Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

Rong, Carola; Park, Caroline; Rosenblat, Joshua D.; Subramaniapillai, Mehala; Zuckerman, Hannah; Fus, Dominika; Lee, Yena L.; Pan, Zihang; Brietzke, Elisa; Mansur, Rodrigo B.; Cha, Danielle S.; Lui, Leanna M. W.; McIntyre, Roger S.

doi:10.3390/ijerph15040771

Cited by 114Treatment of Major DepressionElectroconvulsive Therapy StudiesBipolar Disorder and Treatment

Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

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Rong, Carola, Park, Caroline, Rosenblat, Joshua D., Subramaniapillai, Mehala, Zuckerman, Hannah, Fus, Dominika, Lee, Yena L., Pan, Zihang +5 more·2018·International Journal of Environmental Research and Public Health

DOI 10.3390/ijerph15040771PMC PMC5923813

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Abstract

Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

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The BDNF Val66Met polymorphism is associated with cognitive processes and cognitive impairment in neurodegenerative disease such as Parkinson's disease and Alzheimer's disease, and with several brain disorders including MDD, bipolar disorder, epilepsy, schizophrenia, aging and dementia, and stroke.
“More specifically, BDNF Val66Met polymorphism is associated with cognitive processes [112,123,124,125,126,127], and cognitive impairment in neurodegenerative disease, such as Parkinson’s disease (PD) [128,129] and AD [130,131], and even more with several brain disorders, including MDD and bipolar disorder [132,133,134,135,136,137], epilepsy [138,139,140], schizophrenia [125,141,142,143,144], aging”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [136]
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Sleep improvement is associated with the antidepressant efficacy of repeated-dose ketamine and serum BDNF levels: a post-hoc analysis
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Treatment response to low-dose ketamine infusion for treatment-resistant depression: A gene-based genome-wide association study
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Do sleep changes mediate the anti‐depressive and anti‐suicidal response of intravenous ketamine in treatment‐resistant depression?
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The efficacy and safety of adjunctive intranasal esketamine treatment in major depressive disorder: a systematic review and meta-analysis
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Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression
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Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression
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Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment‐resistant depression
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RETRACTED ARTICLE: ArticleNoteRapid and sustained antidepressant effects of intravenous ketamine in treatment-resistant major depressive disorder and suicidal ideation: a randomized clinical trial
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Retracted
Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials
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A Single Administration of Psilocybin Persistently Rescues Cognitive Deficits Caused by Adolescent Chronic Restraint Stress Without Long-Term Changes in Synaptic Protein Gene Expression in a Rat Experimental System with Translational Relevance to Depression
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Functional connectivity between the habenula and default mode network and its association with the antidepressant effect of ketamine
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The rapid antidepressant effect of acupuncture on two animal models of depression by inhibiting M1-Ach receptors regulates synaptic plasticity in the prefrontal cortex
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Predictors of response and remission in patients with treatment-resistant depression: A post hoc pooled analysis of two acute trials of esketamine nasal spray
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EEG-vigilance regulation is associated with and predicts ketamine response in major depressive disorder
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The Use of Ketamine for the Treatment of Anhedonia in Depression
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The Combination of Propofol and Ketamine Does Not Enhance Clinical Responses to Electroconvulsive Therapy in Major Depression—The Results From the KEOpS Study
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Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression
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A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals?
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Does pre-treatment functioning influence response to intravenous ketamine in adults with treatment-resistant depression?
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Glutamate plus glutamine to GABA ratio as a predictor of ketamine response in treatment-resistant depression: A double-blind, randomized, open-label extension study
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Impact of impaired glucose metabolism on responses to a psychophysical stressor: modulation by ketamine
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A retrospective analysis of iv ketamine outcome on hospitalisations in an unselected psychiatric sample
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Clinical Predictors of Antidepressant Effects of Ketamine and Esketamine in Treatment-Resistant Unipolar and Bipolar Depression: A Systematic Review
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Clinical predictors of antidepressant response to ketamine in unipolar treatment-resistant depression
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224. Biomarkers of ketamine efficacy: role of the kynurenine pathway
Pedraz‐Petrozzi, B., Marszałek‐Grabska, M., Fornal, E., Neumann, E., Danyeli, L. V., Şen, Z. D., Walter, M., Gründer, G., Gilles, M., Sartorius, A., et al. (2026) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyag040.203

Authors: Rong, C., Park, C., Rosenblat, J. D., Subramaniapillai, M., Zuckerman, H., Fus, D., Lee, Y. L., Pan, Z., Brietzke, E., Mansur, R. B., Cha, D. S., Lui, L. M. W., & McIntyre, R. S.
Affiliations: University Health Network (CA)
Corresponding author: McIntyre, Roger S.
ORCID: Rong, Carola
Park, Caroline
Rosenblat, Joshua D.
Subramaniapillai, Mehala
Fus, Dominika
Lee, Yena L.
Pan, Zihang
Brietzke, Elisa
Mansur, Rodrigo B.
Lui, Leanna M. W.
McIntyre, Roger S.
Venue: International Journal of Environmental Research and Public Health
Publisher: MDPI AG
Published: 2018-04-17
Volume: 15
Issue: 4
Pages: 771
ISSN: 1660-4601 (ISSN-L)
DOI: 10.3390/ijerph15040771
PMC: PMC5923813
OpenAlex: W2802678418
Cited by: 114
References: 48
Citations by year: 2026: 6 · 2025: 18 · 2024: 14 · 2023: 15 · 2022: 17 · 2021: 18 · 2020: 17 · 2019: 7 · 2018: 2
FWCI: 1.28
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: International Journal of Environmental Research and Public Health (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
TSpace (University of Toronto) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords: ketamine, treatment-resistant depression, major depressive disorder, bipolar disorder, predictors of treatment response, body mass index, family history of alcoholism, adiponectin, vitamin B12, glutamine/glutamate ratio, anterior cingulate cortex, processing speed, cognitive impairment
MeSH terms: Antidepressive Agents, Bipolar Disorder, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Treatment Outcome, Excitatory Amino Acid Antagonists, Depressive Disorder, Treatment-Resistant

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Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

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