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Pharmacopsychiatry Jul 2022There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis.
INTRODUCTION
There is an imminent need for faster-acting and more effective antidepressants beyond the monoaminergic hypothesis.
METHODS
We systematically searched the US Clinical Trials registry for antidepressant compounds with completed phase II and III trials. Compounds that demonstrated significant superiority over placebo in the primary outcome measure in the latest phase of phase II and III trials were identified. The collateral information was gathered via a PubMed search and press releases.
RESULTS
Nine compounds were identified. AXS-05 (a combination of dextromethorphan and bupropion) and ansofaxine hydrochloride showed a positive result over placebo in a phase III study for major depressive disorder or treatment-resistant depression. MIJ821, nitrous oxide, psilocybin, ayahuasca, facial injection of botulinum toxin A, prasterone, and casopitant demonstrated at least one positive result in phase II trials. Ayahuasca showed a greater response rate than placebo at week one, indicating the rapid antidepressant effect.
DISCUSSION
These new compounds with novel mechanisms of action are expected to provide a greater variety of treatment options for depression if preliminary positive results are confirmed.
Topics: Antidepressive Agents; Clinical Trials, Phase II as Topic; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Humans; Registries
PubMed: 35045580
DOI: 10.1055/a-1714-9097 -
Journal of Pharmaceutical Policy and... Sep 2021Over-the-counter (OTC) medicines are typically safe. However, there is evidence that OTC medicines can sometimes cause harm as a result of their misuse, abuse and... (Review)
Review
A mixed-methods systematic review of the prevalence, reasons, associated harms and risk-reduction interventions of over-the-counter (OTC) medicines misuse, abuse and dependence in adults.
BACKGROUND
Over-the-counter (OTC) medicines are typically safe. However, there is evidence that OTC medicines can sometimes cause harm as a result of their misuse, abuse and dependence.
AIM OF THE REVIEW
To review the literature on OTC medicines misuse, abuse and dependence in adults and identify the implicated medicines, contributing factors, associated harms and risk-mitigating interventions.
METHODS
Following PRISMA guidelines, electronic databases including Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, MEDLINE, PsycINFO Web of Science and Google Scholar were searched for peer-reviewed journal articles published in English between January 2011 and March 2019. Quantitative, qualitative and mixed-methods studies assessing aspects of misuse, abuse and dependence of OTC medicines in individuals aged 18 years or more were included. Studies that solely focused on adolescents only, doping in sports or abuse of OTC medicines in people who are substance abusers were excluded. The random effect meta-analysis model was used to pool the prevalence among the population-based studies.
RESULTS
Of 2355 peer-reviewed studies initially identified, 53 were included in this review. According to the study design, the prevalence varied, but the overall pooled prevalence in the population-based studies was: 16.2% for misuse, 2.0% for abuse, and 7.2% for dependence. The common OTC medicines groups involved in the problematic use were analgesics (with or without codeine), sedative antihistamines, cough mixtures containing dextromethorphan. Physical, psychological, social and financial harms were associated with problematic use of OTC medicines in addition to hospitalisation and death. Interventions for the affected individuals were provided mainly through the community pharmacies, general practices and specialised addiction centres.
CONCLUSION
The problematic use of OTC medicines is quite prevalent in adults, necessitating raising public awareness about their safe use. In addition, innovative harm minimisation models need to be developed, evaluated and implemented across health care settings.
PubMed: 34517925
DOI: 10.1186/s40545-021-00350-7 -
Frontiers in Psychiatry 2021Over the past 20 years or so, the drug misuse scenario has seen the emergence of both prescription-only and over-the-counter (OTC) medications being reported as...
