Impact analysis of expanded access to ketamine for treatment-resistant depression

Major depressive disorder (MDD) is common and can be persistent and disabling; treatment-resistant depression (TRD), defined as failure of at least two antidepressants, affects about one-third of people with MDD and contributes substantially to clinical and economic burden. Electroconvulsive therapy (ECT) has long been an effective option for TRD, typically delivered as 6–12 sessions over 3–5 weeks with ongoing maintenance thereafter. Intravenous ketamine has more recently been shown to have rapid antidepressant effects, and a multicentre randomised trial by Anand et al. reported a response rate of 55.4% for ketamine versus 41.2% for ECT in nonpsychotic TRD, concluding ketamine was noninferior to ECT for this population. Lu and colleagues set out to estimate the economic consequences of expanding access to outpatient intravenous ketamine for adults with nonpsychotic TRD and moderate-to-severe depression who otherwise would be offered ECT. Using a population-level health-economic model, the study compares a standard-of-care mix of ECT and ketamine with a scenario in which all eligible patients are offered ketamine, and reports impacts on direct healthcare costs and indirect time costs from patient, caregiver, payer and societal perspectives over a 5-year horizon. The analysis aims to inform payers and policymakers about potential downstream cost effects of broader ketamine availability for this indication.

The investigators developed a population-level decision-analytic model comprising a 1-month decision tree for the acute treatment phase and a multi-year Markov component for maintenance and relapse over a 5-year horizon. The Markov model used annual cycles (the first year modelled as an 11-month cycle) and allowed entry of a new cohort of incident eligible patients each year. Two treatment-regimen scenarios were compared: a standard of care (SC) in which some eligible patients are offered ECT and some ketamine, and an expanded-access scenario in which 100% of eligible patients are offered intravenous ketamine. Transition probabilities for response, continuation, relapse and stopping treatment were treatment-specific but identical across SC and expanded-access regimes; mortality was modelled as independent of treatment due to lack of long-term comparative data. Model parameters were drawn from published sources, publicly available datasets and clinical expert input; key clinical inputs (response and some transition probabilities) were taken from Anand et al., although the authors did not have access to the trial's primary data. Costs were expressed in 2024 US dollars and discounted at 3% per year. The eligible population in the base case started at an estimated 350,000 adults in year 1 with 11,296 new eligible patients added annually in subsequent years; under SC the authors assumed 85.7% of eligible patients are offered ECT and 14.3% ketamine, with acceptance rates of 25% for ECT and 50% for ketamine. Direct cost inputs included per-session treatment costs (using the 2024 Medicare Physician Fee Schedule and outpatient payment system), psychiatric evaluation costs, medication and anaesthesia costs for ECT, ketamine drug costs and observation/physician visit costs for ketamine, and continuing healthcare costs of TRD. Indirect costs captured patient time and unpaid caregiver time accompanying patients to appointments; hourly valuations used 2021 earnings adjusted to 2024 dollars with fringe benefits. The model assumed session durations of 2 h for ECT and 2.5 h for ketamine plus 1 h travel, additional whole-day recovery for ECT (8 h) in the base case, and that 100% of patients are accompanied by caregivers, with 55% of patients and 65% of caregivers in the labour force. Uncertainty was explored with probabilistic sensitivity analysis (PSA; 1000 iterations) to generate 95% intervals and with one-way sensitivity analyses varying single parameters across plausible ranges. Six scenario analyses examined alternative offer rates (50% ketamine), different assumptions about hours off work after sessions, alternative relapse rates from other studies, and private-insurer reimbursement structures including a scenario in which patients pay the full cost of ketamine.

