This observational study (n=202, 470, and 624) compares ketamine alone (KET) to ketamine combined with psychotherapy (KET+PSY) (35mg x 6) for depression and PTSD. Both treatments led to substantial symptom improvements, but no significant differences were found between groups. Exploratory analyses suggest younger females may benefit more from combined treatment, while older males may do better with ketamine alone.
Abstract of Combined ketamine and psychotherapy provide no additional benefit beyond ketamine alone in treating depression or PTSD
“Depression and PTSD are prevalent psychiatric conditions that often co-occur and significantly impact quality of life. Ketamine has emerged as a promising rapid-acting treatment for both conditions, while traditional treatments like psychotherapy typically require weeks to show effects. This study investigated whether combining ketamine with psychotherapy produces greater symptom improvement compared to ketamine alone. We analyzed overlapping samples of N = 202, N = 470, and N = 624 help-seeking individuals (all samples ∼60 % female, mean age ∼ 42 years) who received either ketamine alone (KET) or ketamine plus psychotherapy (KET+PSY) across 4–14 treatment sessions within a 30- or 180-day period. Depression symptoms were measured using the PHQ-9, and PTSD symptoms were assessed using the PCL-5. Trajectories of symptom change were analyzed using generalized additive mixed-effects models, controlling for baseline symptoms, demographics, and treatment intervals. Both treatment groups showed substantial improvement in depression and PTSD symptoms, with similar patterns of rapid initial decline followed by stabilization. Contrary to our hypothesis, we found no significant differences in symptom trajectories between the KET and KET+PSY groups. Exploratory analyses revealed non-significant but notable patterns where younger females showed better outcomes with combined treatment, while older males showed better outcomes with ketamine alone. These findings suggest that ketamine’s therapeutic effects may be robust enough that additional psychotherapy during the acute treatment phase does not significantly enhance 30-day (and possibly 180-day) outcomes. However, longer-term benefits of combined treatment and potential demographic-specific treatment responses warrant further investigation. These results have important implications for treatment planning and resource allocation in clinical settings.”
Authors: Tyler M. Moore, Kathryn Walker, Emma Tung, Adam R. Teed, Franz Hell, Sivan Kinreich, Rex Jung, Fadi Abdel, Russell W. Hanson & Shobi S. Ahmed
Summary of Combined ketamine and psychotherapy provide no additional benefit beyond ketamine alone in treating depression or PTSD
Depression and post-traumatic stress disorder (PTSD) are highly prevalent psychiatric conditions that often co-occur, severely affecting individuals’ quality of life. Depression is associated with persistent sadness, disrupted sleep, and loss of interest in activities, while PTSD is marked by hyperarousal, avoidance behaviours, and intrusive re-experiencing of trauma. Both are major risk factors for suicide and are linked to specific brain abnormalities, including impaired function in the hippocampus, amygdala, and prefrontal cortex.
Ketamine has emerged as a rapid-acting treatment for depression and PTSD, offering quicker relief than traditional treatments like psychotherapy or standard antidepressants, which often take weeks to become effective. Ketamine acts primarily through antagonism of NMDA receptors in the brain, leading to enhanced glutamate activity, which promotes synaptic plasticity and mood regulation. It also triggers production of brain-derived neurotrophic factor (BDNF), which supports neurogenesis and recovery of neural circuits involved in emotional regulation. Additionally, metabolites of ketamine, including (2R,6R)-hydroxynorketamine, offer antidepressant effects without producing the dissociative side effects typically associated with ketamine.
Given these properties, ketamine has been proposed as a powerful adjunct to psychotherapy, potentially enhancing psychological flexibility and promoting long-term recovery. However, despite growing enthusiasm around ketamine-assisted psychotherapy (KAP), the additive or synergistic benefits of combining ketamine with psychotherapy remain uncertain. Many existing studies lack rigorous control conditions or fail to directly compare combination therapy with monotherapies. This study was designed to assess whether combining ketamine with psychotherapy offers superior improvements in depression and PTSD symptoms compared to ketamine treatment alone.
Methods
Participants
Find this paper
https://doi.org/10.1016/j.jad.2025.04.041
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Cite this paper (APA)
Moore, T. M., Walker, K., Tung, E., Teed, A. R., Hell, F., Kinreich, S., ... & Ahmed, S. S. (2025). Combined ketamine and psychotherapy provide no additional benefit beyond ketamine alone in treating depression or PTSD: Evidence from a help-seeking sample. Journal of Affective Disorders.
Study details
Compounds studied
Ketamine
Topics studied
PTSD
Depression
Study characteristics
Observational
Participants
202
Humans
Compound Details
The psychedelics given at which dose and how many times
Ketamine 35 mg | 6x