Bridging Nonconsecutive Esketamine Weeks with Bupropion and Over-the-Counter Dextromethorphan

Frequent clinic visits required for maintenance intranasal (IN) esketamine therapy can limit treatment feasibility. Our case presents a 52-year-old woman with treatment-resistant depression (TRD) and bipolar II disorder (BD-II) who achieved sustained remission with weekly esketamine, but consistently experienced relapse of depressive symptoms when treatment intervals extended beyond 10 days. Her Patient Health Questionnaire-9 (PHQ-9) score decreased from 27 at baseline to 4 (±1) during maintenance treatment; however, with even a single delayed session, her PHQ-9 score could increase by as many as 8 points (from 4 to 12). To prevent relapse when she could not receive esketamine weekly, she began taking over-the-counter (OTC) dextromethorphan (DXM) and continued bupropion extended-release (XL), which she started prior to esketamine treatment. With 45 mg twice daily (BID) DXM and 450 mg daily bupropion XL, she was able to tolerate every-other-week administration of esketamine without depressive relapse. DXM and esketamine are both believed to function via antagonism of N-methyl-D-aspartate (NMDA) receptors. Bupropion is a competitive inhibitor of cytochrome P450 2D6 (CYP2D6), which is involved in the metabolism of DXM and maintenance of serum DXM concentration.¹ As our patient was already taking bupropion XL, beginning OTC DXM was a low-cost option that we hoped would prevent relapse via continued NMDA antagonism in esketamine's absence. To date, she is stable on a regimen of esketamine administration every 14 days, followed by 1 week of BID OTC DXM, to bridge esketamine doses and maintain NMDA antagonism, without return of depressive symptoms.