Cost-per-remitter for esketamine nasal spray versus quetiapine for treatment-resistant depression

Major depressive disorder is common in the United States and imposes substantial clinical, economic and societal burden. A sizeable subset of people with MDD meet criteria for treatment-resistant depression (TRD), commonly defined as failure to respond to at least two adequate antidepressant trials; recent estimates place TRD prevalence at about 30.9% of medication-treated MDD patients. Standard approaches for TRD include further oral antidepressants, augmentation with atypical antipsychotics (for example quetiapine), esketamine and brain stimulation modalities such as electroconvulsive therapy or repetitive transcranial magnetic stimulation (rTMS). Antipsychotic augmentation and brain stimulation each have practical or safety drawbacks—low adherence and metabolic adverse effects for antipsychotics, and clinical and economic burden for some brain stimulation approaches—so there is interest in treatments that combine clinical effectiveness with feasible use for patients and payers. Clemens and colleagues used the ESCAPE-TRD phase IIIb trial, which compared esketamine nasal spray plus an oral antidepressant (ESK NS + OAD) versus quetiapine extended release plus an oral antidepressant (QTP XR + OAD), as the clinical efficacy source for an economic modelling exercise. The present study develops an Excel-based cost model to estimate cost-per-remitter over 32 weeks from US commercial and Medicaid payer perspectives, incorporating direct healthcare costs and indirect productivity losses. The investigators also tested an alternative post-discontinuation care scenario and conducted probabilistic sensitivity analysis to explore parameter uncertainty.

The analysis used efficacy inputs from the ESCAPE-TRD phase IIIb randomised, open-label, rater-blinded, active-controlled trial, restricted to the subgroup of participants treated in accordance with US prescribing information. Remission and response rates were extracted at 4-week intervals between week 8 and week 32. Remission was defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤10; response was defined as ≥50% improvement in MADRS or a MADRS score ≤10. The time horizon was 32 weeks and outcomes and costs were aggregated per patient and converted into weekly values where required. An Excel-based cost model, building on a prior cost-per-remitter approach for esketamine versus nasal placebo, estimated per-patient treatment costs, direct healthcare costs (medical services and treatments) and indirect costs (productivity losses). Two payer perspectives were modelled separately: a US commercial insurer and Medicaid. Direct cost inputs were taken from published health economic literature and the RED BOOK drug pricing database; indirect costs derived from a WPAI:D (Work Productivity and Activity Impairment: Depression) analysis of ESCAPE-TRD participants combined with US Bureau of Labor Statistics data. Treatment-cost assumptions were specified by arm and phase. Weekly OAD costs were set at $6.16 (commercial) and $5.36 (Medicaid, after a 13.0% statutory rebate). In the acute phase (weeks 1–8) ESK NS dosing was modelled as 1.5 administrations per week with 2.29 devices per session on average; device cost was $341.83 (Medicaid $262.87 after a 23.1% rebate) and an administration cost of $271.48 per visit was assumed. Maintenance-phase ESK NS use (weeks 9–32) averaged one administration per week with roughly 1.99 devices per administration, with some proportion modelled as bi-weekly dosing (76.7% of remitters; 45.2% of non-remitting responders). QTP XR dosing was modelled at average daily doses observed in ESCAPE-TRD, with a generic price of $0.00361 per mg. The model assigned health-state–specific direct healthcare costs for remission, response and non-response, and held indirect costs constant across health states but allowed them to differ by treatment arm based on the WPAI:D analysis. In the base case, when patients discontinued initial treatment half were assumed to initiate atypical antipsychotic augmentation and half rTMS, resulting in an average weekly off-treatment care cost of $600.44. An alternative scenario assumed 100% of patients discontinuing initial treatment would receive rTMS (average weekly cost $1,172.06). Cost-per-remitter was calculated by dividing total per-patient cost over 32 weeks by the remission rate at week 32 for each arm. Finally, a probabilistic sensitivity analysis (PSA) was run using Monte Carlo simulation with 5,000 iterations; efficacy parameters were sampled from binomial distributions and cost parameters from gamma distributions, each with a normalised standard deviation of 0.2 to reflect uncertainty.

