Combined ketamine and psychotherapy provide no additional benefit beyond ketamine alone in treating depression or PTSD: Evidence from a help-seeking sample

Depression and post-traumatic stress disorder (PTSD) are common, often co-occurring conditions that produce substantial functional impairment and elevated suicide risk. Ketamine has emerged as a rapid-acting intervention for both disorders through NMDA receptor antagonism, downstream increases in glutamate and AMPA throughput, and promotion of neuroplasticity (for example via BDNF and mTORC1 pathways). These neurobiological effects can produce quick symptom relief and transient synaptogenesis, distinguishing ketamine from conventional antidepressants that typically require weeks to act. Despite growing interest in ketamine-assisted psychotherapy (KAP), evidence remains mixed and methodologically heterogeneous. Prior studies and reviews have suggested potential additive or synergistic effects when psychotherapy is combined with ketamine, but many investigations lack direct comparisons against ketamine-only treatment, vary in dosing and psychotherapy modality, and are insufficiently powered to demonstrate synergy. Moore and colleagues designed the present study to test whether combining ketamine with psychotherapy produces greater reductions in depression and PTSD symptoms than ketamine alone during the acute treatment phase. Their stated hypothesis was that combined treatment would yield faster symptom decline and/or a lower symptom plateau across six ketamine administrations compared with ketamine without concurrent psychotherapy.

This was a naturalistic, clinic-based comparative study using help-seeking patients treated at a single accredited outpatient centre (Revitalist Treatment Center) between March 2022 and December 2023. The primary analysis used a narrowly defined main sample of N = 202 patients (60% female, mean age 41.3 years) who received exactly six clinic visits within a 30-day window and who received only one treatment type throughout those visits: either ketamine alone (KET) or ketamine plus psychotherapy (KET+PSY). All ketamine administrations were intravenous. Most visits were paid out-of-pocket. The investigators additionally ran three supplementary analyses with relaxed inclusion criteria that expanded the sample to N = 470 (allowing as few as four visits and relaxed group classification thresholds within 30 days) and N = 624 (same relaxed criteria but a 180-day window). Psychotherapy sessions were typically 50–60 minutes, almost always in person, and included a range of modalities. Ketamine-assisted psychotherapy (KAP) accounted for about 80% of therapy sessions, with cognitive behavioural therapy (CBT) approximately 15% and various other approaches making up the remainder. Measures of symptom severity were the Patient Health Questionnaire-9 (PHQ-9) for depression and the PCL-5 for PTSD. The study deliberately included patients with a range of baseline symptom severity, and supplementary analyses restricted samples to clinically significant baseline thresholds (PHQ-9 > 9; PCL-5 > 30). Longitudinal symptom trajectories were modelled using generalized additive mixed-effects models (GAMMs) with random intercepts for participants and penalised splines to capture nonlinear change over time. The primary effect of interest was the interaction between time (modelled either continuously in days or as discrete ordered visits/bins) and treatment group, testing whether trajectories differed between KET and KET+PSY. All models controlled for baseline symptom score, age, gender, mean inter-visit interval and seasonality. Interaction terms were assessed via likelihood ratio tests and information criteria (Akaike and Bayes). A complementary, simpler approach binned continuous time into quantiles or used visits as ordered categories; at each discrete timepoint, group differences were compared using t-tests after regressing out covariates. Exploratory subgroup analyses stratified results by age and gender.

