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BMJ Open Apr 2024Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on...
Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol.
BACKGROUND
Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. The present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD).
METHODS AND ANALYSIS
A randomised, double-blind, add-on, placebo-controlled, group sequential design clinical trial will be conducted on patients with MDD who will be randomly assigned to the control and the test group in a 1:1 ratio. Patients in the test group will get dextromethorphan 30 mg once daily, whereas patients in the control group will receive a placebo once daily as an add-on to ongoing SSRI treatment for 8 weeks. All patients will be evaluated for the primary outcome (change in the Montgomery-Åsberg Depression Rating Scale score) and secondary outcomes (treatment response rate, remission rate, Clinical Global Impression, serum brain-derived neurotrophic factor, serum dextromethorphan and treatment-emergent adverse events) over the period of 8 weeks. Intention-to-treat analysis will be done for all parameters using suitable statistical tools.
ETHICS AND DISSEMINATION
This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR's ethical guidelines for biomedical research on human subjects (2017). Written informed consent will be obtained from the participants before recruitment. The results of this study will be published in peer-reviewed publications.
TRIAL REGISTRATION NUMBER
NCT05181527.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Antidepressive Agents; Depressive Disorder, Major; Dextromethorphan; Double-Blind Method; Drug Repositioning; Drug Therapy, Combination; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 38688675
DOI: 10.1136/bmjopen-2023-080500 -
Neurochemical Research Jul 2024N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present...
N-methyl-D-aspartate receptor-dependent excitotoxicity is one of the most important mechanisms underlying stroke injury and the resulting neuronal death. In the present study, in order to reduce post-stroke brain injury and improve behavioral performance, a new molecule named IC87201, which acts as an inhibitor of PSD95/nNOS interaction in the intracellular signaling pathway of NMDA receptors, was administered. Using the middle cerebral artery occlusion (MCAO) technique, 24 adult male rats were subjected to one hour of cerebral ischemia. Animals were randomly divided into sham, MCAO, MCAO + DXM, and MCAO + IC87201 groups, and in the last two groups, intraperitoneal injection of dextromethorphan hydrobromide monohydrate (DXM), as an NMDA antagonist, and IC87201 was performed after ischemia. Neurobehavioral scores were evaluated for seven days, and on the last two days, the rats' memory performance was appraised using the passive avoidance test. On seventh day, the brain tissue was properly prepared for stereological analysis. Stereological studies of the hippocampus CA1 and CA3 regions revealed that changes in the total and infarcted volumes, total number of neurons, non-neurons, and dead neurons are the consequences of cerebral ischemia. Also, following cerebral ischemia, neurobehavioral and memory function impairments which were assessed by modified neurological severity scores (mNSS) and passive avoidance test, were observed. The aforementioned impairments were recovered after administration of IC87201 significantly and more potently than DXM. Based on our findings, IC87201 successfully attenuated post-ischemia damages. Therefore, this molecule can be considered as a new therapeutic approach in future research.
Topics: Animals; Male; Disks Large Homolog 4 Protein; Infarction, Middle Cerebral Artery; Rats; Neuroprotective Agents; Rats, Wistar; Stroke; Rats, Sprague-Dawley
PubMed: 38656691
DOI: 10.1007/s11064-024-04140-w -
Clinical Pharmacology and Therapeutics Jul 2024Although great progress has been made in the fine-tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of...
Although great progress has been made in the fine-tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug-metabolizing enzymes.
Topics: Humans; Male; Female; Phenotype; Polymorphism, Single Nucleotide; Genotype; Adult; Exome; Caffeine; Dextromethorphan; Losartan; Pharmaceutical Preparations; Young Adult; Omeprazole; Sex Factors; Cytochrome P-450 Enzyme System; Genetic Association Studies; Oligonucleotide Array Sequence Analysis
PubMed: 38637968
DOI: 10.1002/cpt.3270 -
Journal of Ethnopharmacology Aug 2024The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible...
