Can Esketamine Help Teens Who've Lost the Ability to Feel Joy? A Look at New Trial Data

Depression isn't only sadness. For many adolescents, one of the most disabling features is anhedonia — a blunted capacity to feel pleasure or interest in things that once mattered to them. It can persist even when other symptoms ease, and it's notoriously hard to treat with standard antidepressants. A new post-hoc analysis of a randomized controlled trial looked at whether esketamine, a fast-acting agent already studied in adults with treatment-resistant depression, might offer something different for younger patients struggling with this symptom.

Setting Up the Comparison

Researchers in China worked with 74 adolescents, ages 13 to 17, all diagnosed with moderate to severe major depressive disorder. Participants continued on their regular antidepressant medications and were randomly split into two groups: one received low-dose esketamine infusions, the other received midazolam, a sedative used here as an active comparator rather than an inert placebo. Each person received three infusions, spaced every other day, lasting 40 minutes each.

To track anhedonia specifically, the team used a subscale of the Montgomery-Asberg Depression Rating Scale, a standard tool for measuring depressive symptoms, and followed participants at several points after treatment. Statistical models designed to handle repeated measurements over time let the researchers see whether the two groups diverged — and when.

A Delayed but Noticeable Shift

The pattern that emerged was not immediate. In the early days following treatment, there was no meaningful difference between the esketamine and midazolam groups in how anhedonia scores changed. But starting around day 12 and continuing afterward, the esketamine group showed a significantly greater improvement in anhedonia compared with those who received midazolam.

That timing is worth sitting with. Esketamine has built its reputation in adult studies partly on rapid antidepressant effects, sometimes within hours. Here, the anhedonia-specific benefit seemed to take longer to unfold, pointing to a possibly different time course for this particular symptom than for depression overall. The authors describe the effect as "delayed," and suggest it may reflect underlying neurobiological processes that develop gradually rather than one dramatic shift.

Beyond anhedonia scores, the trial's broader findings — described in the paper's conclusions — indicated that adjunctive esketamine was associated with improvements in general depressive symptoms and suicidal thoughts in this adolescent population, alongside the anhedonia effect. These were measured as part of the larger trial from which this analysis was drawn.

What the Data Can and Can't Tell Us

It's useful to be precise about what this study design allows researchers to conclude. This was a post-hoc analysis — meaning the anhedonia-focused comparison was examined after the main trial, using data gathered for a broader purpose. That doesn't invalidate the findings, but it does mean they should be treated as a hypothesis-generating signal rather than a definitive answer. The sample size, 74 participants, is also modest, and the follow-up period, while long enough to detect a delayed signal, wasn't extended indefinitely.

The researchers themselves are candid about this, calling for larger trials with longer follow-up and the addition of neurobiological measurements to help clarify not just whether esketamine helps with anhedonia in teens, but why. Esketamine works on the brain's NMDA receptor system, a different mechanism than the serotonin-focused pathways targeted by most standard antidepressants, and animal and adult human research has pointed to effects on brain circuits involved in reward processing. Whether those same mechanisms explain what was observed in this adolescent sample remains an open question.

Why Anhedonia Deserves Its Own Spotlight

Depression trials often track overall symptom scores, which can obscure what's happening with any single symptom cluster. Anhedonia tends to respond poorly to many existing treatments and has been linked in other research to poorer long-term outcomes, including greater risk of relapse. A treatment that specifically targets this stubborn symptom, even as an add-on rather than a stand-alone therapy, could fill a genuine gap in adolescent mental health care — if these early findings hold up under further scrutiny.

For now, this trial adds a data point to a growing body of esketamine research, extending the conversation from adults into a younger population where treatment options remain limited and the stakes of untreated depression are high. Adolescent psychiatry has historically lagged behind adult treatment research, partly due to legitimate caution about testing newer medications in developing brains, so controlled data like this are valuable even in preliminary form.

Families and clinicians weighing treatment options for adolescent depression should discuss any medication, including esketamine, with a qualified health professional familiar with the individual case. This article is meant to summarize research findings, not to serve as guidance for treatment decisions.

Source: BMC Psychiatry, DOI: 10.1186/s12888-026-08736-0, based on a randomized controlled trial post-hoc analysis by Wu, Li, Luo, and colleagues.