Can Esketamine or Ketamine Therapy Help Adolescents with Major Depressive Disorder?

Can Esketamine or Ketamine Therapy Help With Major Depressive Disorder in Adolescents?

If you or an adolescent you know is navigating major depressive disorder, you know it is one of the most prevalent psychiatric conditions they can face, and the single greatest risk factor for adolescent suicide. A landmark 2026 randomized controlled trial published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) now provides the strongest clinical evidence to date that esketamine nasal spray can rapidly reduce depressive symptoms in adolescents – within 24 hours of a first dose.

If your family is navigating a crisis, that kind of speed matters. Standard oral antidepressants – fluoxetine, escitalopram, sertraline, etc – require four to six weeks to reach full therapeutic effect. Those weeks can represent a challenging gap. The question providers like those at Lumin Health are now grappling with is not only whether rapid-acting interventions have a role in adolescent depression, but how to deliver them responsibly, safely, and with the clinical rigor your adolescent deserves.

This article examines what the new JAACAP data actually show, how the neurobiology of adolescent depression differs from the adult form, and what you should understand about the current – and evolving – landscape of ketamine therapy and Spravato for major depressive disorder in adolescents.

What Does the New JAACAP Esketamine Trial Actually Show?

The phase 2b study published in JAACAP (Kosik-Gonzalez et al., 2026) is unprecedented in several respects. It enrolled 147 adolescents aged 12 to 17 who met DSM-5 criteria for major depressive disorder and were assessed to be at imminent risk for suicide. This is a population that is routinely excluded from antidepressant clinical trials – precisely those for whom existing treatments are most urgently needed and least studied.

Here is what the data revealed:

The primary endpoint was met. Pooled esketamine doses (56 mg and 84 mg) demonstrated statistically significant superiority over the psychoactive placebo (oral midazolam) in reducing depressive symptoms on the Children's Depression Rating Scale – Revised (CDRS-R) at 24 hours after the first dose (between-group difference: −5.8 points, p = .037).
The effect size exceeded standard antidepressants. The between-group difference of −5.8 points at 24 hours post first dose exceeded the effect sizes observed for fluoxetine (−2.8), sertraline (−3.5), and escitalopram (−2.6) at their respective study endpoints of six to twelve weeks in registration trials.
Approximately 95% of participants were moderately to extremely suicidal at enrollment. More than half (54%) had attempted suicide within the preceding 30 days. Eighty percent had a lifetime history of at least one attempt.
Response rates were clinically meaningful. Between 53.6% and 61.3% of esketamine-treated adolescents met response criteria (≥50% improvement in CDRS-R) at just 24 hours post first dose. By day 25, a majority across all treatment groups had responded.
No new safety signals emerged. The adverse event profile in adolescents was consistent with that previously characterized in adults – dizziness, nausea, dissociation, headache, and dysgeusia – with most events occurring on dosing days and resolving within 1.5 hours.
95% of participants completed the four-week treatment phase, and 80% completed the six-month post-treatment follow-up – a remarkable retention rate for a population in acute psychiatric crisis.

This study did not use a saline placebo. The comparator was midazolam, a short-acting benzodiazepine chosen for its own psychoactive properties – sedation and disorientation – to help preserve the blinding. This is a more rigorous design choice than a simple sugar pill, and it means the esketamine signal had to emerge above and beyond a pharmacologically active control. The researchers themselves note that midazolam's sedative effects may have "dampened signal detection," making the statistically significant finding on the primary endpoint all the more noteworthy.

Why Major Depressive Disorder in Adolescents Demands a Different Clinical Lens

It would be a mistake to treat adolescent depression as simply "adult depression in a younger body." The adolescent brain is undergoing a period of extraordinary structural and functional reorganization. Synaptic pruning – the process by which the brain eliminates weaker neural connections to strengthen more efficient ones – is at its peak during this developmental window. Myelination of white matter tracts, particularly those connecting prefrontal executive circuits to limbic emotional centers, is incomplete.

This has profound implications for how depression takes root. If your adolescent is navigating major depressive disorder, overactivity in the Default Mode Network (DMN) – the network of brain regions most active during self-referential thinking, rumination, and mind-wandering – can become entrained during a period when neural circuits are still being sculpted. Thought patterns and behavioral patterns become encoded in white matter tracks in other parts of the brain, growing increasingly inflexible. Reward circuits are skewed. Futility and hopelessness become, in a very real neurobiological sense, hard coded into a brain that is still forming its foundational architecture.

