Pharmacogenomics of ketamine: A systematic review

This review (2021) explores the pharmacogenomic predictors of ketamine’s clinical benefits and adverse effects. The review identified three predictors; 1) brain derived neurotrophic growth factor (BDNF) was associated with reduced antidepressant and anti-suicidal effects, 2) CYB2B6 was associated with more severe dissociative effects and 3) NET was associated with greater cardiovascular complications. Limitations include small sample sizes and heterogeneity of study design.

Abstract

“Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.”

Authors: Shaklia Meshkat, Nelson B. Rodrigues, Joshua D. Di Vincenzo, Felicia Ceban, Saja Jaberi, Roger S. McIntyre, Leanna M. W. Lui & Joshua D. Rosenblat

Summary

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Three genetic variants were found to be associated with ketamine clinical benefits and adverse effects: Val66Met (rs6265), CYP2B6*6 (e.g., metabolizer) and NET allelic variant.

1. Introduction

Ketamine is a stereoselective N-methyl-D-aspartate (NMDA) receptor antagonist, widely employed as a dissociative anesthetic worldwide. It has also been evaluated for additional clinical indications, including pain management and treatment resistant depression.

Although clinical trials have demonstrated the efficacy of ketamine, no predictors of clinical utility have been consistently demonstrated with contradictory results to date. Additionally, pharmacogenomic predictors may be beneficial in reducing the patient burden of ketamine.

Pharmacogenomics holds promise to improve drug selection and dosage optimization, theoretically reducing suffering due to sub-optimal antidepressant selection. However, more research is necessary to further validate pharmacogenomics for specific drugs of interest.

Ketamine is metabolized by the CYP450 system and may skip first pass metabolism in some patients. Pharmacogenomic testing may help predict ketamine’s effectiveness and adverse effects and guide dosage selection to minimize undesirable treatment-emergent adverse events while maximizing therapeutic benefits.

2.1. Literature search

A systematic search was conducted on PubMed, Scopus, and Web of Science databases, as well as Google Scholar and manual searches of reference lists.

2.2. Literature search strategy

We used MeSH terms to search for articles on pharmacogenomics and ketamine, and also found articles on pharmacogenomics and glutamate, and BDNF.

2.3. Study eligibility criteria

Studies involving patients treated with ketamine or esketamine were included if the following criteria were met: (1) genotyping was conducted; (2) treatment emergent adverse events and/or therapeutic effects were reported.

2.4. Data extraction

Two reviewers independently reviewed full-texts of eligible studies and extracted the following data: year of publication, number of patients, dose of ketamine used, method of administration, genes studied, gene extraction method, study outcome, ethnicity, main findings.

2.5. Risk of bias assessment

We assessed the risk of bias in randomized trials using the Cochrane Collaboration’s tool (Table 1).

3.1. Search results

We searched the literature and excluded 2974 articles based on title/abstract. We reviewed 24 articles in detail and included 1219 patients with TRD, 75 patients with elective surgeries who received ketamine as an anesthetic, 49 patients with pain, and 68 healthy participants.

3.2. Characteristics of included studies

The included studies included RCTs, open label studies, non randomized clinical trials and pilot studies. The antidepressant effect of ketamine was assessed using MADRS and HDRS in five and three studies, respectively.

3.3.1. Brain derived neurotrophic factor (BDNF)

BDNF genetic variants designated as Val66Met (rs6265) have been examined in patients with TRD for association with ketamine antidepressant response. Ketamine was found to be effective in reducing suicidal thoughts in individuals with Val/Val or Val/Met of BDNF rs6265, but not in those with Met/Met of BDNF rs6265.

Researchers found that patients with the BDNF rs6265 Val66Met polymorphism were more likely to have an increased antidepressant response to low-dose ketamine infusion than Met carriers.