ETHNOPHARMACOLOGICAL RELEVANCE
The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear.
AIM OF THE STUDY
This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach.
MATERIALS AND METHODS
Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory.
RESULTS
BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds.
CONCLUSIONS
BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.
Topics: Aconitum; Pinellia; Animals; Herb-Drug Interactions; Rats, Sprague-Dawley; Male; Rats; Cytochrome P-450 Enzyme System; Tandem Mass Spectrometry; Plant Extracts; Drugs, Chinese Herbal; Drug Interactions
PubMed: 38636577
DOI: 10.1016/j.jep.2024.118212 -
Dermatitis : Contact, Atopic,... Apr 2024Although psychedelic and hallucinogenic substances have gained popularity for therapeutic use, their dermatologic adverse effects are poorly characterized. This review... (Review)
Review
Although psychedelic and hallucinogenic substances have gained popularity for therapeutic use, their dermatologic adverse effects are poorly characterized. This review characterizes the cutaneous reactions associated with psychedelic and hallucinogenic drugs. A review of PubMed and Scopus was conducted from the inception of databases to August 31, 2023. Search terms included drug names and classes (cannabis, MDMA, ecstasy, 3,4-methylenedioxymethamphetamine, psychedelics, hallucinogens, peyote, marijuana, lysergic acid diethylamide, LSD, ketamine, dimethyltryptamine, DMT, phencyclidine, PCP, dextromethorphan, psilocybin, and ayahuasca), and dermatosis terms (dermatitis, contact dermatitis, drug eruption, skin reaction, and urticaria). Studies were included if there was an association with a psychedelic or hallucinogenic and any cutaneous reaction; studies without both components were excluded. Twenty-two studies met inclusion criteria, describing reactions to cannabis (10 studies), MDMA (5 studies), ketamine (4 studies), and psilocybin (3 studies). Forty total patients were included. Among cannabis-related reactions, the most common reaction was type I hypersensitivity by topical exposure (n = 21). Three patients reported type IV hypersensitivity reactions to contact with cannabis or cannabis-derived oils, all of whom experienced vesicular contact dermatitis. Two additional patients presented with an erythema-multiforme-like reaction and acute generalized exanthematous pustulosis after systemic administration, respectively. MDMA was associated with acneiform eruptions (2 cases), an urticarial eruption, a guttate psoriasis-like reaction, a fixed drug eruption, and Stevens-Johnson syndrome (1 case). Four patients reported type I hypersensitivity reactions to ketamine. Four patients reported vesicular eruptions, cyanosis, or widespread jaundice to psilocybin. Of the cases, 8 patients had cutaneous reactions that resolved with drug cessation, 10 resolved with cessation plus treatment, and resolution in 7 cases was not reported. Zero studies were found describing other psychedelic or hallucinogenic compounds. Further research is required to characterize reactions and treatments linked to the variety of extant psychedelics and hallucinogens.
PubMed: 38634840
DOI: 10.1089/derm.2023.0292 -
Clinical Psychopharmacology and... May 2024For the first time after many decades, many new antidepressants have been approved and many more are under various stages of development and will soon be available in... (Review)
Review
For the first time after many decades, many new antidepressants have been approved and many more are under various stages of development and will soon be available in the market. The new drugs present a range of new mechanisms of action with benefits in terms of speed of action, tolerability and range of treatable disorders. Neurosteroids have been recently approved and their rapid benefit may extend from postpartum depression to anxious depression and bipolar depression, dextromethorphan and bupropion combination may prove useful in major depression but also in treatment resistant depression, dextromethadone is a possible augmentation in partial antidepressant response, psychedelic drugs have the potential of long lasting benefits after a single administration, though are still experimental treatments. Botulinum has the same advantage of psychedelics of a single administration and its antidepressant effects may last for weeks or more. Further potentially interesting new antidepressant mechanisms include new drug targets, drug repurposing and genetic or epigenetic manipulations. It is therefore important that clinicians are kept up to date with new evidence so that new evidence can be rapidly translated into clinical practice.
