Can We Predict Response to Ketamine in Psychiatry?

Researchers, presenting at the American Psychiatric Association 2023 Annual Meeting, discussed recent findings on biomarkers for predicting ketamine treatment response. The session, titled “Emerging Biomarkers of Response to Ketamine: Opportunities and Challenges,” also discussed the antianhedonic effects and potential mechanisms of action of ketamine.

The first speaker, Dr. Gustavo C. Medeiros, stated that, while ketamine has been proven to have antidepressant effects, the rate of individual response to ketamine ranges from 40% to 60%, and it is difficult to predict whether a patient will respond or not. A variety of blood-based biomarkers are being investigated, but, according to Dr. Medeiros, their utility has not been verified.

Dr. Medeiros primarily described findings from a meta-analysis of ketamine biomarkers based on 56 studies published by August 2021. In the analysis, researchers looked at various baseline and longitudinal biomarkers for treatment response.

The most frequently explored category of blood-based biomarkers was neurotrophic factors, with brain-derived neurotrophic factor (BDNF) level being the most common biomarker investigated. Other variables of interest included ketamine and ketamine metabolite levels and inflammatory cytokine levels.

According to Dr. Medeiros, baseline neurotrophic factors were not associated with response to ketamine treatment. Researchers also noted studies identified more longitudinal biomarkers versus baseline biomarkers.

Notably, patients who responded had higher BDNF levels compared with nonresponders; however, Dr. Medeiros noted that, while this was a statistically significant association, there was high variability across the included studies and the effect size was small. Publication bias was also identified.

Additionally, researchers found responders to ketamine treatment had numerically lower levels of inflammatory markers, though the trend was not statistically significant. This finding was initially surprising to the researchers, who theorized that higher levels of inflammatory markers might correlated with response given ketamine’s anti-inflammatory properties, though they eventually likened it to the relationship between lower levels of inflammation and improved response seen in selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors.

In further analysis, neither interleukin-6 nor tumor necrosis factor-alpha showed any statistically significant association with response or nonresponse. Likewise, the investigators did not find any associations between mean ketamine concentrations and response, though Dr. Medeiros noted that various concentration parameters could be explored.

Ultimately, Dr. Medeiros acknowledged the findings were not majorly positive in identifying effective variables for predicting response to ketamine therapy, except potentially for BDNF levels.