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CNS Drugs Nov 2022An oral, fixed-dose combination of dextromethorphan hydrobromide [an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist] and the... (Review)
Review
An oral, fixed-dose combination of dextromethorphan hydrobromide [an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist] and the antidepressant bupropion hydrochloride (an aminoketone and CYP2D6 inhibitor that increases dextromethorphan bioavailability) [AUVELITY; dextromethorphan/bupropion], is being developed by Axsome Therapeutics, Inc. for the treatment of major depressive disorder (MDD), Alzheimer's disease agitation and smoking cessation. Dextromethorphan/bupropion was approved in the USA in August 2022 for the treatment of MDD in adults. This article summarizes the milestones in the development of dextromethorphan/bupropion leading to this first approval for the treatment of adults with MDD.
Topics: Adult; Humans; Antidepressive Agents; Bupropion; Depressive Disorder, Major; Dextromethorphan; Receptors, N-Methyl-D-Aspartate; Drug Approval
PubMed: 36301443
DOI: 10.1007/s40263-022-00968-4 -
The Journal of Clinical Psychiatry May 2022Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05... (Randomized Controlled Trial)
Randomized Controlled Trial
Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral -methyl--aspartate (NMDA) receptor antagonist and σ receptor agonist, in the treatment of major depressive disorder (MDD). This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures. A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 ( = .007) and week 2 ( < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction. In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated. ClinicalTrials.gov Identifier: NCT04019704.
Topics: Bupropion; Depressive Disorder, Major; Dextromethorphan; Double-Blind Method; Humans; Quality of Life
PubMed: 35649167
DOI: 10.4088/JCP.21m14345 -
ACS Chemical Neuroscience Jun 2023Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used... (Review)
Review
Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at -methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.
Topics: Humans; Antitussive Agents; Dextromethorphan; Hallucinogens; Phencyclidine; Ketamine; Receptors, N-Methyl-D-Aspartate
PubMed: 37290117
DOI: 10.1021/acschemneuro.3c00088 -
WMJ : Official Publication of the State... 2023
Topics: Humans; Bupropion; Dextromethorphan
PubMed: 36724488
DOI: No ID Found -
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 -
Pediatric Emergency Care Dec 2004Dextromethorphan is an over-the-counter dissociative agent of increasing popularity as a drug of abuse among younger adolescents. The drug produces a range of toxicities... (Review)
Review
Dextromethorphan is an over-the-counter dissociative agent of increasing popularity as a drug of abuse among younger adolescents. The drug produces a range of toxicities depending upon either the dose or the components of the specific formulation that was ingested. Most cases improve with supportive care alone, but severely intoxicated patients may require significant attention. Because dextromethorphan is misused primarily by younger adolescents, the early identification and treatment of dextromethorphan abuse may be important in preventing broader substance abuse in these children. Consequently, it is important for clinicians to recognize, treat, and appropriately refer those who present with intoxication from this drug.
Topics: Adolescent; Child; Dextromethorphan; Female; Humans; Substance-Related Disorders
PubMed: 15572980
DOI: 10.1097/01.pec.0000148039.14588.d0 -
Expert Review of Neurotherapeutics Mar 2023Major depressive disorder (MDD) is one of the leading causes of disability worldwide. However, many patients do not achieve an adequate clinical improvement with... (Review)
Review
INTRODUCTION
Major depressive disorder (MDD) is one of the leading causes of disability worldwide. However, many patients do not achieve an adequate clinical improvement with pharmacotherapies targeting monoamine receptors, and the onset of therapeutic benefit typically lags by 4-6 weeks. There is a significant need for mechanistically novel treatments with more rapid efficacy. Combinations of dextromethorphan, an oral N-methyl-D-aspartate (NMDA) receptor antagonist, can potentially fill this gap.
