Esketamine Lost the Cost-Effectiveness Race in Hong Kong

TL;DR: A 5-year Hong Kong model found esketamine plus an antidepressant bought only a small quality-adjusted survival gain at US$29,061 per patient, leaving it behind cheaper third-line options like combination therapy.

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

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

Why Real-World Third-Line Comparators Matter After Two Failed Antidepressants

Treatment-resistant depression is exactly where health systems get squeezed. Patients are still profoundly symptomatic, clinicians want something more powerful than another oral drug shuffle, and esketamine offers a rapid-acting mechanism that feels modern and clinically urgent. The problem is that drug novelty does not erase opportunity cost.

This paper is useful because it did not compare esketamine with a straw-man oral antidepressant alone. Instead, the authors built a seven-arm model around options clinicians actually use in practice: augmentation, combination therapy, psychotherapy alone, psychotherapy plus antidepressants, rTMS, ECT, and esketamine.

The question becomes sharper. If you have a limited budget, where in the sequence does esketamine really belong?

The answer from Hong Kong’s payer perspective was uncomfortable for the drug. Esketamine improved outcomes, but not by enough to justify the added cost against the more practical comparators.

What the 5-Year Hong Kong Model Said About Cost and Quality-Adjusted Survival

The base-case table is the clearest part of the paper. Combination therapy cost US$16,163 per patient and generated 2.903 quality-adjusted life-years, a standard health-economics measure that combines survival time with quality of life.

Psychotherapy plus an antidepressant cost US$21,555 and produced 2.926 quality-adjusted life-years. Esketamine plus an antidepressant came in at US$29,061 for 2.950 quality-adjusted life-years. So the drug did buy extra quality-adjusted survival, but the gain was small relative to the price jump.

That is why the incremental cost-effectiveness ratio mattered so much. On the efficient frontier, moving from psychotherapy plus an antidepressant to esketamine required US$312,750 for each extra quality-adjusted life-year gained.

The willingness-to-pay threshold in this study was US$50,000 per quality-adjusted life-year, roughly one Hong Kong GDP per capita. Esketamine missed that threshold by a wide margin.

It also helps to notice what did not happen. The paper did not show esketamine to be economically useless in every comparison.

It dominated rTMS, meaning it was cheaper and more effective in the model, and it looked more favorable than ECT in the Hong Kong cost structure. But that is different from saying it was the smartest place to spend money overall.

Combination Therapy Won the Model So Decisively

The strongest policy message in the study is not really about esketamine. It is about how underappreciated combination therapy may be in this treatment tier.

In the model, it was both the least costly and the most economically attractive nondominated option. That means the system can gain a lot before it ever reaches the nasal-spray conversation.

That result is easy to miss because esketamine carries the novelty premium. But the numbers point in the opposite direction.

Combination therapy was slightly more effective than augmentation and cheaper than everything else. For a payer, that kind of position is hard to beat. For a clinician, it means the economically rational sequencing strategy can still look surprisingly conventional.

• Lowest modeled cost: combination therapy came in at US$16,163 per patient.
• Competitive benefit: it produced 2.903 quality-adjusted life-years.
• Sequencing implication: cheaper conventional strategies still deserve serious placement before esketamine in this payer model.

The model also complicates the usual “esketamine versus ECT” argument. ECT delivered the highest quality-adjusted survival in the table at 3.004 quality-adjusted life-years, but it 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-quality-adjusted-life-year step from esketamine to ECT. That is a local-system constraint as much as a treatment-effect claim.

What 8-Week Monitoring and Price Cuts Changed, and What They Didn’t

The sensitivity analyses are where the paper becomes more realistic. The most favorable scenario for esketamine was not a miraculous efficacy shift.

It was a structural change: stretching the treatment cycle from 4 weeks to 8 weeks reduced the ICER to US$73,556 per quality-adjusted life-year. Better, but still above the base threshold.

A 75% cut in acquisition price also failed to make the drug clearly cost-effective at the US$50,000 benchmark, lowering the ICER to US$116,327 per quality-adjusted life-year versus augmentation. That is the kind of result health-policy people notice because it means the problem is not only the sticker price. Monitoring, delivery, and broader care-pathway costs matter too.

The threshold analysis drove that home: the total esketamine arm cost would need to drop by roughly 35% to get close to acceptable value at the chosen threshold. In other words, squeezing the vial price alone is probably not enough. Systems would need a more efficient delivery model as well.

This Still Doesn’t Close the Esketamine Debate

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, so they had to rely on indirect evidence from heterogeneous clinical populations. Utility estimates also did not fully capture treatment-specific burdens such as dissociation with esketamine or cognitive adverse effects with ECT.

That means the exact rankings could shift in another healthcare system. Lower labor costs could make ECT look better.

Different pricing agreements could make esketamine more competitive. A different patient subgroup, especially one more refractory than the modeled population, might also change the value equation.

But the paper still lands a clear punch. In Hong Kong, under current assumptions, esketamine looked clinically useful yet economically outmatched by cheaper third-line options. The question is less whether the drug works and more how fast innovation runs into budget reality.