Across analytic approaches, both treatment groups showed substantial reductions in PHQ-9 and PCL-5 scores over the acute treatment window. In the main N = 202 sample (six visits within 30 days), symptom trajectories exhibited a rapid initial decline followed by a nonlinear plateau, with PHQ and PCL levels stabilising after roughly 11–15 days. GAMM comparisons that tested whether allowing different trajectories for KET and KET+PSY improved model fit produced non-significant results across the primary tests (all p > 0.05). Supplementary tables of model coefficients likewise showed no significant main effects favouring ketamine plus psychotherapy. Using the discrete, binned “low-tech” approach, investigators performed 22 t-tests comparing groups at ordered timepoints; only one comparison reached nominal significance (PHQ, Days 4–8) but this did not survive correction for multiple comparisons. Visual inspection of plotted trajectories reinforced substantial overlap between the two groups. The supplementary analyses with relaxed inclusion criteria and larger Ns (N = 470 and N = 624) largely supported the primary null finding. A small number of models showed statistically significant interaction terms: in the N = 470 sample the PHQ model with continuous time reported p = 0.019, and in the N = 624 sample the PHQ model using sequential time points reported p = 0.043. In the subset restricted to participants with clinically significant baseline symptoms, the PTSD model with continuous time also showed a significant interaction. However, the authors report that visual inspection suggested these isolated significances were likely attributable to differences in trajectory shape or intercept rather than convincing evidence that combined treatment produced superior clinical outcomes; in several cases the KET+PSY group appeared worse (higher symptoms) across much of the trajectory. Exploratory stratified analyses by age and gender revealed suggestive but non-significant patterns: younger females (≤40 years) tended to show relatively better PTSD outcomes with combined treatment, while older males (41+ years) tended to fare better with ketamine alone. None of these subgroup effects survived correction for multiple comparisons. The extracted text does not report adverse events or safety outcomes beyond symptom trajectories. The authors also note that most visits (98%) involved at least some out-of-pocket payment and that the initial screening reduced an inventory of 1428 patients (9,433 visits) to the analytic main sample of 202 (1,212 visits).

Moore and colleagues interpret their primary finding as evidence that adding psychotherapy to an acute course of ketamine administrations did not produce measurable additional benefit in reducing depression or PTSD symptoms over a 30-day window. Both groups improved rapidly and reached a similar plateau around 11–15 days, suggesting that ketamine’s direct neurobiological actions may dominate short-term symptom change during the acute treatment phase. The authors note that this outcome contrasts with some prior suggestions of synergy between ketamine and psychotherapy, but they argue their results align with ketamine’s known rapid antidepressant properties and capacity to produce a temporally limited “therapeutic window” that may operate independently of concurrent psychotherapeutic input. The investigators acknowledge several limitations that temper interpretation. Chief among these is the short, acute observation window: advantages of combined treatment might emerge later, for relapse prevention, functional recovery, or quality-of-life outcomes not captured by PHQ-9 and PCL-5. The naturalistic, non-randomised design introduces potential selection biases (for instance clinic or clinician influences on who receives combined treatment) and leaves open the possibility that some KET patients were receiving external psychotherapy not recorded in the clinic dataset. Treatment heterogeneity in psychotherapy modalities and the predominance of KAP and CBT limit inferences about modality-specific interactions with ketamine. A between-group age difference (KET mean 38.3 years; KET+PSY mean 44.2 years) could have influenced results despite covariate adjustment. The absence of a psychotherapy-only control arm prevents conclusions about superiority to psychotherapy alone. In terms of implications, the authors suggest that, during the acute phase, clinicians may have flexibility when structuring care and that resources might be prioritised where psychotherapeutic capacity is limited. Nevertheless, they caution that this should not be taken to diminish psychotherapy’s broader value; instead, timing and integration with ketamine warrant further study. Future research directions recommended by the authors include longer-term, controlled trials that compare different psychotherapeutic modalities in combination with ketamine, use broader outcome measures beyond symptom scales, and prospectively test demographic moderators such as age and gender to clarify whether subgroups derive particular benefit from combined approaches. The authors conclude that while ketamine and ketamine-plus-psychotherapy both produced robust short-term symptom reductions, there was no consistent evidence in their samples that concurrent psychotherapy enhanced 30-day outcomes, and that further investigation is needed to determine whether combined treatment offers advantages over longer follow-up or in other outcome domains.