Ketamine-Derived Nasal Spray Drug Shows Promise Against Loss of Pleasure in Depressed Teens

Anhedonia, the crushing inability to feel pleasure from activities that once brought joy, is one of the most stubborn and disabling symptoms of adolescent depression. Unlike low mood, which can fluctuate across a day or respond to psychotherapy, anhedonia often persists even when other depressive symptoms improve, and it is strongly linked to poor functional outcomes, chronic illness trajectories, and suicidal thinking. Now, a randomized controlled trial conducted at The Affiliated Brain Hospital of Guangzhou Medical University suggests that esketamine, the S-enantiomer of ketamine already approved for treatment-resistant depression in adults, may offer adolescents with moderate to severe major depressive disorder a meaningful path back to the capacity for enjoyment. The study, published in BMC Psychiatry, reports that adjunctive esketamine infusions produced significant, delayed improvements in anhedonia compared with an active control, alongside reductions in overall depressive and suicidal symptoms.

The trial enrolled 74 adolescent patients aged 13 to 17 who were diagnosed with moderate to severe depression and were already receiving standard antidepressant medication. In a prospective, randomized, double-blind design, participants were assigned to receive either intravenous esketamine at a dose of 0.25 milligrams per kilogram of body weight or midazolam at 0.02 milligrams per kilogram. Midazolam, a short-acting benzodiazepine, served as an active comparator because it produces similar sedative and psychoactive side effects without ketamine’s antidepressant pharmacology, allowing researchers to separate genuine therapeutic action from the subjective experience of receiving an infusion. Each participant received three infusion sessions, administered every other day, with each session lasting 40 minutes. The study was prospectively registered at the Chinese Clinical Trial Registry under number ChiCTR2000041232, and it was approved by the hospital’s ethics committee and conducted in accordance with the Declaration of Helsinki, with written informed consent obtained from all participants and their legal guardians.

The primary focus of the analysis was anhedonia, measured using the anhedonia subscale of the Montgomery-Asberg Depression Rating Scale, a clinician-rated instrument widely regarded as one of the most sensitive tools for tracking depressive symptom change over time. Because the trial design involved repeated assessments at multiple time points after treatment, the researchers employed mixed-effects models, a statistical framework that handles longitudinal data by modeling both fixed effects, such as treatment assignment and time, and random effects that account for individual variability between patients. This approach is particularly well suited to detecting how treatment differences evolve across a follow-up period rather than collapsing everything into a single endpoint, which is essential when a drug’s effects are expected to emerge on a delayed schedule.

That delayed schedule turned out to be one of the most striking features of the results. In the earliest phase of follow-up, the statistical analysis found no significant drug-by-time interaction between the esketamine and midazolam groups, meaning that the two treatments could not yet be distinguished in their effects on anhedonia. However, from Day 12 onward, significant interactions favoring esketamine emerged, and these differences remained statistically significant across the subsequent assessment points, with all reported P values below 0.05. In practical terms, this means that adolescents who received esketamine began to pull away from the control group in their recovery of pleasure and interest roughly two weeks after the infusion series began, and that advantage persisted over the longer term of the observation window.

The delayed onset pattern is notable because it complicates the popular narrative that ketamine-class drugs act as rapid-acting antidepressants. In adults, single doses of ketamine have been shown to reduce depressive symptoms within hours, a property that has generated enormous enthusiasm for managing acute suicidal crises. The adolescent data from this trial suggest a more nuanced picture: while esketamine’s overall antidepressant and anti-suicidal effects in this cohort were significant, its specific benefit for anhedonia appears to build gradually, accumulating across repeated infusions and consolidating in the second week of follow-up. This temporal profile may reflect the biology of the symptom itself. Anhedonia is thought to arise from dysfunction in the brain’s reward circuitry, particularly the mesolimbic dopamine pathways connecting the ventral tegmental area to the nucleus accumbens, and restoring the plasticity of these circuits may require sustained molecular remodeling rather than a single pharmacological trigger.

