Dextromethorphan/Bupropion: A Novel Treatment for Patients With Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) affects millions of people and is the leading cause of disability worldwide. Patients report decreased quality of life and ability to perform activities of daily living. It is estimated that the current standard of care, which includes pharmacologic therapy with a selective serotonin reuptake inhibitor, is effective in 40%-60%. Additional treatment options are warranted. The combination of dextromethorphan (DEX) and bupropion (BUP) (Auveulty) was approved for treatment in 2022. This unique combination offers an interesting mechanism of action and favorable onset of action for patients with MDD. PHARMACODYNAMICS AND PHARMACOKINETICS: The mechanism of action of DEX-BUP when used in combination is unique. DEX is a noncompetitive N-methyl-d-aspartate receptor antagonist rapidly metabolized through the CYP450 2D6. BUP is an aminoketone and CYP2D6 inhibitor, which results in increased plasma levels of DEX through competitive CYP2D6 inhibition. CLINICAL TRIALS: In a phase 2 clinical study, the efficacy of DEX-BUP was compared with BUP alone in patients with clinically diagnosed MDD. At baseline, participants had moderate-to-severe depression using the Montgomery-Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions Severity (CGI-S) scales. There was a significant overall reduction in MADRS and CGI-S scores in the treatment group compared with the BUP monotherapy with improvement observed as early as week 1 of treatment. Later, a phase 3 study was conducted comparing DEX-BUP 45 mg/105 mg with placebo in patients with moderate-to-severe MDD. Similarly, MADRS and CGI-S scores were significantly reduced in the treatment group. Adverse effects were similar in all groups. THERAPEUTIC ADVANCE: Clinical response to first line treatment options for MDD are reported to be 40%-60%. Availability of additional treatment options, particularly those with reduced time to efficacy, may improve overall treatment and patient quality of life. DEX-BUP is a combination option that has been shown to improve depression symptoms as early as 1 week after initiation.

Combinations of dextromethorphan for the treatment of mood disorders - a review of the evidence.

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.

New Combination Drug for Depression.

Auvelity, an extended-release fixed combination of dextromethorphan and bupropion, is approved for the treatment of major depressive disorder in adults.Like all antidepressants, dextromethorphan-bupropion carries a boxed warning that it may increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Seizures can also occur and are more likely at higher doses.The most common adverse effects of dextromethorphan-bupropion include dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, hyperhidrosis, anxiety, constipation, decreased appetite, and insomnia.

Dextromethorphan premedication in the alleviation of cough during flexible bronchoscopy in adults: A randomized double-blind placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Cough is invariably encountered during flexible bronchoscopy despite sedation and topical anaesthetics. The ideal cough suppressant during flexible bronchoscopy is not known. We assessed the role of dextromethorphan premedication in relieving the cough during flexible bronchoscopy in adults. METHODS: In this single-centre study, we randomized patients aged ≥18 years to receive dextromethorphan syrup 30 ml (90 mg) or an equal volume of placebo 1 h before the procedure. Patients rated their cough severity and discomfort on a visual analogue scale at the end of the procedure. Bronchoscopists also rated cough severity at the end of the procedure. RESULTS: Out of 112 patients screened, 94 patients (median (interquartile range [IQR]) age 51 (36.25-60.75) years, male: female 2.13:1) were randomized to either the dextromethorphan (n = 47) or placebo (n = 47) groups. The patients-rated median (IQR) cough scores at the end of the procedure were 15 (10-23) mm in dextromethorphan versus 20 (12-45.5) mm in placebo groups (p = 0.03). Patients-rated median cough scores at 1 h (5 mm vs. 6 mm, p = 0.21), discomfort scores (12.5 mm vs. 12.5 mm, p = 0.49), and midazolam and lignocaine usage were similar between the two groups. The bronchoscopist-rated median cough score was non-significantly lower in the intervention compared to the placebo (26 mm vs. 35 mm, p = 0.09) groups. CONCLUSION: Dextromethorphan premedication 1 h before flexible bronchoscopy may have an additive effect on cough suppression under conscious sedation and topical lignocaine. Further trials are needed to reiterate our findings with certainty.

Antitumor Effect of Traditional Drugs for Neurological Disorders: Preliminary Studies in Neural Tumor Cell Lines.

