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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.

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Fig. 1: PRISMA flow diagram of systematic searches for studies assessing blood-based biomarkers of antidepressant response to ketamine and esketamine.
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).
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).
Fig. 4: Meta-analytical calculations comparing post-treatment and baseline blood levels of pro-inflammatory markers in responders and non-responders to ketamine.

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Funding

This systematic review/meta-analysis has not been directly funded by any legal entities or organizations. We received operational support from the Johns Hopkins School of Medicine. TDG is supported by NIH R01-MH107615 and RAI145211A, and VA Merit Awards 1I01BX004062 and 101BX003631-01A1. FSG received partial support from the Johns Hopkins Catalyst Award.

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Contributions

GCM: conceptualized the study; designed the study; selected the manuscripts; extracted the data; conducted the statistical analysis; conducted the analysis of bias; drafted the manuscript; revised the manuscript; edited the manuscript for critical intellectual content. TDG: helped conceptualize the study; assisted in statistical design, analysis, and interpretation; drafted the manuscript; revised the manuscript; edited the manuscript for critical intellectual content. WLP: assisted in statistical design, analysis, and interpretation; conducted the analysis of bias; revised the manuscript; edited the manuscript for critical intellectual content. JL: conducted the literature search; revised the manuscript; edited the manuscript for critical intellectual content. MFG, NBF, BS, SS, RMV, EDA, SVP, MAF, and CAZJ: assisted in statistical design, analysis, and interpretation; revised the manuscript; edited the manuscript for critical intellectual content. FSG: conceptualized the study; designed the study; selected the manuscripts; extracted the data; assisted in statistical design, analysis, and interpretation; drafted the manuscript; revised the manuscript; edited the manuscript for critical intellectual content; provided research supervision.

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Correspondence to Fernando S. Goes.

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Competing interests

TDG is listed as co-author on patent and patent applications related to the pharmacology and use of (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the University of Maryland Baltimore, but will share a percentage of any royalties that may be received. TDG has received research funding from Allergan and Roche Pharmaceuticals, and has served as a consultant for FSV7 LLC, during the preceding 3 years. NBF holds patents pertaining to improved use of NMDA antagonists as therapeutic agents. EDA has served on advisory boards for Alkermes, Janssen, Lundbeck/Otsuka, Roche, Sunovion and Teva and reports previous stock holdings in AstraZeneca, Johnson & Johnson, Moderna, and Pfizer. EDA has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, Takeda and serves on the SMI Adviser LAI Center of Excellence (unpaid). BS reports research time support from Medibio (unrelated to the current study); grant support from Mayo Clinic. SS has received grants/research support from NIMH R21 (1R21MH119441 – 01A1) and SAMHSA (FG000470-01) and research supplement funds from The University of Texas Health Science Center at Houston. SS has received speaking honoraria from British Medical Journal Publishing Group and received research support from Compass pathways, Janssen and LivaNova. RMV has received consulting fees from Eurofarma Pharmaceuticals. Abbott and BioStrategies group, and has a research contract for trials with Janssen and Boehringer-Ingelheim Pharmaceuticals. RMV has also received speaker fees from Otsuka, Lundbeck, EMS, and Cristalia and is a member of the scientific board of Symbinas Pharmaceuticals and Allergan. SVP has received honoraria for consulting or research funds from Assurex (Myriad), Sage, Otsuka, Takeda, Janssen, Aifred, Mensante, Canadian Institutes for Health Research, Ontario Brain Institute, and the Flinn Foundation. MAF has received Grant Support from Assurex Health, and Mayo Foundation. He also has financial interests in Chymia LLC. CAZ is a full-time U.S government employee. He is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as a coinventor on a patent for the use of (2 R,6 R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CAZ is listed as co-inventor on a patent application for the use of (2 R,6 R)-hydroxynorketamine and (2 S,6 S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. CAZ has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. FSG has received research grant support from Janssen Therapeutics. GCM, WLP, JN, and MFG do not have conflicts of interest to report.

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Medeiros, G.C., Gould, T.D., Prueitt, W.L. et al. Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01652-1

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