Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

“…The uncompetitive NMDAR antagonists memantine, dextromethorphan (combined with quinidine), and esketamine (the (+)-enantiomer of ketamine) have been approved by the U.S. Food and Drug Administration (FDA) to treat Alzheimer’s disease, pseudobulbar affect, and treatment-resistant depression (TRD), respectively. The dextromethorphan-bupropion combination as well as esmethadone have shown rapid, robust, and sustained efficacy for MDD in Phase 2 clinical trials and have advanced to Phase 3 development [ 17 , 18 , 19 ]. The dextromethorphan-bupropion combination was recently FDA-approved for the treatment of MDD.…”

“…However, the induction of dissociative effects by ketamine and esketamine may not be necessary for their rapid antidepressant effects [ 26 ], and, in fact, low doses of IV ketamine (0.1 mg/kg) were found to be therapeutic without dissociative effects [ 27 ]. The lack of association between dissociative and antidepressant effects for uncompetitive NMDAR antagonists is supported by the rapid, robust, and sustained antidepressant effects seen with low-potency NMDAR antagonists such as the dextromethorphan-bupropion combination [ 17 , 19 ] and esmethadone [ 18 ], which lack dissociative effects. The early findings by Trullas and Skolnick with MK-801 involving reversal of depressive-like behavior and activation of neural plasticity [ 24 ] were subsequently also shown with ketamine [ 10 ] and the non-dissociative, low-potency, uncompetitive NMDAR antagonist esmethadone [ 28 ].…”

“…Uncompetitive NMDAR antagonists reverse neural plasticity impairment and depressive-like behavior in animal models [ 10 , 11 , 12 , 32 , 33 ]. Uncompetitive NMDAR antagonists reverse the depressive phenotype in patients with MDD [ 17 , 18 , 19 , 21 , 23 ]. Notably, the reversal of the depressive phenotype in patients with MDD includes improvements in subjective cognitive symptoms [ 38 ], further indicating that restoration of physiological neural plasticity may be the mechanism underlying phenotype improvement in patients, confirming results seen in experimental models [ 10 , 11 , 12 , 32 , 33 ].…”

“…Ketamine, at standard antidepressant doses (e.g., 0.5 mg/kg IV), causes short-lived dissociation and at higher doses is a dissociative anesthetic. In contrast, the lack of dissociative effects seen in patients with MDD successfully treated with esmethadone [ 18 ] and dextromethorphan [ 17 , 19 ] indicates that these low-potency NMDAR antagonists do not interfere with phasic NMDAR-mediated Ca 2+ currents at concentrations that are therapeutic for MDD, unlike racemic ketamine and esketamine at doses currently used for MDD [ 21 , 39 ]. Like ketamine, esmethadone blocks tonic NMDAR-mediated Ca 2+ influx and induces brain-derived neurotrophic factor (BDNF)-dependent neural plasticity in animal models of depression, reversing depressive-like behavior [ 10 , 11 , 12 , 32 ].…”

Olfactory loss is a predisposing factor for depression, while olfactory enrichment is an effective treatment for depression

“…Another drug with a more convenient, oral method of administration also has been approved recently for use in treatment-resistant major depression and it also seems to have a rapid action to suppress depression symptoms. Called Auvelity, it contains dextromethorphan, which is an anti-tussive that is a non-competitive antagonist for the NMDA receptor and to the sigma opioid receptor, and bupropion, an antidepressant on its own that increases synaptic norepinephrine and dopamine by decreasing their reuptake ( Stahl et al, 2004 ; Iosifescu et al, 2022 ).…”