Over the past 20 years or so, the drug misuse scenario has seen the emergence of both prescription-only and over-the-counter (OTC) medications being reported as ingested for recreational purposes. OTC drugs such as antihistamines, cough/cold medications, and decongestants are reportedly the most popular in being diverted and misused. While the current related knowledge is limited, the aim here was to examine the published clinical data on OTC misuse, focusing on antihistamines (e.g., diphenhydramine, promethazine, chlorpheniramine, and dimenhydrinate), dextromethorphan (DXM)- and codeine-based cough medicines, and the nasal decongestant pseudoephedrine. A systematic literature review was carried out with the help of Scopus, Web of Science databases, and the related gray literature. For data gathering purposes, both the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and PROSPERO guidelines were followed (PROSPERO identification code CRD42020209261). After completion of the selection, eligibility, and screening phases, some 92 articles were here taken into consideration; case reports, surveys, and retrospective case series analyses were included. Findings were organized according to the specific OTC recorded. Most articles focused here on DXM ( = 54) and diphenhydramine ( = 12). When specified, dosages, route(s) of administration, toxicity symptoms (including both physical and psychiatric ones), and outcomes were here reported. Results from the systematic review showed that the OTC misusing issues are both widespread worldwide and popular; vulnerable categories include adolescents and young adults, although real prevalence figures remain unknown, due to a lack of appropriate monitoring systems. Considering the potential, and at times serious, adverse effects associated with OTC misusing issues, healthcare professionals should be vigilant, and preventative actions should be designed and implemented.
PubMed: 34025478
DOI: 10.3389/fpsyt.2021.657397 -
Expert Opinion on Emerging Drugs Mar 2021The large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the...
INTRODUCTION
The large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the need for mechanistically novel treatments. Convergent evidence implicates glutamatergic signaling as a potential therapeutic target in MDD.
AREAS COVERED
The synthesis herein of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and exhibits clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with MDD. DXM efficacy has been preliminarily reported in adults with bipolar depression. The combination of DXM and bupropion represents a pharmacokinetic and pharmacodynamic synergy which may account for the rapidity of action in MDD.
EXPERT OPINION
The combination of DXM and bupropion is a safe, well tolerated and efficacious treatment option in adults with MDD. Priority questions are whether DXM/bupropion is uniquely effective across discrete domains of psychopathology (e.g. anhedonia, reward processing, general cognitive systems) and/or whether it is able to significantly improve patient-reported outcomes (e.g. quality of life, psychosocial functioning). The availability of ketamine/esketamine and DXM/bupropion instantiates the relevance of glutamate as a treatment target in MDD. Studies in bipolar depression with DXM/bupropion are warranted as well as in MDD with suicidality.
Topics: Adult; Animals; Antidepressive Agents; Bipolar Disorder; Bupropion; Depressive Disorder, Major; Dextromethorphan; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Humans; Molecular Targeted Therapy
PubMed: 33682569
DOI: 10.1080/14728214.2021.1898588 -
BMC Geriatrics Jun 2020Prescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Prescribing trends suggest that pharmacologic alternatives to antipsychotics are gaining in popularity, but randomized trial (RCT) data of their comparative safety is scarce. Our objective was to describe the comparative safety of pharmacologic interventions for treating neuropsychiatric symptoms in dementia.
METHODS
We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, from inception to May 28, 2019, for studies of pharmacologic interventions used to treat neuropsychiatric symptoms in dementia. Dementia care partners selected fracture risk as our primary outcome. Pairs of reviewers, working independently, conducted all study screening, data abstraction, and risk of bias appraisal. We conducted Bayesian random-effects network meta-analyses (NMAs) using data from RCTs to derive odds ratios (ORs). In secondary analyses, we conducted frequentist random-effects NMAs using data from RCTs and Bayesian three-level hierarchical random-effects NMAs incorporating data from RCTs and non-randomized studies.
RESULTS
Our systematic review included 209 randomized and non-randomized studies (889,378 persons with dementia). In NMAs of data from randomized trials, there were no increased odds of fracture associated with any intervention in primary analyses; however, data were sparse. We found increased odds of cerebrovascular events associated with antipsychotics (odds ratio [OR] 2.12, 95% credible interval [CrI] 1.29 to 3.62; number needed to harm [NNH] = 99) and increased odds of falls associated with dextromethorphan-quinidine (OR 4.16, 95% CrI 1.47 to 14.22; NNH = 55) compared to placebo in persons with dementia. In a subgroup of persons with Alzheimer disease, antipsychotics were associated with increased odds of fracture compared to anticonvulsants (OR 54.1, 95% CrI 1.15 to 38,300; NNH = 18). In older persons (mean age ≥ 80 years) with dementia, anticonvulsants were associated with increased odds of death compared to placebo (OR 8.36, 95% CrI 1.17 to 203.4; NNH = 35) and antipsychotics were associated with increased odds of death compared to antidepressants (OR 5.28, 95% CrI 1.06 to 3.51; NNH = 47).