This is why the speed of intervention matters so critically. Standard oral antidepressants take four to six weeks to reach optimal effect – the JAACAP study's authors explicitly acknowledge this gap as the rationale for their trial design. If your adolescent's suicidal ideation can move from thought to attempt in a matter of hours, that timeline represents a challenging clinical vulnerability.

"Your child's brain isn't broken – it may be stuck. For some, the hope for rapid intervention offers something that’s been difficult to come by, to date. The treatments aren’t for everyone and there are special considerations when regarding the application of ketamien or esketamine in the adolescent population. Nevertheless, respecting the nuance in addressing depression in this particular class of people, ketamine and esketamine may be viable options to consider." — Dr. Ben Yudkoff, Chief Medical Officer at Lumin Health

How Esketamine Is Thought to Work in the Adolescent Brain

Esketamine – the S-enantiomer of the ketamine molecule (the "s" stands for sinistrum, Latin for "left," as the esketamine molecule is oriented to the left) and the more active component – is FDA-approved for adults with treatment-resistant depression and major depression with suicidal thoughts. It is not yet approved for adolescents, which is precisely why the JAACAP trial represents such a critical step forward in establishing an evidence base for this population.

The primary mechanism of action for Spravato centers on glutamate, the brain's most abundant excitatory neurotransmitter. By antagonizing the NMDA receptor, esketamine triggers a downstream surge in glutamate signaling that activates AMPA receptors and, through them, stimulates the release of brain-derived neurotrophic factor (BDNF) – a protein essential for synaptogenesis (the formation of new synaptic connections between neurons) and neuroplasticity (the brain's capacity to reorganize and form new functional pathways).

If your adolescent's brain feels trapped in rigid depressive circuitry, this mechanism is particularly relevant:

Synaptic restoration. Chronic stress and depression are associated with dendritic atrophy – the physical retraction of the branching structures on neurons that receive signals. Glutamate-mediated BDNF release aims to reverse this process, promoting the regrowth of synaptic connections, particularly in prefrontal cortical areas critical for emotional regulation.
Circuit recalibration. The adolescent reward system is uniquely vulnerable to depression-driven anhedonia. By modulating glutamatergic tone, esketamine may help sensitize reward circuitry that has gone dark and help establish healthy perspective and entrain healthy habits.

This does not guarantee an outcome. It is more accurately understood as a biologically receptive window – a period during which the brain is temporarily more plastic, more capable of forming new connections, and more responsive to an adolescent's own capacity for change, self-guided intent, and the behavioral support work that occurs alongside treatment.

The Adolescent Suicide Crisis: Why Speed of Onset Is a Clinical Priority

The urgency behind studying rapid-acting interventions for major depressive disorder in adolescents is not academic. It is existential. Consider the epidemiological context surrounding this trial:

MDD is associated with a five-fold higher risk of suicide attempts in adolescents.
Up to 80% of adolescents who attempt suicide meet criteria for depression at the time of their attempt.
Up to 60% of adolescents who die by suicide have a depressive disorder at the time of death.
The JAACAP study cites research showing that 13% of nonpsychotic adolescents hospitalized in a psychiatric facility attempted or reattempted suicide within six months of discharge – underscoring that hospitalization alone is an incomplete solution.

There are currently no regulatory-approved pharmacological treatments specifically indicated for adolescents with MDD who are at imminent risk for suicide. The standard of care – hospitalization, initiation of an oral antidepressant, evidence-based behavioral support – has significant limitations. Hospitalization provides temporary stabilization but cannot address the neurobiological drivers of the depressive episode. Oral antidepressants require weeks to take effect. Access to evidence-based support structures is variable and often challenging.

The JAACAP trial was designed explicitly to address this gap. The four-week double-blind treatment phase was structured to "rapidly control depressive symptoms and to bridge the gap of the delayed onset of the newly initiated or optimized oral antidepressant therapy." The results suggest that esketamine, as part of comprehensive care, may help close this dangerous window.

What Does "Comprehensive Standard of Care" Mean in This Trial – and What It Means for You

A critical nuance of the JAACAP study is that no participant received esketamine alone. All 147 adolescents received what the researchers term "comprehensive standard of care," which included:

Initial psychiatric hospitalization (recommended duration of at least five days post-randomization)
Initiation or optimization of an oral antidepressant – fluoxetine, escitalopram, or sertraline – ideally on day 1, no later than day 7
Evidence-based psychotherapy through at least day 81 of the study
Esketamine nasal spray (or midazolam control) administered twice weekly for four weeks under clinical supervision

This matters because the rapid improvement seen in the esketamine groups occurred in the context of this multimodal approach. The researchers explicitly note that "the comprehensive nature of the care provided – including initial hospitalization, supportive psychosocial intervention, initiation or optimization of oral antidepressant, and evidenced-based psychotherapy – likely had a significant therapeutic effect."

