Auvelity, a pill combining dextromethorphan and bupropion, brought in $180.3 million in the second quarter of 2026, 83 percent of Axsome Therapeutics’ net product sales that quarter. On October 21, the Journal of Medical Economics published a claims study, funded by Axsome and co-written by three of its employees, that puts a cost figure next to the drug. Adults with major depression who started Auvelity incurred an adjusted $18,715 in all-cause healthcare costs over the following six months. People who started Johnson & Johnson’s Spravato incurred $41,954.
That gap is the number most likely to travel, and it is the one the study is least able to explain. The comparison set is also telling for what it leaves out. Every comparator is a branded drug. The drugs patients are typically expected to try before Auvelity are generics, as the paper itself acknowledges, and the study does not test any of them.
What the study compared
The analysis used Merative MarketScan commercial and Medicare supplemental claims for adults with major depression who started Auvelity, cariprazine (AbbVie’s Vraylar), brexpiprazole (Otsuka’s Rexulti) or esketamine (Spravato) between January 2022 and March 2024, with six months of continuous coverage before and after the start. Cohorts were assigned in order, Auvelity first, so the Auvelity group could include people who had already tried a comparator: in the prior six months, 9.4 percent had used cariprazine, 7.9 percent brexpiprazole and 5.3 percent esketamine.
The comparator groups were then reweighted to resemble the 1,472 Auvelity patients on age, sex, region, comorbidity, five mental health conditions and the number of prior depression drugs, and the cost models adjusted for each patient’s earlier spending. The imbalances were large before weighting. The esketamine group began with 853 patients, and the paper does not report how heavily individual patients were weighted. In the cariprazine group of 11,061, 39.8 percent carried a bipolar diagnosis code, against 16.8 percent of Auvelity patients. Weighting balanced the groups on those measured variables. It did not make them clinically equivalent.
Nor did it include when patients started. Auvelity was approved in August 2022, so its starts fall later in the window than some comparator starts could. Because the paper does not report start-date distributions by cohort, the size or direction of any calendar-time imbalance cannot be determined from the published analysis. Converting costs to 2023 dollars handles inflation, not changes in prescribing, coverage, benefit design or drug prices over the period.
Adjusted mean total costs over six months were $18,715 for Auvelity, $19,931 for cariprazine, $20,762 for brexpiprazole and $41,954 for esketamine. The difference from cariprazine had a p-value of 0.05, and the paper does not count it as significant; the brexpiprazole and esketamine differences were significant. Medical and pharmacy costs, each modeled separately, were significantly lower for Auvelity against all three. The abstract’s conclusion nonetheless describes lower total costs against all three, without the cariprazine caveat.
The utilization results are narrower still. Emergency room visits were significantly less likely among Auvelity patients than in each comparator group, whose patients had 1.23 to 1.35 times the odds of a visit. Inpatient admissions were numerically higher in every comparator group but significantly different only for cariprazine. The paper’s own plain-language summary says Auvelity patients were less likely to have “hospital stays compared with the other treatments”; its results support that for one of the three. No adjustment for multiple comparisons was prespecified, and the paper reports no sensitivity analyses.
None of this is a measure of clinical benefit. The study recorded spending and two kinds of hospital use, not symptoms, response or remission.
Why the Spravato number says the least
The esketamine comparison produces the study’s largest gap, more than double Auvelity’s total, and it is the comparison least able to say what Auvelity does for a given patient.
Spravato is a different kind of treatment. Its label limits it to adults with treatment-resistant depression, or with depressive symptoms and acute suicidal ideation or behavior, and it is available only through a restricted REMS program. Each session is nasal dosing under the direct supervision of a healthcare provider, followed by at least two hours of monitoring before the patient can leave. The authors write that esketamine’s drug, administration and observation costs can be billed through medical claims and “are not expected to appear only within pharmacy costs.” Part of the $23,934 medical-cost figure for esketamine is therefore likely the cost of delivering the drug, not of downstream illness. That is a reading of how esketamine is billed, not a breakdown the paper provides, and the paper does not say how much.
The paper also defines each cohort’s start as the first observed prescription claim. Spravato can instead be bought and billed by clinics under the medical benefit, and the paper does not say whether starts billed only that way were captured, so it is unclear how fully the esketamine group represents Spravato patients.
The patients differ too, in ways claims cannot see. Claims record no symptom severity, treatment response, or suicide attempts that never produce a coded encounter, and the authors say line of therapy cannot be reliably determined from six months of history. The weighting matched the number of prior depression drugs, not which drugs or in what order. A patient sent to a certified clinic for repeated supervised dosing and a patient handed an oral prescription may carry the same diagnosis code and the same count of prior drugs and still sit at very different points in their illness. The authors make the point themselves: patients receiving adjunctive or treatment-resistant therapy “may be expected to have greater disease severity, treatment resistance, clinical urgency, or treatment complexity.” They also note the Auvelity group was not an easy one, since 89 percent had taken another depression drug in the prior six months, and they name channeling bias and confounding by indication among the study’s limits.
So the study can say that a weighted group of Spravato starters cost more over six months than a group of Auvelity starters. It cannot say the same patient would have cost less on Auvelity, and the paper does not claim that. Its discussion calls the findings “adjusted real-world associations rather than causal evidence.”
The comparison a formulary starts with
All three comparators are branded, and the paper explains why: in US practice, patients usually try generic antidepressants before any branded drug, “because of guideline recommendations, payer requirements, and cost considerations.” The authors say the study was not intended to “evaluate all available MDD treatment options.”