Population flow and treatment uptake: The base-case model estimated 350,000 eligible patients in year 1 and 11,296 incident eligible patients added each subsequent year. Expanded access to ketamine was projected to result in 75,000 additional patients starting acute treatment in year 1 and 4,292 additional patients annually thereafter receiving ketamine, driven by higher assumed acceptance of ketamine versus ECT. In year 1, of the 75,000 additional starters, 52,174 additional patients were estimated to respond acutely and 11,324 of those would continue into maintenance in that year. In subsequent years, of 2,420 additional acute starters, 1,684 additional patients would respond annually and 365 would enter maintenance in the same year. Overall, expanded access reduced the numbers refusing treatment, not responding, relapsing or experiencing no complications on stopping by 31,545 patients in year 1 and 29,991 annually thereafter. The model reported that 95%–98% of patients reached an absorbing state within 1 year. Aggregate and per-patient costs: Across all model years the authors estimated annual societal savings of $828.2 million under expanded ketamine access compared with SC. Savings accrued mainly to payers ($743.7 million annually), while patients were estimated to save $95.3 million annually. Caregivers, however, would incur an additional $10.8 million in time costs annually due to increased treatment uptake. From the patient perspective, total annual savings included $1.2 million in direct treatment-cost savings, $81.4 million in reduced continuing TRD healthcare costs, and $12.7 million in indirect savings from 544,486 fewer patient-hours spent in treatment-related activities. Caregivers were estimated to spend an additional 331,031 hours transporting patients, valued at $10.8 million. Payer savings included $11.2 million in treatment-cost reductions and $732.5 million in reduced continuing TRD healthcare costs. On a per-patient-in-treatment basis, societal savings were $19,940, payer savings $17,910 per treated patient, patient savings $2,300 per treated patient (composed of $1,990 lower out-of-pocket healthcare costs and $310 from less time in treatment), and caregiver costs increased by $260 per patient. Uncertainty and scenario findings: Probabilistic sensitivity analysis produced confidence intervals for cost outcomes that did not include 0, which the authors interpret as consistent evidence of net savings across the eligible population. One‑way sensitivity analyses identified the societal savings as most sensitive to the annual relapse rate among patients continuing ketamine in maintenance (range modelled 0.28–0.41), the proportion of eligible patients being offered ECT (0.63–1.00), the proportion with moderate-to-severe depression (0.68–1.00), the prevalence of treated major depressive episodes (0.01–0.02) and the ketamine response rate (0.51–0.67). Scenario analyses produced the following illustrative results: a 50% offer-rate scenario yielded $345.1 million societal savings; assuming longer ECT-related time off work raised savings to $856.7 million; assuming patients taking a full day off for ketamine reduced savings slightly to $795.6 million. Using alternative relapse rates from Nordenskjöld et al. and Daly et al. increased societal savings to $1,172.0 million. Applying private-insurer reimbursement rates (ECT $2,500 per session; ketamine $600 per session) produced societal savings of $722.5 million; if patients instead paid the full ketamine cost, societal savings remained similar but the distribution shifted so that patients incurred an additional $57.2 million in total costs rather than savings.

Lu and colleagues interpret their modelling as indicating that expanding outpatient intravenous ketamine access to all eligible adults with nonpsychotic TRD and moderate-to-severe depression would increase treatment uptake and produce substantial net societal savings, most of which accrue to payers. The authors highlight that savings remain positive across a broad range of sensitivity and scenario analyses, although the magnitude of savings is most sensitive to the relapse rate among patients who continue ketamine into maintenance. The discussion situates the findings alongside prior economic work on TRD treatments: while the authors state no prior published studies directly compared ECT and intravenous ketamine economically, they note earlier analyses that supported the value of ECT versus pharmacotherapy and suggested intravenous ketamine may dominate esketamine in some settings. In this context, the current analysis is presented as additional evidence that ketamine can be an attractive option for patients, payers and society when coverage is available. Key limitations acknowledged by the authors include reliance on Anand et al. for clinical inputs without access to individual patient data and the possibility that Anand et al. reported a lower ECT response than other studies because of trial population characteristics (for example, fewer elderly or inpatient patients and exclusion of psychotic features). The model assumes payer coverage for ketamine at specified reimbursement rates, which the authors note would represent a lower bound if private reimbursement were higher. Structural simplifications were made for parsimony: the authors assumed indefinite maintenance, excluded treatment effects on mortality, and treated states such as 'refuse treatment', 'no response' and 'relapse' as absorbing for the remainder of the horizon rather than allowing subsequent switches to other therapies. The team also acknowledged that real-world patients might receive other treatments not captured by the model (for example repetitive transcranial magnetic stimulation, intranasal ketamine, at‑home non‑parenteral ketamine, or ketamine-assisted psychotherapy), and that a more complex model would be needed to compare such alternatives fully. Finally, the authors draw attention to an equity and operational consideration: expanded ketamine access would increase caregiver time burdens due to transportation needs, and the authors recommend that payers and policymakers consider coverage and support for transportation services to mitigate this burden and ensure patients can receive treatment.

Modelling an expanded-access policy in which all eligible adults with nonpsychotic TRD and moderate-to-severe depression are offered outpatient intravenous ketamine, the authors found that treatment uptake would increase by an estimated 75,000 patients in year 1 and by 4,292 patients annually thereafter. Over the 5‑year model, expanded access was projected to lower annual costs to payers by $743.7 million and to patients by $95.3 million, while increasing informal caregiver time costs by $10.8 million, yielding a net societal saving of $828.2 million annually. The authors conclude that expanded access to intravenous ketamine could produce meaningful downstream economic benefits for payers, patients and society, while imposing additional time burdens on caregivers; payment coverage and support services are therefore important considerations for implementation.