The esketamine did not replace these other elements. It accelerated the trajectory of improvement beyond what those elements could achieve alone.

For your family, this means understanding that a rapid-acting intervention like esketamine is best conceptualized not as a standalone solution, but as a catalyst – a way to create the neurobiological conditions under which your adolescent's own self-guided intent, ongoing treatment, and capacity for change can take hold more quickly and more effectively.

Safety in Adolescents: What the Data Show and What Parents Need to Know

Any conversation about ketamine treatment or Spravato in adolescents must confront safety transparently. The JAACAP trial provides the most robust safety dataset to date for esketamine in this age group.

Common Side Effects

The most frequently reported treatment-emergent adverse events (incidence ≥20% across esketamine dose groups) were:

Dizziness (57.8%)
Nausea (43.4%)
Dissociation (42.2%)
Headache (36.1%)
Dysgeusia – an altered or bitter taste (32.5%)
Somnolence (32.5%)
Vomiting (21.7%)
Hypoesthesia – reduced sensation of touch (27.7%)

Critically, the vast majority of these events occurred on dosing days and resolved the same day. For example, 93% of dizziness events, 95.3% of nausea events, and 94.8% of dissociation events resolved on the day they occurred. Most were mild to moderate in severity. Dissociative symptoms typically peaked at approximately 40 minutes post-dose and resolved by 1.5 hours – consistent with the profile observed in adult studies.

Sedation Was Actually Lower With Esketamine

An important and somewhat counterintuitive finding: moderate or greater sedation was nearly three times more common in the midazolam (placebo) group than in the esketamine groups. Only 2.4% of esketamine-treated participants experienced an MOAA/S score ≤2 (indicating deeper sedation), compared with 36.5% of midazolam-treated participants. No participant in either group required medical intervention for sedation, and no respiratory depression was observed.

Cognitive Safety

Analyses of cognitive testing identified no systematic effects of any dose of esketamine on attention, processing speed, executive function, working memory, or visual or verbal learning and memory. If you are worried about the impact of these treatments on your adolescent's developing cognitive capacity, this is a meaningful data point.

Self-Injurious Behavior and Suicide Attempts

Rates of treatment-emergent intentional self-injury during the double-blind phase were similar between treatment groups: 20.5% for esketamine and 19.0% for midazolam. During the six-month follow-up, 15% of participants across both groups attempted suicide – a rate consistent with the previously reported 13% incidence among hospitalized adolescents who attempt or reattempt within six months of discharge. The researchers note that these rates are "not unexpected" given that the study specifically enrolled adolescents at imminent risk for suicide, 80% of whom had a lifetime history of attempts.

Ketamine for Depression in Adolescents: Where Does the Broader Evidence Stand?

The JAACAP esketamine trial does not exist in a vacuum. A small but growing body of evidence supports the potential of ketamine-based interventions for adolescent depression:

A 2021 randomized, midazolam-controlled trial published in the American Journal of Psychiatry (Dwyer et al.) found that a single intravenous ketamine infusion reduced depressive symptoms at 24 hours in 17 adolescents with treatment-resistant MDD. Response rates were 76% for ketamine versus 35% for midazolam.
Zhou et al. (2024) randomized 54 adolescent inpatients with moderate-to-severe MDD and suicidal ideation to receive three intravenous esketamine or midazolam infusions over five days. Significantly greater reduction in suicidal ideation was observed with esketamine beginning at 24 hours post first dose.

Ketamine therapy – an evidence-based, off-label application of a medicine that has been in clinical use for over 50 years – uses the racemic mixture containing both the S-ketamine and R-ketamine molecules. If you are an adult exploring options, Lumin Health provides Intramuscular (IM) ketamine injections, which offer distinct advantages in speed and comfort compared to the IV ketamine infusion. While ketamine treatment is currently used for adults, the accumulating research in adolescents – including the JAACAP trial – is building the foundation for understanding how these mechanisms translate to younger demographics.

It is important to note that ketamine for depression in adolescents remains investigational and off-label. The JAACAP trial studied esketamine nasal spray specifically, not racemic ketamine. Families exploring these options should work closely with experienced providers who understand the distinctions between these agents, their evidence bases, and the regulatory landscape.

The Role of Your Adolescent's Own Agency in Recovery

One of the most important clinical insights from the JAACAP data is what happened after the treatment phase ended. During the six-month post-treatment follow-up – when no study drug was being administered – there was no rebound of depressive symptoms. CDRS-R and MADRS scores (scales used to rate depression) remained improved, suggesting that the rapid symptom reduction achieved during the treatment phase created a foundation upon which ongoing recovery could build.