Published coverage criteria show what that means in practice. The requirements differ, but every policy reviewed here places generic therapy before Auvelity for depression. A CVS Caremark criteria document posted for one client plan requires trials of four antidepressants from four drug classes, one of them bupropion, and treats a concurrent bupropion prescription as a contraindication. UnitedHealthcare’s step-therapy program requires at least three generics. An Express Scripts policy places generic long-acting bupropion first. The CVS and UnitedHealthcare criteria set no step requirement for Alzheimer’s agitation. These are individual policies, not a national rule, but they share the shape of the gate.
Bupropion is also the comparator in Axsome’s two active-controlled trials of Auvelity in depression. ASCEND, a Phase 2 trial published in the American Journal of Psychiatry in 2022, followed 80 evaluable patients for six weeks. Auvelity reduced depression scores more than sustained-release bupropion at the same 105 mg bupropion dose, by 13.7 points against 8.8 on the MADRS scale averaged over the six weeks, with remission at week six of 46.5 percent against 16.2 percent. That is evidence the dextromethorphan adds something to bupropion. It is a small, short trial with no cost data.
The larger test was mixed. STRIDE-1, a Phase 3 trial of 312 adults with treatment-resistant depression, compared Auvelity’s formulation with 150 mg of bupropion twice daily. Axsome reported in March 2020 that it missed its primary endpoint, depression scores at week six (p=0.12), while meeting key secondary endpoints, including the average improvement over the six weeks. Its full results are not posted on ClinicalTrials.gov or published in PubMed. Read together, the two trials show an early advantage over bupropion that did not hold up on the primary endpoint in the harder-to-treat population, and neither says anything about value for money. Axsome’s newer test against the same generic, a Phase 4 relapse-prevention trial (NCT06223880) that randomizes Auvelity responders to continue it or switch to bupropion, is still listed as recruiting, with an estimated primary completion of March 2026 that has passed and no results posted.
The adjunctive comparators have a generic counterpart too. Aripiprazole, generic since 2015 and an established add-on (adjunctive) option for depression in the same class as cariprazine and brexpiprazole, was the most-used antipsychotic in the six months before treatment in all four weighted cohorts. It was not a comparator.
Whether prescribers will instead assemble Auvelity’s two long-approved ingredients from generic bupropion and over-the-counter dextromethorphan is a narrower question, and the published record of it is sparse: a February 2026 case report in the Mental Health Clinician and one earlier German case. In August, a commentary in the Journal of the American Geriatrics Society, on the Alzheimer’s agitation indication, put about $1,498 for 30 days of Auvelity against $45.60 to $145.20 for the components, using wholesale list prices. The commentary itself listed drawbacks, including state restrictions on dextromethorphan sales and the risk of errors when two drugs replace one. A commentary is not trial evidence, and the separate ingredients are not the same product: Auvelity’s fixed extended-release doses are built around bupropion raising dextromethorphan’s blood levels, and no trial has compared the two approaches. Two case reports and a commentary do not make component prescribing a market force.
The stronger generic pressure is the one already written into coverage criteria. Under criteria like these, a patient reaches Auvelity after generics have been tried, and the study’s cost comparison begins at that point, among branded drugs only. The question coverage criteria encode is not whether Auvelity costs less than Spravato. It is whether Auvelity is worth its price over the generic that would otherwise come next.
What Auvelity carries for Axsome
That gate matters because Auvelity is most of Axsome’s business: about 80 percent of its net product sales in 2025. The market is also changing. FDA approved Auvelity for agitation associated with dementia due to Alzheimer’s disease in April 2026, and Axsome launched it in that indication in June. Axsome said new-to-brand prescriptions among patients 65 and older rose 126 percent in the first eight weeks. That growth arrives through an indication where the CVS and UnitedHealthcare criteria set no generic step, and in an older population the study, whose data end in March 2024, does not cover.
As of August, Axsome put Auvelity’s coverage at about 89 percent of lives across all channels, including about 82 percent in commercial plans, up from 75 percent in November 2025. Axsome does not define the figure, and nothing in its disclosures says whether a covered life comes with prior authorization or step therapy. A plan can cover Auvelity and still require four generic trials first.
Who funded the study, and how it is being used
Axsome funded the study and its medical writing support. Three of the seven authors are Axsome employees and two Merative employees ran the analysis. The paper says the sponsor contributed to the study’s conception, interpretation and manuscript review, and the two outside authors disclose consulting or speaking fees from Axsome and from the makers of all three comparators. Results were presented in part at AMCP Nexus 2025, the Academy of Managed Care Pharmacy’s meeting, and the paper says they “may be useful for payers and clinicians,” while cautioning against reading them as “proving a causal economic benefit.”
A cost study presented to managed-care pharmacists and published in a health-economics journal is clearly relevant to the people who write coverage criteria. The public record does not establish how Axsome is deploying it: no public Axsome filing or presentation reviewed here mentions the study. Nor does it settle what a payer spends, since the paper does not say whether its pharmacy figures reflect manufacturer rebates.
What would strengthen the payer case
The evidence most likely to move a formulary committee is a comparison against a generic: results from the bupropion relapse trial, or an independent claims analysis of Auvelity against generic augmentation such as aripiprazole, with start dates balanced. Movement in published prior-authorization criteria for depression would show whether payers are loosening the generic steps. Evidence that the cost study appears in Axsome’s payer or commercial materials would show it is part of how the company argues for the drug. Axsome’s third-quarter results, due November 2, will show whether commercial coverage moves from 82 percent, though not what steps come with it.
For now, Axsome has published an association between Auvelity and lower six-month medical and pharmacy costs than three branded alternatives. It may support a branded-comparator argument. A payer’s harder comparison sits on the generic shelf, and that is the one the study did not run.