, with 2425 participants enrolled. Daridorexant was superior to placebo in reducing wake time after sleep onset (MD = -13.26; 95% CI, -15.48 to -11.03; P < 0.00001), latency to persistent sleep (MD = -7.23; 95% CI, -9.60 to -4.85; P < 0.00001), with increasing the total sleep time (MD = 14.80; 95% CI, 11.18-18.42; P < 0.00001) and subjective total sleep time (MD = 14.80; 95% CI, 11.18-18.42], P < 0.00001). The 25 mg and 50 mg were the most officious doses. Treatment with daridorexant has resulted in a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI, 1.05-1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13-3.23; P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21-3.36; P = 0.007). Daridorexant is superior to placebo in improving sleep quality. However, the drug resulted in a slightly higher incidence of adverse events, including somnolence and fatigue.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Randomized Controlled Trials as Topic
PubMed: 36473030
DOI: 10.1097/YIC.0000000000000425 -
Sleep Medicine Reviews Oct 2020Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically...
Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically evaluated. Thus, we performed a systematic review to assess how these compounds effect sleep architecture in healthy and clinical human samples. Relevant articles were identified via searches of PubMed, Embase, the Cochrane central register of controlled trials, and clinicaltrials. gov. From 1147 retrieved records, 18 satisfied inclusion criteria and formed the basis of this review. Of these, fifteen studies administered dual orexin receptor antagonists (DORA) in a healthy control (five studies) or clinical sample (ten studies). By contrast, three studies administered selective orexin receptor-2 antagonists (2-SORA) in either a healthy control (one study) or clinical sample (two studies). Results reveal DORAs increase total sleep time primarily by promoting REM sleep, without affecting, or even decreasing, non-REM sleep, especially in clinical samples. Therefore, the clinical utility of DORAs may depend on the specific sample being treated. For 2-SORAs, limited evidence available precludes firm conclusions about their influence on human sleep architecture and, thus, further investigation of 2-SORAs is required to define their effects and make comparisons on this basis with DORAs.
Topics: Azepines; Healthy Volunteers; Humans; Orexin Receptor Antagonists; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep, REM; Triazoles
PubMed: 32505969
DOI: 10.1016/j.smrv.2020.101332