CONCLUSION
Although antipsychotics were associated with greater harm than antidepressants and anticonvulsants in subgroups of persons with dementia, medications used in lieu of antipsychotics for treating neuropsychiatric symptoms in dementia, such as anticonvulsants and dextromethorphan-quinidine, were also associated with harm. Decision-making concerning treatments prescribed in lieu of antipsychotics should include potential harms.
PROSPERO REGISTRATION
CRD42017050130.
Topics: Aged; Aged, 80 and over; Antidepressive Agents; Antipsychotic Agents; Bayes Theorem; Dementia; Humans; Network Meta-Analysis
PubMed: 32546202
DOI: 10.1186/s12877-020-01607-7 -
Drug and Alcohol Dependence Mar 2020Demand for treatments for severe opioid use disorder is increasing worldwide. The current pharmacotherapy is mainly focused on opioid and adrenergic receptors. The...
BACKGROUND
Demand for treatments for severe opioid use disorder is increasing worldwide. The current pharmacotherapy is mainly focused on opioid and adrenergic receptors. The N-methyl-d-aspartate receptor (NMDAR) is among other receptors that can also be targeted to treat the disease. Findings from randomized controlled trials (RTCs) on NMDAR antagonists to treat severe opioid use disorder amply varied. This study aimed to evaluate the clinical benefits and assess the potential risks for adverse events or side effects of NMDAR antagonists that were investigated for the treatment of severe opioid use disorder.
METHODS
Articles were searched in PubMed, Scopus, Google Scholar, Proquest. Cochrane Review Database, Medline Ovid, and EMBASE from their inception to March 2019. RTCs on NMDAR antagonists for the treatment of severe opioid use disorder were independently screened and assessed by two authors. The results were synthesized qualitatively.
RESULTS
Nineteen RTCs of 1459 participants met the inclusion criteria. There is moderate evidence suggesting that ketamine, memantine, amantadine, and dextromethorphan may be able to manage opioid withdrawal symptoms. There is little evidence suggesting that memantine may be able to reduce methadone maintenance dose in participants on methadone, reduce opioid use, and reduce craving. Dropout is noticeable among dextromethorphan's participants. Safety concerns are more likely associated with dextromethorphan and ketamine.
CONCLUSIONS
NMDAR antagonists have the potentiality to treat severe opioid use disorder. There is insufficient evidence to recommend them for the treatment of severe opioid use disorder due to several limitations inherent to the RCTs reviewed. Further exploration is needed.
Topics: Analgesics, Opioid; Excitatory Amino Acid Antagonists; Humans; Ketamine; Memantine; Methadone; Opiate Substitution Treatment; Opioid-Related Disorders; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Risk Assessment; Severity of Illness Index; Substance Withdrawal Syndrome; Treatment Outcome
PubMed: 31978670
DOI: 10.1016/j.drugalcdep.2020.107845 -
Neuropsychology Review Mar 2020Pseudobulbar affect is a debilitating condition that significantly reduces quality of life for many individuals following traumatic brain injury (TBI). It is...
