Bupropion‐Memantine Combination in the Treatment of Major Depressive Disorder and Treatment‐Resistant Depression

Treatment-resistant depression (TRD) remains a formidable challenge in psychiatry, with nearly one-third of patients with major depressive disorder (MDD) failing to respond adequately to first-line pharmacological treatments. Pathophysiology in MDD has highlighted the N-methyl-D-aspartate (NMDA) glutamatergic system as a promising therapeutic target. In 2022, the US Food and Drug Administration (FDA) approved the bupropion and dextromethorphan (DXM) combination (BDC), the first oral combination that affects both the NMDA receptor and norepinephrine-dopamine systems. DXM is an uncompetitive NMDA receptor antagonist, and in combination with bupropion, it has been shown to be a rapidly acting oral medication with clinically significant improvement in the first week of treatment. BDC, however, has many inherent limitations such as contraindications in those with eating disorders and a history of seizures. Anxiety is a common comorbidity in MDD, and bupropion has been shown to lack efficacy in treating anxiety. In addition, BDC did not improve cognition. Memantine can treat depression and cognitive impairments concurrently. Fixed-dose combination pills can be less flexible than prescribing each drug separately, as BDC is limited to a 105 mg (bupropion)-45 mg (DXM) combination. The projected 1-month cost of possible combinations of memantine ($5.00) with a selective serotonin reuptake inhibitor (SSRI, $4.00), serotonin-norepinephrine reuptake inhibitor (SNRI, $15.00), and bupropion ($18.00) are cheaper than BDC ($1119.00). Instead of BDC, we propose various alternatives such as a bupropion-memantine combination or SSRI/SNRI and memantine for MDD/TRD.