This aligns with what providers at Lumin Health observe: if you are receiving ketamine treatment, the medication does not do the work for you. It aims to create a biologically receptive window – a period of enhanced neuroplasticity and cognitive flexibility – during which your own self-guided intent, behavioral support work, and capacity for change become the primary engines of sustained improvement.

For your adolescent, this framework is particularly important. If your teenager is in the grip of severe depression, they may feel utterly powerless – trapped in a brain that tells them nothing will ever change. The experience of rapid symptom reduction, even partial, can be profoundly validating. It provides experiential evidence that their suffering is not permanent, that their brain is capable of feeling differently, and that their own efforts toward recovery are not futile.

What You Should Know: Frequently Asked Questions

Is Spravato approved for adolescents?

No. Spravato (esketamine nasal spray) is FDA-approved for adults with treatment-resistant depression and major depression with suicidal thoughts. It is not currently approved for use in those under 18. The JAACAP phase 2b trial is a critical step toward establishing the evidence base for potential future regulatory consideration. The study's authors explicitly state that "the results support further investigation of esketamine nasal spray for the rapid reduction of depressive symptoms in larger trials of adolescents."

Does Lumin Health treat adolescents?

Lumin Health's current treatment programs – including Intramuscular (IM) ketamine therapy and Spravato – are designed for adults. However, as an organization led by academically-affiliated providers and a psychiatrist-led clinical team, Lumin Health closely follows the evolving research on rapid-acting antidepressant mechanisms in adolescent populations. If you are a parent exploring options, we would be grateful to answer questions and help you understand the current evidence landscape. In specific circumstances, we have provided care to people between 16-18 years old.

Is the dissociation experienced during esketamine treatment like a "bad trip"?

Dissociation was reported by 42.2% of esketamine-treated adolescents in the JAACAP trial, but the clinical profile is important to understand. These experiences typically peaked at approximately 40 minutes after dosing and resolved by 1.5 hours. They attenuated with repeated dosing – meaning they tended to become less intense over the four-week treatment course. All dosing occurred under direct clinical supervision with vital sign monitoring. The study reported no instances requiring medical intervention for dissociative symptoms.

What about long-term cognitive effects on a developing brain?

The JAACAP trial's cognitive battery – measuring attention, processing speed, executive function, working memory, and visual and verbal learning and memory – identified no systematic effects of any esketamine dose on cognitive functioning. While longer-term studies will be needed, this is a reassuring signal, particularly given the concerns you may understandably have about interventions affecting a brain still in development.

Why was midazolam used as the control instead of a simple placebo?

Because esketamine produces noticeable psychoactive effects (dissociation, dizziness, altered perception), using a saline nasal spray or sugar pill as a placebo would make it obvious to participants and clinicians who was receiving the active drug – a problem known as functional unblinding. Midazolam produces its own psychoactive effects (sedation, disorientation), helping to preserve the integrity of blinding. This is actually a higher evidentiary bar: the esketamine signal had to emerge above an active comparator, not just above doing nothing.

The Path Forward: What This Research Means for Adolescent Mental Health Care

The JAACAP trial is not the final word. It is a phase 2b dose-ranging study with a relatively small sample size – powered for the primary efficacy endpoint but not for suicidality endpoints or other secondary measures. The researchers themselves acknowledge methodological limitations including the potential for functional unblinding and the nonspecific therapeutic effects of hospitalization and study participation.

But the significance of what was accomplished should not be understated. This trial enrolled the most vulnerable adolescent psychiatric population – actively suicidal, severely depressed, majority with prior attempts – and demonstrated that esketamine, alongside comprehensive care, can produce statistically significant and clinically meaningful reductions in depressive symptoms within 24 hours. It did so with a safety profile consistent with the known adult data, with no new concerns emerging, and with no evidence of cognitive harm.

For the field of adolescent psychiatry, the implications are substantial. If you have watched your child cycle through weeks of hospitalization and medication trials while remaining in crisis, the prospect of an intervention that may help reduce suffering quickly enough to allow other treatments time to take effect suggests meaningful relief may be possible.

At Lumin Health, our role is to remain at the clinical forefront of these developments: to provide expert, evidence-grounded care to adults today, and to ensure that families navigating adolescent mental health crises have access to accurate, nuanced information rather than hype or oversimplification.

If you are exploring what rapid-acting interventions may mean for your family, or if you are an adult living with treatment-resistant depression and seeking care grounded in this level of clinical rigor, we would be grateful to walk with you toward relief. Explore whether this may be a fit.