AREAS COVERED
US Clinical Trials registration was systematically searched for studies examining the effects of dextromethorphan in mood disorders. Results were gathered via a PubMed search, adding also press releases, and poster presentations. Two case reports and eight clinical trials were identified for the treatment of MDD or treatment resistant depression (TRD); we also reviewed additional studies in bipolar disorder.
EXPERT OPINION
Clinical studies show that the combinations of dextromethorphan with quinidine or bupropion have been effective in decreasing depressive symptomatology in MDD. However, dextromethorphan studies in adults with TRD or with bipolar depression have shown mixed results. The combination of dextromethorphan and bupropion is a well-tolerated, safe, and efficacious treatment option for adults with MDD. Additional studies analyzing the effects of dextromethorphan and bupropion for TRD and bipolar depression are needed.
Topics: Adult; Humans; Bipolar Disorder; Bupropion; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Dextromethorphan; Mood Disorders
PubMed: 36943010
DOI: 10.1080/14737175.2023.2192402 -
CNS Spectrums Oct 2019Although currently available antidepressants increase monoamine levels soon after the start of treatment, therapeutic benefits are often delayed by several weeks and the... (Review)
Review
Although currently available antidepressants increase monoamine levels soon after the start of treatment, therapeutic benefits are often delayed by several weeks and the majority of patients with major depressive disorder fail to achieve an adequate response to first- or second-line therapies targeting monoamines. The recent approval of the NMDA (N-methyl-d-aspartate) antagonist esketamine given intranasally for treatment-resistant depression has reinforced the need for agents with rapid onset with alternate mechanisms of action. Dextromethorphan/bupropion, an investigational medicine currently in development, is one such candidate.
Topics: Administration, Oral; Animals; Antidepressive Agents, Second-Generation; Bupropion; Dextromethorphan; Dopamine; Humans; Norepinephrine; Receptors, N-Methyl-D-Aspartate
PubMed: 31566163
DOI: 10.1017/S1092852919001470 -
CNS Drugs May 2011Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the... (Review)
Review
Pseudobulbar affect is characterized by uncontrollable, inappropriate laughing and/or crying that is either unrelated or out of proportion to the emotions felt by the patient and occurs in patients with neurological disorders, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis or traumatic brain injury. Dextromethorphan/quinidine is indicated in the US for the treatment of pseudobulbar affect. Dextromethorphan, when its metabolism is inhibited by the coadministration of quinidine, has been shown to have a positive effect on the symptoms of pseudobulbar affect. Dextromethorphan/quinidine 20 mg/10 mg twice daily was associated with a significantly greater decrease in the rate of pseudobulbar affect episodes per day (primary endpoint) than placebo in the 12-week, randomized, double-blind, placebo-controlled, multicentre STAR trial (Safety, Tolerability, And efficacy Results trial of AVP-923 in PBA [pseudobulbar affect]) involving patients with pseudobulbar affect and ALS or multiple sclerosis. Moreover, the mean change from baseline in Center for Neurologic Study-Lability Scale score at 12 weeks was significantly greater among recipients of dextromethorphan/quinidine 20 mg/10 mg twice daily than those receiving placebo. Dextromethorphan/quinidine 20 mg/10 mg twice daily was generally well tolerated. The drug has been shown to cause dosage-dependent corrected QT interval (QTc) prolongation; however, in the STAR trial, dextromethorphan/quinidine 20 mg/10 mg twice daily appeared to be well tolerated with regard to QTc prolongation.
Topics: Amyotrophic Lateral Sclerosis; Crying; Dextromethorphan; Drug Combinations; Emotions; Female; Humans; Laughter; Male; Mood Disorders; Multiple Sclerosis; Quinidine
PubMed: 21476614
DOI: 10.2165/11207260-000000000-00000 -
The Medical Letter on Drugs and... Dec 2022
Topics: Humans; Bupropion; Dextromethorphan; Depression; Selective Serotonin Reuptake Inhibitors; Smoking Cessation
PubMed: 36542346
DOI: No ID Found