That remodeling is precisely what preclinical research proposes esketamine accomplishes. As an antagonist of the N-methyl-D-aspartate receptor, a glutamate-gated ion channel, esketamine blocks a major brake on excitatory neurotransmission, triggering a cascade that includes increased release of brain-derived neurotrophic factor, stimulation of the mammalian target of rapamycin signaling pathway, and a burst of synaptic protein synthesis that strengthens connections among neurons. Animal studies have implicated this cascade in the medial prefrontal cortex, the ventral hippocampus, and D1 receptor-expressing medium spiny neurons projecting to the nucleus accumbens, all nodes of the reward network whose dysfunction is associated with anhedonic behavior. If the same mechanisms operate in the human adolescent brain, the delayed improvement observed in the trial could represent the time course of synaptic restoration within these circuits, a hypothesis the authors themselves flag as requiring dedicated neurobiological testing in future work.

The clinical significance of the finding is difficult to overstate. Adolescents with major depressive disorder are typically treated with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, medications that take weeks to show benefit and that leave a substantial fraction of patients with residual symptoms. Anhedonia is among the most common residuals, and it is a powerful predictor of relapse, social withdrawal, academic decline, and suicide risk. Current alternatives for treatment-resistant adolescents, such as electroconvulsive therapy or repetitive transcranial magnetic stimulation, carry logistical burdens, access barriers, or stigma that limit their reach. A pharmacological adjunct that can be delivered in three 40-minute infusions over the course of a week, layered onto existing antidepressant treatment, would represent a genuinely new option for a population in which approved rapid-acting interventions are essentially absent.

The authors are appropriately measured in their conclusions. As a post-hoc analysis of a randomized controlled trial with 74 participants, the study provides evidence of signal rather than definitive proof of efficacy, and the anhedonia outcome was extracted from the broader MADRS framework rather than serving as the trial’s pre-registered primary endpoint. The follow-up period, while long enough to capture the delayed divergence between groups, cannot speak to durability over months or years, a critical question for any intervention in a developmental window as sensitive as adolescence. The authors explicitly call for larger, long-term studies incorporating neurobiological measures to verify the therapeutic effects and to illuminate the mechanisms underlying them. Questions about optimal dosing, the ideal number of infusions, the safety profile of repeated esketamine exposure in developing brains, and the identification of which adolescent patients are most likely to benefit all remain open.

Safety and ethical oversight were nonetheless built carefully into the trial’s architecture. The double-blind design, the use of midazolam as an active comparator, and the restriction of esketamine to a moderate dose of 0.25 milligrams per kilogram reflect a conservative approach to first-line investigation in minors. Oversight was provided by the hospital’s Department of Education and Information and its Academic Management Committee, with dual annual audits of trial progress and continuous feedback to investigators. Participants and their families received both verbal and written explanations of the procedures, potential benefits, and risks, and were free to withdraw at any time without penalty. The study was supported by the National Natural Science Foundation of China and by Guangzhou municipal health and clinical research programs, and the authors declare no competing interests.

For clinicians and families confronting adolescent depression, the trial offers a cautiously hopeful message: the capacity for pleasure, often the last symptom to surrender and the first sign that a young person is truly recovering, may be reachable even when standard medications have fallen short. For researchers, it opens a concrete agenda, from replication in larger cohorts to neuroimaging studies of reward circuitry before and after treatment. And for the broader field of psychiatry, it adds to the accumulating evidence that glutamatergic agents can reach symptom dimensions, such as anhedonia and suicidal thinking, that monoaminergic antidepressants have long struggled to touch. The road from a 74-patient post-hoc analysis to routine clinical practice is long, but the destination, an effective, mechanistically grounded treatment for the joylessness at the core of teenage depression, has rarely seemed closer.

Subject of Research: Esketamine treatment of anhedonia in adolescents with major depressive disorder

Article Title: Esketamine’s therapeutic effect on anhedonia in adolescents: a post-hoc of a randomized controlled trial

Article References: Wu, Q., Li, W., Luo, Z., Wang, C., Lan, X., Shen, J., Chen, Z., Pan, J., Liu, X., Zhu, H., Xue, Y., Wu, Z., Ning, Y., & Zhou, Y. (2026). Esketamine’s therapeutic effect on anhedonia in adolescents: a post-hoc of a randomized controlled trial. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08736-0

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08736-0

Keywords: esketamine, anhedonia, adolescent depression, major depressive disorder, randomized controlled trial, NMDA receptor, MADRS, psychopharmacology, suicidal ideation, treatment-resistant depression, reward circuitry, BMC Psychiatry