Pseudobulbar affect is a debilitating condition that significantly reduces quality of life for many individuals following traumatic brain injury (TBI). It is characterized by embarrassing and often uncontrollable episodes of crying or laughter. The aim of this systematic review was to evaluate the effectiveness of pharmacotherapy as compared to all other comparators for the management of pseudobulbar affect in adults who have sustained TBI. Six databases were searched, with additional hand searching of journals, clinical trials registries and international drug regulators to identify published and unpublished studies in English up to June 2018. Studies were eligible for this review if they included adults who had sustained a medically confirmed TBI and presented with pseudobulbar affect. All pharmacotherapy and comparator interventions were considered for inclusion, and study design was not limited to randomised controlled trials. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Two quasi-experimental studies examining the effectiveness of dextrometamorphan/quinidine (DM/Q) were identified. These studies reported that DM/Q was effective in reducing symptoms of pseudobulbar affect and had a positive safety profile, over follow-up periods of 3 months (n = 87) and 12 months (n = 23). However, both studies were limited by lack of a control group and a high dropout rate. The findings of twelve case reports examining the effectiveness of DM/Q (n = 6) and anti-depressants (n = 6) are also discussed. Further research is required to determine which pharmacological interventions provide the best outcomes for individuals with pseudobulbar affect following TBI, with consideration given to side effect profiles and financial costs.
Topics: Affective Symptoms; Brain Injuries, Traumatic; Dextromethorphan; Drug Combinations; Humans; Neurotransmitter Agents; Quinidine
PubMed: 31942705
DOI: 10.1007/s11065-020-09427-7 -
British Journal of Anaesthesia Aug 2019Intense pain can last several days after tonsillectomy. It is often undertreated and improved analgesic strategies that can be safely used at home are needed. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intense pain can last several days after tonsillectomy. It is often undertreated and improved analgesic strategies that can be safely used at home are needed.
METHODS
We conducted a systematic review and meta-analysis on the effectiveness of systemic medications used for post-tonsillectomy pain in adult and adolescent (13 yr old) patients. Studies were identified from PubMed, the Cochrane Library, and by hand searching reference lists from studies and review articles. Randomised, double-blind, placebo-controlled studies reporting on pain intensity or use of rescue analgesia were included.
RESULTS
Twenty-nine randomised controlled trials representing 1816 subjects met the inclusion criteria. Follow-up time was ≤24 h in 15 studies, in which the majority were taking nonsteroidal anti-inflammatory drugs. Thirteen studies were suitable for meta-analysis. In pooled analysis, paracetamol, dexamethasone, and gabapentinoids reduced pain intensity on the day of operation. In individual studies, ketoprofen, ibuprofen, lornoxicam, parecoxib, rofecoxib, indomethacin and dextromethorphan reduced pain intensity, need for rescue analgesics, or both on the day of operation. Oral celecoxib for 2 postoperative weeks or i.v. ketamine on the day of operation were not effective at the studied doses. Dexamethasone in multiple doses provided analgesia beyond 1 postoperative day. Pain was moderate to strong in both study and control groups during the first postoperative week.
CONCLUSIONS
Single analgesics and dexamethasone provide only a weak to moderate effect for post-tonsillectomy pain on the day of operation and thus a multimodal analgesic strategy is recommended. Short follow-up times and clinical heterogeneity of studies limit the usefulness of results.
Topics: Adult; Analgesics; Anti-Inflammatory Agents; Dexamethasone; Humans; Pain, Postoperative; Tonsillectomy
PubMed: 31221427
DOI: 10.1016/j.bja.2019.04.063 -
Frontiers in Neurology 2018Perinatal and perioperative brain injury is a fundamental problem in infants with severe congenital heart disease undergoing neonatal cardiac surgery with...
