Cost-effectiveness of esketamine versus alternative treatment strategies for treatment-resistant depression in Hong Kong: A multi-armed modeling study

BACKGROUND: Treatment-resistant depression (TRD), defined as failure to respond to at least two adequately administered antidepressant (AD) regimens, imposes major clinical and economic burdens. Esketamine nasal spray offers rapid antidepressant clinical effects, yet previous evaluations compared it only with unrealistic comparators such as AD monotherapy. This study assessed the cost-effectiveness of esketamine versus multiple alternative third-line strategies for TRD from the Hong Kong healthcare payer's perspective. METHODS AND FINDINGS: A Markov cohort model simulated adults with TRD in Hong Kong over 5 years with 4-week cycles. The model compared esketamine plus AD with six alternative third-line treatment strategies: combination therapy (AD plus AD), augmentation therapy (AD plus antipsychotic or lithium), psychotherapy alone, psychotherapy plus AD, repetitive transcranial magnetic stimulation (rTMS) plus AD, and electroconvulsive therapy (ECT) plus AD. Primary outcomes were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) under a US$50,000/QALY willingness-to-pay (WTP) threshold. Deterministic and probabilistic sensitivity analyses and scenario analyses were conducted, focusing on alternative esketamine dosing, delivery strategies, and comparisons with other treatment options to assess the robustness of the results. In base-case analysis, esketamine was not cost-effective versus augmentation, combination, psychotherapy, or psychotherapy plus AD with ICERs ranging from US$134,127 to US$312,750 per QALY but was more cost-effective than rTMS (dominated) and ECT (ICER: US$322,407/QALY). Combination therapy was the most cost-effective among all strategies evaluated. The main limitation of this study is the reliance on indirect comparisons and assumptions derived from heterogeneous clinical trial populations, which may not fully reflect real-world patient characteristics and treatment pathways. CONCLUSIONS: Esketamine appeared more cost-effective than rTMS and ECT, but not cost-effective compared with other commonly used third-line treatment strategies for TRD. These findings suggest that cost-effectiveness evidence may help inform more context-sensitive treatment sequencing strategies beyond conventional line-of-therapy frameworks. Policy approaches such as price negotiation, optimized service delivery, and alternative dosing strategies may improve the value of esketamine for TRD management.