Esketamine Was Not “Cost-Effective” for Treatment-Resistant Depression in Hong Kong

TL;DR: A 2026 Hong Kong Markov model in PLOS Medicine found esketamine improved treatment-resistant depression outcomes but was not cost-effective against cheaper third-line options under current payer assumptions.

Source: PLOS Medicine (2026) | Li et al.

Esketamine keeps getting attention because it can move faster than standard antidepressants in treatment-resistant depression. This paper asked a harder issue than most clinical writeups: not whether the drug works, but whether a public healthcare system should pay for it before cheaper third-line options have been exhausted.

ECT, rTMS, Medication, and Psychotherapy Comparators Changed Esketamine’s Value

Treatment-resistant depression creates a difficult sequencing problem for health systems.

Patients remain symptomatic after standard medication trials, clinicians need more effective options, and esketamine offers a rapid-acting mechanism. The model tested whether that benefit justified the added cost from a Hong Kong payer perspective.

The model did not compare esketamine with antidepressant monotherapy alone.

Modeled strategies were:

• Augmentation therapy (antidepressant plus antipsychotic or lithium)
• Antidepressant combination therapy (one antidepressant plus another antidepressant)
• Psychotherapy alone
• Psychotherapy plus antidepressant
• rTMS plus antidepressant
• ECT plus antidepressant
• Esketamine plus antidepressant

That comparator set made sequencing the central economic question: does esketamine belong before lower-cost medication and psychotherapy strategies have been tried?

Esketamine improved outcomes, but supervised dosing, monitoring visits, and delivery costs pushed the payer model above the cost-effectiveness threshold compared with lower-cost strategies.

5-Year Hong Kong Model Compared Esketamine With Antidepressant Combination Therapy

The base-case table is the clearest part of the paper:

• Antidepressant combination therapy (AD + AD): US$16,163 / 2.903 QALYs.
• Psychotherapy + antidepressant: US$21,555 / 2.926 QALYs.
• Esketamine + antidepressant: US$29,061 / 2.950 QALYs — small QALY gain, big price jump.
• ECT: US$46,471 / 3.004 QALYs — highest effectiveness, highest cost.

The drug bought extra quality-adjusted survival, but the gain was small relative to the price increase. The incremental cost-effectiveness ratio on the efficient frontier — moving from psychotherapy + antidepressant to esketamine — was US$312,750 per QALY.

The willingness-to-pay threshold in this study was US$50,000/QALY (roughly one Hong Kong GDP per capita). Esketamine missed by a wide margin.

The comparison was not uniformly negative for esketamine.

It dominated rTMS, meaning it was cheaper and more effective in the model, and it had a lower next-step ICER than ECT in the Hong Kong cost structure.

Those comparisons did not make it cost-effective against cheaper medication and psychotherapy strategies.

Antidepressant Combination Therapy Was the Lowest-Cost Modeled Strategy

The value result depended heavily on the low cost of antidepressant combination therapy, defined in the paper as antidepressant plus antidepressant.

In the model, that AD + AD strategy was both the cheapest option and the most economically attractive nondominated option. It delivered 2.903 QALYs at US$16,163 per patient before the model moved to higher-cost options.

Esketamine produced more QALYs, but the added gain was small relative to the added cost.

Antidepressant combination therapy was slightly more effective than augmentation and cheaper than every other modeled strategy. For a payer, the model therefore favored trying lower-cost medication sequencing before paying for monitored esketamine delivery.

The model also separates the esketamine-versus-ECT comparison from the lower-cost medication comparisons.

ECT delivered the highest QALYs — 3.004 — but cost US$46,471 per patient.

In Hong Kong, labor and service costs around ECT drove much of that burden, leaving a US$322,407-per-QALY step from esketamine to ECT. That is a local-system constraint as much as a treatment-effect claim.

Esketamine Price Cuts Still Did Not Clear Hong Kong ICER Thresholds

The sensitivity analyses are where the paper got more realistic.

The most favorable scenario for esketamine was not an efficacy boost.

It was structural — stretching the treatment cycle from 4 weeks to 8 weeks reduced the ICER to US$73,556/QALY. Better, still above threshold.

A 75% cut in acquisition cost also failed to make the drug clearly cost-effective at US$50,000/QALY, dropping the ICER vs. augmentation to US$116,327.

That result reflects costs drug pricing alone cannot fix. Monitoring, delivery, and broader care-pathway costs also shaped the result.

The threshold analysis put a number on it: total esketamine arm cost would need to drop by roughly 35% to approach acceptable value.

Squeezing the vial price alone is not enough — systems would need a more efficient delivery model.

Esketamine Cost-Effectiveness Still Depends on Local Prices and Relapse Assumptions

Modeling papers are only as good as their assumptions, and the authors are open about that.

There were no head-to-head trials for every comparison; they had to rely on indirect evidence from heterogeneous clinical populations.

Utility estimates also did not fully capture treatment-specific burdens like dissociation with esketamine or cognitive effects with ECT.

The exact rankings could shift in another health system. Lower labor costs could make ECT look better.

Different pricing agreements could make esketamine more competitive. A more refractory patient subgroup might change the value equation.

In Hong Kong, under current assumptions, esketamine looked clinically useful and economically outmatched by cheaper third-line options. The model places the drug later in the sequence unless delivery costs, dosing assumptions, or payer prices change.