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Despite new treatments developed including immunomodulation using vaccines and cell therapies, mortality remains high due to the resistance mechanisms presented by these tumor cells and the function of the blood-brain barrier that prevents the entry of most drugs. In this context of searching for new glioblastoma therapies, the study of the existing drugs to treat neurological disorder is gaining great relevance. The aim of this study was to determine, through a preliminary in vitro study on human glioblastoma (A172, LN229), anaplastic glioma (SF268) and neuroblastoma (SK-N-SH) cell lines, the possible antitumor activity of the active principles of several drugs (levomepromazine, haloperidol, lacosamide, valproic acid, levetiracetam, glatiramer acetate, fingolimod, biperiden and dextromethorphan) with the ability to cross the blood-brain barrier and that are commonly used in neurological disorders. Results showed that levetiracetam, valproic acid, and haloperidol were able to induce a relevant synergistic antitumor effect when associated with the chemotherapy currently used in clinic (temozolomide). Regarding the mechanism of action, haloperidol, valproic acid and levomepromazine caused cell death by apoptosis, while biperiden and dextromethorphan induced autophagy. Fingolimod appeared to have anoikis-related cell death. Thus, the assayed drugs which are able to cross the blood-brain barrier could represent a possibility to improve the treatment of neural tumors, though future in vivo studies and clinical trials will be necessary to validate it.

Dextromethorphan/Bupropion: First Approval.

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) [AUVELITYTM; 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.

Eficacia de la miel para el tratamiento de la tos aguda en niños atendidos en forma ambulatoria / Efficacy of honey for treatment of acute cough in pediatric outpatients

A partir de una consulta en la central de emergencias de un niño con tos aguda, el autor del artículo realiza una búsqueda bibliográfica para revisar la evidencia sobre el uso de la miel para aliviar este síntoma. Luego de la lectura crítica de una revisión sistemática, el autor concluye que ésta podría ser una alternativa elegible frente a los jarabes para la tos, por su perfil de seguridad y su posible beneficio en el alivio de la tos. (AU)

Based on a consultation at the emergency room of a child with acute cough, the author of this article performs a bibliographic search to review the evidence on the use of honey to alleviate this symptom. After the critical appraisal of a systematic review, the author concludes that honey could be an eligible alternative to cough syrups, due to its safety profile and its possible benefit in cough relief. (AU)

Management of the pseudobulbar affect (PBA) in Kabuki syndrome combined dextromethorphan-fluoxetine treatment as an alternative to dextromethorphan/quinidine

A case report of a patient with pseudo bulbar affect previous treatments included haloperidol (10mg), Inosina pranobex (600mg), clozapine (600mg), olanzapine (20mg), carbamazepine (200mg), paroxetine (20mg), phenobarbital (100mg) and topiramate (50mg), all suspended at August 2016, with current use of quetiapine (700mg) Chlorpromazine (600mg) (+ 200mg on demand of aggression), clonazepam (4 mg), valproate 2500 mg, propranolol (40mg). that was successful treated with off label treatment (dextromethorphan plus quinidine). Previous Brief Psychiatric Rating Scale and Clinical Global Impression-Improvement was applied after and before treatment with dextromethorphan (20mg) plus fluoxetine (20 mg, further increased to 40 mg). Previous Brief Psychiatric Rating Scale BPRS score 56 points and Clinical Global Impression-Severity (CGI-S) Score was 6 (severely ill). The addition of dextromethorphan (20mg) and fluoxetine (20 mg, further increased to 40 mg), allowed clear improvement of pathological crying and outbursts, with BPRS decrease of 8 points and Clinical Global Impression-Improvement (CGI-I) 2 (much improved) ­ especially pertaining to PBA related symptoms and aggressive behavior. There were no noticeable side-effects. This case report shown an interesting clinical response. It's could be a great alternative in treatment of pseudobulbar affect symptoms. Even though an only case and a great clinical study be necessary. (AU)

Dextromethorphan/Bupropion: A Novel Oral NMDA (N-methyl-d-aspartate) Receptor Antagonist with Multimodal Activity.

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.

Clinical Benefit of NMDA Receptor Antagonists in a Patient With ATP1A2 Gene Mutation.

Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient's condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10 One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation.

Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment.

Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/ß-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.

Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3ß and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection.

