Ketamine Plus Psychotherapy 'Highly Effective' for PTSD

Editor's Note: This story has been updated with additional comments March 1, 2023.

Combining ketamine and psychotherapy is a promising approach for treating posttraumatic stress disorder (PTSD), new research suggests.

In a systematic review and meta-analysis of four studies investigating combined use of psychotherapy and ketamine for PTSD, results showed all the studies showed a significant reduction in PTSD symptom scores.

Overall, the treatment was "highly effective, as seen by the significant improvements in symptoms on multiple measures," the researchers report.

"Ketamine, when combined with psychotherapy, may present a new path forward for clients struggling with PTSD; [and] this study suggests that these two treatment modalities can be effectively administered alongside one another," lead author Aaron E. Philipp-Muller, MSc, formerly of the Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada, told Medscape Medical News.

"In terms of generalizability, of course we have to be hesitant when interpreting these findings," said Philipp-Muller, who is currently a PhD candidate at the University of Regina, Saskatchewan, Canada. "This is very much an emerging area, and it can be tempting to latch onto a new treatment before it's properly understood."

The investigators also note that only 34 participants were included in the analysis.

At this point, "we are depending on a very small number of recent papers for our results, and so the future of this treatment may still be unpredictable. However, new studies continue to emerge on this topic, which will hopefully clarify our findings,” Philipp-Muller said.

The findings were published online February 6 in the Journal of Clinical Psychiatry.

Emerging Treatment

Ketamine is an "emerging treatment for a number of psychopathologies, such as major depressive disorder and PTSD, with a higher response than other pharmacologic agents," the researchers write.

It is hypothesized that ketamine rapidly facilitates long-term potentiation, "thereby allowing a patient to disengage from an established pattern of thought more readily," they write.

However, ketamine has several drawbacks, including the fact that it brings only 1 week of relief for PTSD. Also, because it must be administered intravenously, it is "impractical for long-term weekly administration," they note.

Pharmacologically enhanced psychotherapy is a potential way to prolong ketamine's effects. Several prior studies have investigated this model using other psychedelic medications, with encouraging results.

The current investigators decided to review all literature to date on the subject of ketamine plus psychotherapy for the treatment of PTSD.

To be included, the study had to include patients diagnosed with PTSD, an intervention involving ketamine alongside any form of psychotherapy, and assessment of all patients before and after treatment using the Clinician-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL).

Four studies met inclusion criteria. Of these, two were of "moderate" quality and two were of "low" quality, based on the GRADE assessment. The studies encompassed a total of 34 patients with "diverse traumatic experiences" and included several types of ketamine administration protocols, including one used previously for treating depression and another used previously for chronic pain.

The psychotherapy modalities also differed between the studies. In two studies, patients received 12 sessions of trauma interventions using mindfulness-based extinction and reconsolidation therapy; in a third study, patients received 10 weekly sessions of prolonged exposure therapy; and in the fourth study, patients received five daily sessions of exposure therapy.

Across the studies, the psychotherapies were paired differently with ketamine administration, such as the number of ketamine administrations in conjunction with therapy.

Despite the differences in protocols, all the studies of ketamine plus psychotherapy showed a significant reduction in PTSD symptoms, with a pooled standardized mean difference (SMD) of -7.26 (95% CI, -12.28 to -2.25; P = .005) for the CAPS and a pooled SMD of -5.17 (95% CI, -7.99 to -2.35; P < .001) for the PCL.

The researchers acknowledge that the sample size was very small "due to the novelty of this research area." This prompted the inclusion of nonrandomized studies that "lowered the quality of the evidence," they note.

Nevertheless, "these preliminary findings indicate the potential of ketamine-assisted psychotherapy for PTSD," the investigators write.

A Promising Avenue?

Commenting for Medscape Medical News, Dan Iosifescu, MD, professor of psychiatry, New York University School of Medicine, New York City, called the combination of ketamine and psychotherapy in PTSD "a very promising treatment avenue."

Iosifescu, who was not involved with the research, noted that "several PTSD-focused psychotherapies are ultimately very effective but very hard to tolerate for participants." For example, prolonged exposure therapy has dropout rates as high as 50%.

In addition, ketamine has rapid but not sustained effects in PTSD, he said.

"So in theory, a course of ketamine could help PTSD patients improve rapidly and tolerate the psychotherapy, which could provide sustained benefits," he added.

However, Iosifescu cautioned that the data supporting this "is very sparse for now."

He also noted that the meta-analysis included only "four tiny studies" and had only 34 total participants. In addition, several of the studies had no comparison group and the study designs were all different — "both with respect to the administration of ketamine and to the paired PTSD psychotherapy."

For this reason, "any conclusions are only a very preliminary suggestion that this may be a fruitful avenue," he said.

Iosifescu added that additional studies on this topic are ongoing. The largest one at the Veterans Administration will hopefully include 100 participants and "will provide more reliable evidence for this important topic," he said.

The study was indirectly supported by the Internal Faculty Grant from the Department of Psychiatry, Queen's University. The investigators' disclosures are fully listed in the original article. Iosifescu reported no financial relationships relevant to this particular topic. In general, he has received consulting honoraria from Alkermes, Allergan, Angelini, Axsome, Biogen, Boehringer Ingelheim, Centers for Psychiatric Excellence, Clexio, Global Medical Education, Jazz, Lundbeck, Neumora, Otsuka, Precision Neuroscience, Relmada, Sage, and Sunovion and research support through his academic institution from Alkermes, AstraZeneca, Brainsway, LiteCure, NeoSync, Otsuka, Roche, and Shire.

J Clin Psychiatry. Published online February 6, 2023. Full text

Batya Swift Yasgur MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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