Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis

Abstract

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

Fig. 1. PRISMA flow diagram of systematic searches for studies assessing blood-based biomarkers of antidepressant response to ketamine and esketamine.

^aDatabases used in the searches: Medline (PubMed), Cochrane Library, Embase, PsycInfo, and Web of Science. ^bHand searching included screening of review articles, grey literature, included papers and manuscripts that cited the included papers. ^cMeta-analytical calculations were conducted only if there were comparable data on the same blood-based biomarker for at least three studies. If a biomarker was examined in studies with overlapping samples, only the study with largest sample size was included.

Fig. 2. Meta-analytical calculations comparing post-treatment and baseline blood levels of brain-derived neurotrophic factor (pg/ml) in responders and non-responders to ketamine (n = 331, 11 studies).

*Responder = participant with least at 50% improvement in depression scores. **The manuscript by Kang & Vasquez (2021) had only one non-responder, therefore, it was not possible to conduct meta-analytical calculations for the non-responder group in their study.

Fig. 3. Meta-analytical calculations comparing the blood levels of ketamine (pg/ml) and norketamine (pg/ml) in responders and non-responders to ketamine (n = 286, 9 studies).

*Responder = participant with at least 50% improvement in depression scores. **Blood levels of ketamine and norketamine were measured at the same timepoint for responders and non-responders in individual studies. However, the timepoints were not the same across all studies (varied from during the infusion to 24 h post-infusion). The specific timepoints were: Andrashko et al. (2020) = immediately post-infusion; Chen et al. (2021) = 200 min post-infusion; Diazgranados et al., (2010) = 190 min post-infusion; Farmer et al. (2020) = 190 min post-infusion; Grunebaum et al., (2017) = immediately post-infusion; Grunebaum et al., (2019) = immediately post-infusion; Lenze et al. (2016) = 24 h post-infusion; Milak et al. (2020) = area under the curve calculated as the sum of the blood levels at 50 and 80 min post-infusion; Siegel et al. (2021) = 24 h post-infusion.

Fig. 4. Meta-analytical calculations comparing post-treatment and baseline blood levels of pro-inflammatory markers in responders and non-responders to ketamine.

*Responder = participant with at least 50% improvement in depression scores. **The manuscript by Kang & Vasquez (2021) had only one non-responder, therefore, it was not possible to conduct meta-analytical calculations for the non-responder group in their study.