Group A Streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phox and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3ß (GSK-3ß) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3ß/NF-κB/NO signaling pathway.

The Effect of Dextromethorphan Premedication on Cough and Patient Tolerance During Flexible Bronchoscopy: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Patients undergoing bronchoscopy can experience problems such as anxiety and cough, requiring various doses of sedatives and analgesics. The purposes of this study were to investigate the effect of premedication with dextromethorphan on patients' cough and anxiety, and the use of analgesics/sedatives during flexible bronchoscopy (FB). METHODS: A randomized, double-blind, placebo-controlled, prospective study was performed to assess the effect of dextromethorphan premedication on patients who underwent diagnostic bronchoscopy. Seventy patients included in this study were randomly allocated into 2 groups: group A consisted of 35 patients who received dextromethorphan before FB; and group B consisted of 35 patients who received a placebo. A questionnaire was given to the patients and bronchoscopist about perception of cough, anxiety, and discomfort. The amount of sedative medication and lidocaine use during the procedure and the procedure time were recorded. RESULTS: The group that was premedicated with dextromethorphan had lower complaint scores, significantly less coughing, significantly less stress assessed by the patient and the physician evaluation, shorter total procedure time, and fewer midazolam requirements during FB (P-value <0.05). CONCLUSION: Considering its safety profile, dextromethorphan premedication is an effective approach to facilitate the performance of FB for the physician, and could improve patient comfort.

EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement.

Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX neurotoxicity, we observed an electroencephalographic (EEG) with extreme delta brush. Extreme delta brush is an EEG pattern previously described in patients with NMDAR autoimmune encephalitis. The observations suggest that the mechanism of this neurotoxicity may be mediated by the NMDAR. Furthermore, extreme EEG delta brush should suggest a diagnosis of MTX associated subacute neurotoxicity.

A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms. CASE REPORT: An 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics.

Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder.

Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-naïve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-α, transforming growth factor [TGF]-ß1, interleukin [IL]-6, IL-8 and IL-1ß) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P < 0.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P = 0.005) and TGF-ß1 (P = 0.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression.

[Drug therapy for cough]. / Yskän Iääkehoito.

An efficient therapy for cough usually requires identification and treatment of the underlying disease, like asthma. However an underlying disease in cough is not found in all cases and conventional treatment of the underlying disease is ineffective against cough. Drug therapy options are available also for these situations. Honey or menthol can be tried for cough associated with respitatory infections, antihistamines for cough associated with allergic rhinitis, blockers of the leukotriene receptor or muscarinic receptor for asthma-associated cough and morphine for cough associated with a malignant disease. Menthol, blockers of the muscarinic receptor, or dextrometorphan can be tried for prolonged idiopathic cough. Codeine is not necessary in the treatment of cough. Refraining from drug treatment should always be considered.

Dextromethorphan provides neuroprotection via anti-inflammatory and anti-excitotoxicity effects in the cortex following traumatic brain injury.

Traumatic brain injury (TBI) is caused by primary and secondary injury mechanisms. TBI induces a certain amount of inflammatory responses and glutamate excitotoxicity that are believed to participate in the pathogenesis of secondary injury. The non­narcotic anti­tussive drug dextromethorphan (DM) has been reported to have a high safety profile in humans and its neuroprotective against a variety of disorders, including cerebral ischemia, epilepsy and acute brain injury. However, few studies have explored the underlying mechanisms of the neuroprotective effects of DM in animals in the setting of TBI. The aim of the present study was to investigate the neuroprotective effects of DM on TBI and to determine the underlying mechanisms. Rats were subjected to a controlled cortical impact (CCI) injury and randomly divided into three groups: Sham­operated, TBI and DM treatment groups. The DM treatment group was administered DM (30 mg/kg of body weight, intraperitoneally) immediately after injury. It was identified that DM treatment following TBI significantly reduced brain edema and neurological deficits, as well as increased neuronal survival. These effects correlated with a decrease of tumor necrosis factor α, interleukin­1ß (IL­1ß) and IL­6 protein expression and an increase of glutamate/aspartate transporter and glutamate transporter­1 in the cortex of the brain. These results provided in vivo evidence that DM exerts neuroprotective effects via reducing inflammation and excitotoxicity induced following TBI. The present study has shed light on the potential use of DM as a neuroprotective agent in the treatment of cerebral injuries.