3.3.2. CYP450 system

Multiple polymorphisms were studied in three papers, including CYP2B65, CYP2B66, CYP2C9, CYP2C19, CYP3A4, CYP3A5. CYP2B66 is the most frequent polymorphism, with CYP2B67 being the least frequent.

Li et al. found that patients with the CYP2B6*6 allele had a lower steady-state ketamine plasma clearance, which was associated with a higher incidence of ketamine treatment emergent adverse events. In another study, the association of CYP450 genotypes with response and treatment emergent adverse events to ketamine infusion was examined in 67 patients with TRD. The results indicated that CYP450 genotypes had no significant impact on response and side effects of ketamine.

The opioid receptor isoform encoded by the OPRM1 gene SNP A118G exhibits a threefold greater binding affinity for opioid ligands.

A clinical trial was conducted to investigate the effect of OPRM gene polymorphism (rs1799971) on the antidepressant response to esketamine nasal spray in patients with TRD. The results did not indicate a treatment by genotype interaction effect on 24-h post-treatment scores for the Beck Scale for Suicidal Ideation, POMS, or HDRS.

3.3.4. Glutamate ionotropic receptor NMDA type subunit (GRIN)

One paper evaluated the association between GRIN2B polymorphism and EP in 75 patients having minor elective outpatient surgeries. The result showed no significant link.

3.3.5. Norepinephrine transporter (NET)

Liebe et al. found that the genotype of the norepinephrine transporter (NET), gender, and baseline blood pressure were all significant predictors of cardiovascular response to single subanesthetic dose of ketamine. Chen et al. found that twelve ketamine-related genes were significantly associated with antidepressant impact of ketamine infusion and the ketamine blood level.

A GWAS study was conducted on 326 patients with TRD who received 0.5 mg/kg IV ketamine. The study found that eight SNPs were significantly associated with treatment response to ketamine over 2 – 6 days after infusion, and three SNPs were significantly associated with treatment response on 14 days after infusion.

The authors examined the association of SEC11A, KRASP1, OSBP2, MRPL 50P1, C18orf42, RASGRF2, ROBO2, C20orf196, FAM179A, FITM2, LINC00923 genes and ketamine antidepressant effect, and found no association.

4. Discussion

The study found that BDNF with Val allele is linked to increased antidepressant and anti-suicidal effects of ketamine in patients with TRD in comparison with Met allele. This result suggests that BDNF Met allele expression causes baseline synaptic deficiencies, which inhibit ketamine’s synaptogenic and antidepressant effects.

BDNF with a Met allele may not be properly processed by dendrites, resulting in decreased levels of BDNF and decreased antidepressant effects of ketamine. However, more research is needed to determine if higher doses of ketamine are beneficial in individuals with TRD who are Met carriers.

Ketamine is metabolized by CYP450 enzymes, and the CYP2B66 allele of the CYP2B6 gene is associated with treatment-emergent adverse effects. Despite the CYP2B66 allele, other CYP2B6 genotypes were not associated with ketamine treatment-emergent adverse effects. This may be due to very low genotype frequencies which prevent a feasible analysis, or the influence of inflammatory indicators, diabetes management, obesity, and other systemic or metabolic factors.

Ketamine’s antidepressant effects may not be opioid-related and be mediated by mu-opioid receptor activation, but may require opioid system activation for its acute antidepressant effect. The GRIN gene may be associated with suicidality and treatment resistance.

Poor antidepressant response to ketamine infusion is associated with suicide-related genes and disease severity-related genes, and the sympathetic nervous system is influenced by genetic polymorphisms in components of the noradrenergic system, such as NET.

The present study is the most comprehensive review designed in a systematic manner to investigate the association of genetic variations and treatment response and adverse effects of ketamine. However, the study has several limitations and future studies should aim to include larger samples.

5. Conclusion

The current systematic review summarizes the pharmacogenomics findings to date of ketamine. It suggests that pharmacogenomics might play a role in ketamine treatment in the future, but more prospectively designed studies are needed to confirm this.