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Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression

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Abstract

Background and Objective

Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression.

Methods

Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion.

Results

Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mg/kg and 0.2 mg/kg) ketamine.

Conclusions

Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine.

Clinical Trial Registration

University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985.

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Acknowledgements

We thank all research assistants, physicians, pharmacists, and nursing staff at D020 Unit of Taipei Veterans General Hospital for their assistance during the study process. We thank Mr I-Fan Hu, M.A. (Courtauld Institute of Art, University of London; National Taiwan University) for his friendship and support in English editing.

Author information

Author notes

  1. Shih-Jen Tsai and Chung-Feng Kao contributed equally to the article.

Authors and Affiliations

  1. Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan

    Shih-Jen Tsai, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ya-Mei Bai, Pei-Chi Tu & Mu-Hong Chen

  2. Division of Psychiatry, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Shih-Jen Tsai, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ya-Mei Bai, Pei-Chi Tu & Mu-Hong Chen

  3. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

    Tung-Ping Su & Pei-Chi Tu

  4. Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Shih-Jen Tsai, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ya-Mei Bai & Mu-Hong Chen

  5. Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan

    Tung-Ping Su

  6. Department of Agronomy, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan

    Chung-Feng Kao

  7. Advanced Plant Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

    Chung-Feng Kao

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Corresponding author

Correspondence to Mu-Hong Chen.

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Funding

The study was supported by grant from Taipei Veterans General Hospital (V111C-010, V111C-040, V111C-029), Yen Tjing Ling Medical Foundation (CI-109-21, CI-109-22, CI-110-30), Ministry of Science and Technology, Taiwan (MOST110-2314-B-075-026, MOST110-2314-B-075-024-MY3, MOST109-2314-B-010-050-MY3, MOST111-2314-B-075-014-MY2, MOST111-2314-B-075 -013), Taipei, Taichung, Kaohsiung Veterans General Hospital, Tri-Service General Hospital, Academia Sinica Joint Research Program (VTA112-V1-6-1) and Veterans General Hospitals and University System of Taiwan Joint Research Program (VGHUST112-G1-8-1). The funding source had no role in any process of our study.

Conflicts of Interest

Shih-Jen Tsai, Chung-Feng Kao, Tung-Ping Su, Cheng-Ta Li, Wei-Chen Lin, Chen-Jee Hong, Ya-Mei Bai, Pei-Chi Tu, and Mu-Hong Chen have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

This study was performed in accordance with the Declaration of Helsinki and was approved by the Taipei Veterans General Hospital Institutional Review Board. This clinical trial is registered at UMIN Clinical Trials Registry (UMIN-CTR) [trial registration number: UMIN000016985].

Consent to Participate

Informed consent was provided by all of the participants.

Consent for Publication

No identified confidential data were included in the study.

Availability of Data and Material

The datasets generated and/or analyzed during the current study are not publicly available because of Taiwan’s clinical trial ethical regulation but are available from the corresponding author on reasonable request.

Code Availability

Analytic codes are available from the corresponding author on reasonable request.

Authors’ Contributions

Conceptualization: MHC and TPS; methodology: MHC, TPS, SJT, and CFK; formal analysis: MHC and CFK; investigation: MHC, TPS, CTL, and WCL; writing, original draft: MHC, SJT, and CFK; writing, review and editing: all authors. All authors have read and approved the final submitted manuscript, and agree to be accountable for the work.

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Tsai, SJ., Kao, CF., Su, TP. et al. Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression. CNS Drugs 37, 243–253 (2023). https://doi.org/10.1007/s40263-023-00989-7

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