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Current Opinion in Neurology Oct 2023The purpose is to review the results and clinical implications of recent studies of neuropathology in relation to neuropsychiatric symptoms (NPS) in Alzheimer's disease... (Review)
Review
PURPOSE OF REVIEW
The purpose is to review the results and clinical implications of recent studies of neuropathology in relation to neuropsychiatric symptoms (NPS) in Alzheimer's disease and related dementias, and discuss new therapeutic approaches based on evidence from clinical trials.
RECENT FINDINGS
In a large autopsy series from a national consortium, multiple neuropathologies of dementia subtypes were common and increased severity of specific NPS during life was associated with greater severity of neuropathology across diagnoses. Based on three clinical trials, brexpiprazole, which is an antipsychotic with dopamine and serotonin receptor partial agonism properties, was recently approved for the treatment of agitation in Alzheimer's dementia by the U.S. Food and Drug Administration (FDA). Its therapeutic profile indicates modest efficacy with high safety. Brexpiprazole has not been compared to other antipsychotics that are commonly prescribed to treat agitation in dementia, though none of them have been approved for this indication. Other drugs that showed positive results in Phase 2 trials are being tested in Phase 3 trials. These include cannabinoids and drug combinations that inhibit dextromethorphan metabolism peripherally, thereby increasing its bioavailability in the brain. Apathy is common in several types of dementia, and there is initial evidence that treatment with methylphenidate, a psychostimulant, may be efficacious with good tolerability.
SUMMARY
Greater understanding of the associations between NPS and dementia subtypes can improve clinical management of these disorders. In addition to the approval of brexpiprazole to treat agitation in Alzheimer's dementia, there is optimism about other medications based on ongoing clinical trials. Along with short-term improvement, altering the adverse impact on NPS on long-term prognosis remains an important challenge for the field.
Topics: United States; Humans; Alzheimer Disease; Quinolones; Thiophenes; Apathy; Antipsychotic Agents
PubMed: 37639488
DOI: 10.1097/WCO.0000000000001199 -
International Clinical... Sep 2023Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a... (Review)
Review
Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.
Topics: Humans; Depressive Disorder, Major; Antidepressive Agents; Bupropion; Sleep Initiation and Maintenance Disorders; Comorbidity
PubMed: 37381161
DOI: 10.1097/YIC.0000000000000488 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with... (Review)
Review
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, -glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.
PubMed: 38004437
DOI: 10.3390/ph16111572 -
CNS Drugs Oct 2023A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as...
BACKGROUND
A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants.
OBJECTIVES
The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion, in adults with MDD.
METHODS
We searched PubMed, Embase, Google Scholar, and ClinicalTrials.gov for current studies reporting on efficacy and/or safety of AXS-05 in patients with MDD. The search terms included: "AXS-05" OR "dextromethorphan and bupropion" AND "depression". Studies from database inception to January 2023 were evaluated. Risk of bias was assessed using the Cochrane Risk of Bias tool.
RESULTS
The search yielded 54 studies of which 5 were included. All studies had low risk of bias. Depression severity, measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) significantly decreased as early as 1-week post-treatment from baseline when compared to a placebo-controlled group (LS mean difference 2.2; 95% CI 0.6-3.9; p = 0.007) and at 2 weeks compared to an active control group (LS mean difference 4.7; 95% CI 0.6-8.8; p = 0.024). Treatment efficacy could be maintained for up to 12 months with mean MADRS score reduction of 23 points from baseline. Clinical remission and response rates also improved at week 1 and were maintained for 12 months. The treatment was well-tolerated, with some transient adverse events reported.
CONCLUSION
Current evidence suggests that the combination of dextromethorphan and bupropion is a well-tolerated, rapid-acting treatment option for adults with MDD. Initial success with AXS-05 supports the mechanistic role of glutamatergeric and sigma 1 signaling in the pathophysiology of MDD.
Topics: Adult; Humans; Antidepressive Agents; Bupropion; Depression; Depressive Disorder, Major; Dextromethorphan; Clinical Trials as Topic
PubMed: 37792265
DOI: 10.1007/s40263-023-01032-5 -
The Journal of Clinical Psychiatry Aug 2023Among the greatest unmet needs in major depressive disorder (MDD) is a lack of effective pharmacotherapies for patients who do not respond to first- and second-line...
Among the greatest unmet needs in major depressive disorder (MDD) is a lack of effective pharmacotherapies for patients who do not respond to first- and second-line antidepressant medications. After decades of muted progress, optimism regarding the future of MDD therapy rose after scientists serendipitously uncovered the antidepressant effects of ketamine. The discovery of ketamine's antidepressant effects inspired the search for related newer medications, such as -ketamine. Orally administered NMDA antagonists have also demonstrated considerable promise in recently concluded, late-stage clinical trials. Researchers evaluating an extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) found that recipients experienced a decline in MADRS total score. Neurosteroids, such as brexanolone and zuranolone, appear to represent another class of antidepressants. These drugs appear to modulate GABA neurotransmission, which has long been known to be a pathway for drugs that are used to treat insomnia and anxiety. After nearly 50 years of legal injunctions against their use, psychedelic drugs have attracted interest among researchers seeking alternative antidepressants. Psilocybin, derived from mushrooms, remains under investigation for its benefits in treatment-resistant depression.
