Dextromethorphan-Bupropion vs Esketamine: US MDD Cost Outcomes

Real-World Data Show Lower Costs With Dextromethorphan-Bupropion in MDD

A 2026 analysis of US insurance claims data finds that adults with major depressive disorder (MDD) who initiate dextromethorphan-bupropion (marketed as Auvelity) incur significantly lower healthcare costs and resource utilization than those starting esketamine, cariprazine, or brexpiprazole. The study, published on October 21, 2026 and drawing on Merative MarketScan Commercial and Medicare data from January 2021 to March 2024, compared 1,472 propensity score-weighted patients in each treatment cohort. Over the six months following treatment initiation, adjusted mean total healthcare costs were $18,715 for dextromethorphan-bupropion, versus $19,931 for cariprazine, $20,762 for brexpiprazole, and a striking $41,954 for esketamine. Medical and pharmacy costs followed similar patterns, with esketamine-associated costs more than double those of dextromethorphan-bupropion.

Mechanisms and Context: Why Might Costs Differ?

Dextromethorphan-bupropion and esketamine are both approved for treatment-resistant depression but differ markedly in administration and monitoring requirements. Auvelity is an oral, fixed-dose combination, while esketamine is administered intranasally under direct medical supervision, with post-dose monitoring for dissociation and blood pressure changes per US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) requirements. This difference in care setting and supervision likely contributes to higher resource use and costs for esketamine. The claims data also show higher odds of emergency room visits and inpatient admissions for the comparator drugs, but the underlying clinical drivers—such as patient severity or adverse events—are not captured in administrative data.

Policy, Payer, and Research Implications

The observed cost differential, especially between dextromethorphan-bupropion and esketamine, is likely to inform payer coverage decisions, prior authorization criteria, and formulary placement. Insurers and pharmacy benefit managers may view Auvelity as a cost-saving alternative, particularly for patients who are not contraindicated for oral therapy or who prefer to avoid in-clinic procedures. However, the lack of clinical severity and treatment response data in claims analyses limits the ability to draw conclusions about comparative effectiveness or appropriateness for individual patients. Policymakers and guideline committees may call for head-to-head randomized controlled trials (RCTs) or pragmatic studies to confirm these findings and address potential confounding. Notably, the study’s use of propensity score weighting is a methodological strength, but unmeasured confounding—such as channeling sicker patients to esketamine—remains a concern.

Risks, Limitations, and Unknowns

Claims data analyses are subject to important limitations, including incomplete clinical information, potential coding errors, and residual confounding. The study could not account for depression severity, prior lines of therapy, or patient preference, all of which may influence both treatment selection and outcomes. There is a risk that lower observed costs reflect selection of less severe or more stable patients for dextromethorphan-bupropion, rather than an intrinsic advantage of the drug itself. Additionally, the relatively short six-month follow-up period may not capture longer-term differences in relapse, remission, or adverse events. For esketamine, the high costs may partly reflect its use in more refractory or complex cases, which are not fully controlled for in administrative data. These factors mean that findings should be interpreted with caution and not as evidence of clinical superiority or cost-effectiveness in all settings.

Looking Forward: Comparative Effectiveness and Access Debates

As payers and policymakers seek value-based approaches to mental health care, real-world evidence like this study will play an increasing role in shaping access to novel antidepressant therapies. The striking cost gap between oral dextromethorphan-bupropion and in-clinic esketamine highlights the importance of considering both clinical and economic outcomes in coverage decisions. Future research should prioritize direct comparative trials, longer-term follow-up, and integration of patient-reported outcomes to address current evidence gaps. For clinicians, these data may prompt more nuanced discussions with patients about treatment options, balancing convenience, cost, and clinical profile. As the landscape for psychedelic-inspired and rapid-acting antidepressants evolves, robust real-world data will be essential for informed decision-making by all stakeholders.

Authored by Dr. Alex J. Hartman, PhD (Neuroscience & Health Policy). Reviewed by Dr. Emily Tran, MD, on 2026-10-22. Research based on primary analysis of Merative MarketScan claims and published study at OpenAlex W7223141823.