Age-related moderation of adjunctive psychotherapy and early life stress effects on depression symptom reductions following ketamine treatment: Initial insights from a large, naturalistic sample.
Raquel Kosted, Alli Waddell, Ken Adolph, Gregory A. Fonzo
Journal of Affective Disorders February 4, 2026 DOI: 10.1016/j.jad.2026.121350 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 224 |
| Population | Patients receiving five ketamine infusions at a private clinic |
| Interventions | Ketamine infusions Ketamine-assisted therapy |
| Duration | Five infusions |
| Topics | Depression Ketamine Esketamine |
| Keywords | Adverse childhood experiences Early life stress Ketamine-assisted therapy |
| Key findings | Higher ACE scores were associated with greater symptom reduction over time, independent of whether patients received ketamine-assisted therapy or infusions alone. |
Abstract
Ketamine is known to be a rapid-acting antidepressant, but there is limited evidence regarding which types of patients are best-suited to this treatment and whether adjunctive psychotherapy improves outcomes. In a sample of 224 patients who received five ketamine infusions at a private clinic, this study uses Bayesian mixed modeling to examine the effects of early life stress (measured with the Adverse Childhood Experiences [ACE] survey) and treatment modality (ketamine-assisted therapy [KAT] vs. infusions only) on antidepressant response, and whether these effects interact. Depression symptoms were assessed prior to each infusion using the Patient Health Questionnaire-9 survey. Depression symptoms improved over time (time: β = -4.4, 95% Credible Interval [-6.8, -1.9]), with decelerating rates of improvement (quadratic time: β = 2.6, [0.4, 4.8]). Symptom trajectories did not differ between treatment modalities (time*treatment condition: β = 0.8, [-1.6, 3.1]). Higher ACE scores were associated with greater symptom reduction (time*ACE: β = -0.6, [-0.9, -0.3]), independent of treatment modality (time*ACE*treatment condition: β = -0.5, [-1.1, 0.2]). Exploratory analyses revealed that younger adults show greater treatment response to ketamine infusions alone compared to KAT, while the opposite is observed in older adults (time*treatment condition*age: β = -0.1, [-0.3, -0.03]). Furthermore, the relationship between higher ACE scores and greater symptom reduction may be particularly strong within younger adults, with this association reversing at older ages (time*ACE*age: β = 0.02, [0.002, 0.04]). In summary, enhanced magnitude of symptom reduction for those with greater early life stress exposure, especially in younger adults, suggests a potentially unique and targeted benefit of ketamine over conventional antidepressants for this population.
Comparable studies
Other observational and cohort studies on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
| Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... | 2017 | Observational cohort | n = 59 |
| Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... | 2014 | Post hoc analysis of pooled data from four studies | n = 108 |
| An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder | 2011 | Observational cohort | n = 14 |
| Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... | 2019 | Observational cohort | n = 25 |