Concomitant Use of SPRAVATO with Auvelity® (dextromethorphan HBr and bupropion HCl)

SUMMARY  

• There are no studies evaluating the efficacy or safety of concurrent treatment with Auvelity and SPRAVATO. The two medications are indicated for different patient populations.
• SPRAVATO is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated for the treatment of¹
  • Treatment-resistant depression (TRD) in adults, as monotherapy or in conjunction with an oral antidepressant¹
  • Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant¹
• Auvelity is a combination of dextromethorphan, an uncompetitive NDMA receptor antagonist and sigma-1 receptor agonist, and bupropion, an aminoketone and CYP450 2D6 inhibitor, indicated for the treatment of MDD in adults.²
• Although the two products are NMDA receptor antagonists, the pharmacodynamic effect of coadministration is unknown. According to an in vitro study using a porcine model, the binding affinity (Ki) of esketamine to the phencyclidine (PCP) binding site on the NMDA receptor was 440±100 nM and the Ki of dextromethorphan was 3400±800 nM.³ Therefore, esketamine had ~8-fold greater affinity compared to dextromethorphan.
• There is a potential for exacerbation of high blood pressure since both products have warnings regarding increased blood pressure in the Prescribing Information and require monitoring prior to initiating, and during, treatment.^1,2 The high blood pressure is mainly attributed to the bupropion component in Auvelity.²
  • Other side effects, such as dizziness, nausea, and somnolence, are also reported as adverse reactions in the Prescribing Information for both products.
• Clinically significant drug interactions are not expected with esketamine and bupropion based on pharmacokinetic studies.¹
• There are no PK studies with dextromethorphan and esketamine.
  • Esketamine is primarily metabolized through CYP2B6 and CYP3A4.¹
  • Dextromethorphan does not cause induction of CYP1A2, CYP3A4, or CYP2B6 and does not inhibit transporters at therapeutically relevant concentrations.²
• Please contact the manufacturer of Auvelity for more information regarding the safety and drug-drug interactions for this product.

Clinical Data

Eloge et al (2025)⁴ conducted a case series including three patients with TRD from the SPRAVATO monotherapy trial (NCT04599855⁵) who showed minimal improvement after 4 weeks of monotherapy with SPRAVATO 84 mg administered twice weekly during the induction phase. These patients continued into the open‑label phase, where they were initiated on augmentation therapy with dextromethorphan/bupropion 45 mg/105 mg daily for 3 days, which was then increased to twice daily administration.

Patient A was a 30-year-old male who had a continuous depressive episode for 21 years, with comorbid generalized anxiety disorder (GAD) and social anxiety disorder. He previously trialed and failed escitalopram, venlafaxine, and bupropion. At double-blind (DB) baseline, he had a MADRS score of 37. After 4 weeks of SPRAVATO monotherapy, his MADRS score decreased to 31 and was further reduced to 2 after 6 weeks of augmentation with dextromethorphan/bupropion. He reported no adverse events during treatment.

Patient B was a 35-year-old female with TRD, GAD, and attention deficit/hyperactivity disorder who had a depressive episode lasting 22 months. She previously failed paroxetine, bupropion, and duloxetine. At DB baseline, she had a MADRS score of 36. After 4 weeks of SPRAVATO monotherapy, her MADRS score decreased to 28 and was further reduced to 14 after 9 weeks of augmentation therapy with dextromethorphan/bupropion. She reported no adverse events during treatment.

Patient C was a 27-year-old male with TRD, social anxiety disorder, and GAD, with an ongoing depressive episode spanning a 4-year period. During this time, he had inadequate responses to venlafaxine, bupropion, imipramine/aripiprazole, tranylcypromine, sertraline, and vortioxetine. At DB baseline, his MADRS score was 30. After 9 weeks of augmentation with dextromethorphan/bupropion, he showed no improvement and no adverse events were reported.

Literature Search

A literature search of Ovid MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENTDrug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 14 July 2025.