Perinatal and perioperative brain injury is a fundamental problem in infants with severe congenital heart disease undergoing neonatal cardiac surgery with cardiopulmonary bypass. An impaired neuromotor and neurocognitive development is encountered and associated with a reduction in quality of life. New neuroprotective drugs during surgery are described to reduce brain injury and improve neurodevelopmental outcome. Therefore, our aim was to provide a systematic review and best-evidence synthesis on the effects of neuroprotective drugs on brain injury and neurodevelopmental outcome in congenital heart disease infants requiring cardiac surgery with cardiopulmonary bypass. A systematic search was performed in PubMed, Embase and the Cochrane Library (PRISMA statement). Search terms were "infants," "congenital heart disease," "cardiac surgery," "cardiopulmonary bypass," and "neuroprotective drug." Data describing the effects on brain injury and neurodevelopmental outcome were extracted. Study quality was assessed with the Cochrane Risk of Bias Tool. Two reviewers independently screened sources, extracted data and scored bias. Disagreements were resolved by involving a third researcher. The search identified 293 studies of which 6 were included. In total 527 patients with various congenital heart diseases participated with an average of 88 infants (13-318) per study. Allopurinol, sodium nitroprusside, erythropoietin, ketamine, dextromethorphan and phentolamine were administered around cardiac surgery with cardiopulmonary bypass. Allopurinol showed less seizures, coma, death and cardiac events in hypoplastic left heart syndrome (HLHS) infants (OR: 0.44; 95%-CI:0.21-0.91). Sodium nitroprusside resulted in lower post cardiopulmonary bypass levels of S100ß in infants with transposition of the great arteries after 24 ( < 0.01) and 48 ( = 0.04) h of treatment. Erytropoietin, ketamine and dextromethorphan showed no neuroprotective effects. Phentolamine led to higher S100ß-levels and cerebrovascular resistance after rewarming and at the end of surgery (both < 0.01). Risk of bias varied between studies, including low (sodium nitroprusside, phentolamine), moderate (ketamine, dextromethorphan), and high (erytropoietin, allopurinol) quality. Allopurinol seems promising for future trials in congenital heart disease infants to reduce brain injury given the early neuroprotective effects in hypoplastic left heart syndrome infants. Larger well-designed trials are needed to assess the neuroprotective effects of sodium nitroprusside, erytropoietin, ketamine and dextromethorphan. Future neuroprotective studies in congenital heart disease infants should not only focus on the perioperative period, however also on the perinatal period, since significant brain injury already exists before surgery.
PubMed: 30018590
DOI: 10.3389/fneur.2018.00521 -
British Journal of Clinical Pharmacology Jul 2018To determine the most efficacious and acceptable treatments of agitation in dementia. (Meta-Analysis)
Meta-Analysis
AIMS
To determine the most efficacious and acceptable treatments of agitation in dementia.
METHODS
MEDLINE, EMBASE, PsycINFO, CENTRAL and clinicaltrials.gov were searched up to 7 February 2017. Two independent reviewers selected randomized controlled trials (RCTs) of treatments to alleviate agitation in people with all-types dementia. Data were extracted using standardized forms and study quality was assessed using the revised Cochrane Risk of Bias Tool for RCTs. Data were pooled using meta-analysis. The primary outcome, efficacy, was 8-week response rates defined as a 50% reduction in baseline agitation score. The secondary outcome was treatment acceptability defined as treatment continuation for 8 weeks.
RESULTS
Thirty-six RCTs comprising 5585 participants (30.9% male; mean ± standard deviation age, 81.8 ± 4.9 years) were included. Dextromethorphan/quinidine [odds ratio (OR) 3.04; 95% confidence interval (CI), 1.63-5.66], risperidone (OR 1.96; 95% CI, 1.49-2.59) and selective serotonin reuptake inhibitors as a class (OR 1.61; 95% CI, 1.02-2.53) were found to be significantly more efficacious than placebo. Haloperidol appeared less efficacious than nearly all comparators. Most treatments had noninferior treatment continuation compared to placebo, except oxcarbazepine, which was inferior. Findings were supported by subgroup and sensitivity analyses.
CONCLUSIONS
Risperidone, serotonin reuptake inhibitors as a class and dextromethorphan/quinidine demonstrated evidence of efficacy for agitation in dementia, although findings for dextromethorphan/quinidine were based on a single RCT. Our findings do not support prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability. The decision to prescribe should be based on comprehensive consideration of the benefits and risks, including those not evaluated in this meta-analysis.
Topics: Antipsychotic Agents; Dementia; Dextromethorphan; Drug Combinations; Humans; Network Meta-Analysis; Psychometrics; Psychomotor Agitation; Quinidine; Randomized Controlled Trials as Topic; Risperidone; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Treatment Outcome
PubMed: 29637593
DOI: 10.1111/bcp.13604