In the base case, remission at week 32 was 50.3% for ESK NS + OAD and 32.5% for QTP XR + OAD. Per-patient treatment costs over 32 weeks for ESK NS + OAD were $28,337 (commercial) and $24,117 (Medicaid); direct healthcare costs were $8,992 (commercial) and $9,076 (Medicaid); and indirect economic costs were $16,921 (commercial) and $10,322 (Medicaid). For QTP XR + OAD, per-patient treatment costs were $6,404 (commercial) and $6,387 (Medicaid); direct healthcare costs were $10,236 (commercial) and $10,029 (Medicaid); and indirect economic costs were $19,408 (commercial) and $11,839 (Medicaid). These inputs produced cost-per-remitter estimates at 32 weeks of $107,817 for ESK NS + OAD versus $110,919 for QTP XR + OAD in the commercial setting, and $86,483 versus $86,939 respectively in the Medicaid setting. Thus, the cost-per-remitter for ESK NS + OAD was $3,102 lower than QTP XR + OAD in the commercial model and $456 lower in the Medicaid model. The investigators highlight that although ESK NS + OAD incurred substantially higher treatment acquisition and administration costs, superior efficacy and lower downstream direct and indirect costs yielded a net advantage in cost-per-remitter. Under the alternative off-treatment care scenario (100% of discontinuers initiating rTMS), per-patient treatment costs rose to $31,354 (ESK NS, commercial) and $12,263 (QTP XR, commercial), while direct and indirect costs remained as in the base case. Cost-per-remitter in that scenario was $113,813 for ESK NS + OAD versus $128,947 for QTP XR + OAD in the commercial setting, and $92,479 versus $104,967 in Medicaid. The resulting differences favoured ESK NS + OAD by $15,134 (commercial) and $12,488 (Medicaid). The PSA (5,000 Monte Carlo runs varying efficacy and cost inputs) found that 2,706 runs (54%) produced a lower cost-per-remitter for ESK NS + OAD than for QTP XR + OAD, indicating moderate sensitivity of the result to parameter uncertainty.

Clemens and colleagues interpret the findings as indicating that ESK NS + OAD delivers higher remission and response rates than QTP XR + OAD in the ESCAPE-TRD population, and that those improved clinical outcomes translate into a lower cost-per-remitter over 32 weeks despite higher treatment costs. The authors note consistency with an earlier cost-per-remitter analysis comparing ESK NS + OAD with nasal placebo + OAD, while acknowledging the gap versus quetiapine is smaller because quetiapine is an active comparator with its own treatment effect. The study is presented as relevant to payers considering coverage of esketamine, because it links trial-observed efficacy to real-world cost inputs for both commercial and Medicaid perspectives and explores alternative care pathways after treatment discontinuation. The investigators also emphasise that results were robust to an alternative assumption that discontinuers all received rTMS and to probabilistic sensitivity analysis, although the PSA showed only a slight majority of simulations favouring ESK NS + OAD. Several limitations are acknowledged. The model is restricted to the ESCAPE-TRD trial population treated according to US prescribing information, and trial participants were not located in the US, which limits generalisability. Differences in adherence and visit frequency (ESK NS participants had more clinic visits early on) could confound outcomes. Treatment costs used do not necessarily reflect negotiated commercial arrangements and indirect cost assumptions held productivity constant across health states within each arm, which may not capture real-world variation. The model did not incorporate mortality beyond noting one death of undetermined cause in ESCAPE-TRD, nor did it model adverse-event costs; the authors note that adverse events associated with antipsychotic augmentation (for example weight gain and hypertriglyceridaemia) could raise the cost-per-remitter for QTP XR, while longer-term esketamine safety signals reported in pharmacovigilance (for example addiction and suicidal risks) might increase esketamine-associated costs. Finally, the analysis did not compare ESK NS with other treatments used in TRD such as intravenous racemic ketamine, and the authors recommend future studies to assess cost implications relative to other accepted therapies. Overall, the investigators conclude that, within the modelled assumptions and the ESCAPE-TRD efficacy data, ESK NS + OAD is associated with a lower cost-per-remitter than QTP XR + OAD in both commercial and Medicaid settings over 32 weeks, with the advantage more pronounced under assumptions that non-responders receive rTMS as subsequent care.