Topics: Humans; Depressive Disorder, Major; Ketamine; Antidepressive Agents; Hallucinogens; Depressive Disorder, Treatment-Resistant
PubMed: 37585245
DOI: 10.4088/JCP.mulmdd3048sho -
Journal of Pharmaceutical and... Jan 2024Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in...
Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in forensic toxicology. The detection of drugs in fingerprint samples can be used to show that an individual touching an item has consumed specific drugs. The aim of this study was to check the usefulness of fingerprints in drug analyses and detection of some analytes in this material. Fingerprint samples were collected on glass slides from a volunteer who consumed separately tablets containing pseudoephedrine, codeine, dextromethorphan, and used lidocaine spray. Moreover, fingerprints of individuals receiving sertraline, hydroxyzine and trazodone as part of their long-term treatment were analysed. The detection of drugs was conducted using the liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. After administration of single doses of drugs, they were detected up to 36 h (pseudoephedrine), 24 h (codeine), and less than 6 h (dextromethorphan and lidocaine) with maximum concentrations observed at 1-4 h. In fingerprints of a person who has finished treatment with hydroxyzine and sertraline it was possible to detect these drugs even 20 days after last drug administration. Cetirizine (hydroxyzine metabolite) and mCPP (trazodone metabolite) were determined in fingerprints of individuals under long-term treatment. This work has demonstrated that forensic toxicology can use fingerprints as alternative material. Drugs can be detected in fingerprints even after their single doses. Parent compounds predominate over metabolites in the fingerprints. The detection window depends on the type of drug and duration of the treatment.
Topics: Humans; Chromatography, Liquid; Trazodone; Tandem Mass Spectrometry; Dextromethorphan; Pseudoephedrine; Sertraline; Substance Abuse Detection; Pharmaceutical Preparations; Hydroxyzine; Codeine; Lidocaine
PubMed: 37926037
DOI: 10.1016/j.jpba.2023.115835 -
Der Nervenarzt May 2024Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established... (Review)
Review
Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile.
Topics: Humans; Depressive Disorder, Treatment-Resistant; Antidepressive Agents; Hallucinogens; Ketamine
PubMed: 38568318
DOI: 10.1007/s00115-024-01647-z -
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 -
Molecular Metabolism Sep 2023Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and...
OBJECTIVE
Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties.
METHODS
Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses.
RESULTS
Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability.
CONCLUSIONS
We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.
Topics: Mice; Humans; Animals; Diabetes Mellitus, Type 2; Insulin; Morphinans; Islets of Langerhans; Glucose; Hypoglycemic Agents; Oxidative Stress
PubMed: 37451343
DOI: 10.1016/j.molmet.2023.101775 -
Turkish Journal of Pharmaceutical... May 2024The aim of this study was to develop a simple, accurate, and precise method for the estimation of bupropion and dextromethorphan in a fixed-dose combination of tablets...
OBJECTIVES
The aim of this study was to develop a simple, accurate, and precise method for the estimation of bupropion and dextromethorphan in a fixed-dose combination of tablets and robust high-performance liquid chromatography for assay analysis of such a fixed combination.
MATERIALS AND METHODS
Chromatographic analysis was performed and separations were achieved on a Denali C18 150 × 4.6 mm, 5 micron using a mobile phase composition of acid and acetonitrile in the ratio of 600:400 (), flow rate of 1.0 mL/min, injection volume is 10 µL and run time of 6 min in isocratic elution. Ultraviolet (UV) detection was performed at a wavelength of 221 nm. The temperature was maintained at 30 °C. Well-resolved peaks were observed with a high number of theoretical plates, lower tailing factor, and reproducible relative retention time. The method was validated, and all validation parameters were found to be within the acceptance limits.
RESULTS
A simple, accurate, and precise method has been developed for estimating bupropion and dextromethorphan in a fixed dose combination of tablets. The optimized method included the following parameters: column temperature of 30 °C, 40% acetonitrile as the mobile phase, and flow rate of 1.0 mL/min. Retention times were 2.25 min and 3.12 min for bupropion and dextromethorphan, respectively. The method was found to be linear in the range of 17.5-105 µg/mL [for R < 0.999) and 7.5-45 µg/mL (for R > 0.999] for bupropion and dextromethorphan, respectively. Both active pharmaceutical ingredients dissolved more than 90% within 5 min.
CONCLUSION
The current study describes a new, simple, reliable, and economical elution reversed-phase high performance liquid chromatography method for estimating bupropion and dextromethorphan in a fixed combination tablet dosage form. The forced degradation studies were conducted using several degradation conditions such as acidic, alkali, oxidation, thermal, UV, and neutral conditions; the proposed method was effectively employed from the resolution of sample peaks. To the best of our knowledge, no such detailed and stability-indicating method has been reported for a fixed tablet dosage form.
PubMed: 38742814
DOI: 10.4274/tjps.galenos.2023.87522