PubMed: 38627068
DOI: 10.9758/cpn.23.1145 -
Neuropsychopharmacology Reports Jun 2024To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after... (Comparative Study)
Comparative Study
Comparison of patients with benzodiazepine receptor agonist-related psychiatric disorders and over-the-counter drug-related psychiatric disorders before and after the COVID-19 pandemic: Changes in psychosocial characteristics and types of abused drugs.
AIM
To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after COVID-19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug-related Psychiatric Disorders."
METHOD
A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022.
RESULT
A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD-10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years.
CONCLUSION
By comparing NPH Surveys before and after the COVID-19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor-made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan-containing OTC drugs has increased alarmingly.
Topics: Humans; Female; COVID-19; Male; Adult; Substance-Related Disorders; Nonprescription Drugs; Mental Disorders; Middle Aged; GABA-A Receptor Agonists; Young Adult; Adolescent
PubMed: 38622878
DOI: 10.1002/npr2.12440 -
Clinical Drug Investigation May 2024Viloxazine extended-release (ER) [Qelbree] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for...
Impact of Viloxazine Extended-Release Capsules (Qelbree) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.
BACKGROUND AND OBJECTIVE
Viloxazine extended-release (ER) [Qelbree] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.
METHODS
Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.
RESULTS
The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (C), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan C, AUC and AUC, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam C, AUC and AUC, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were C 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC 125.66 (105.36-149.87)).
CONCLUSION
Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.
Topics: Humans; Cytochrome P-450 CYP2D6; Male; Adult; Delayed-Action Preparations; Polymorphism, Genetic; Viloxazine; Female; Young Adult; Caffeine; Dextromethorphan; Capsules; Midazolam; Cytochrome P-450 Enzyme System; Healthy Volunteers
PubMed: 38598106
DOI: 10.1007/s40261-024-01356-0 -
Orphanet Journal of Rare Diseases Apr 2024We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore...
AIM
We aim to describe the behavioral phenotype of children and adolescents with the good to intermediate attenuated form of non-ketotic hyperglycinemia (NKH) and to explore associations between the behavioral phenotype and age, sex, plasma glycine levels and drug treatment.
METHOD
Parents of children with attenuated NKH completed questionnaires assessing maladaptive behavior, adaptive behavior, social communication, speech/language development and motor development in addition to demographic and medical questions.
RESULTS AND INTERPRETATION
Twelve children, age 6 to 21y, functioned at mild to severe intellectual disability levels. Their speech/language development was in line with their developmental quotient. Relative to their intellectual functioning, their motor development and communication were weaker in comparison to their general development. Their adaptive behavior, however, appeared a relative strength. There was no evidence for autism spectrum disorder occurring more frequently than expected, rather social skills, except for communication, were rated as a relative strength. Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children. Maladaptive behaviors were significantly related to female sex and to taking dextromethorphan, but no significant relation between plasma glycine levels and behavior was found. Future studies will need to evaluate causality in the observed relation between dextromethorphan use and maladaptive behaviors. Clinicians should reconsider the benefit of dextromethorphan when presented with disruptive behaviors in children with attenuated NKH.
Topics: Child; Humans; Female; Adolescent; Young Adult; Adult; Hyperglycinemia, Nonketotic; Autism Spectrum Disorder; Dextromethorphan; Phenotype; Glycine
PubMed: 38589924
DOI: 10.1186/s13023-024-03172-3 -
Journal of the Chinese Medical... May 2024The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased...
BACKGROUND
The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats.
METHODS
Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT.
RESULTS
MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction.
CONCLUSION
Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.
Topics: Animals; Male; Rats; Dextromethorphan; N-Methyl-3,4-methylenedioxyamphetamine; Positron-Emission Tomography; Rats, Sprague-Dawley; Reward; Serotonin Plasma Membrane Transport Proteins
PubMed: 38587377
DOI: 10.1097/JCMA.0000000000001087