Antidepressants that increase mitochondrial energetics may elevate risk of treatment-emergent mania

Manuel Gardea-Resendez, Brandon J. Coombes, Marin Veldic, Susannah J. Tye, Francisco Romo-Nava, Aysegul Ozerdem, Miguel L. Prieto, Alfredo Cuellar-Barboza, Nicolas A. Nunez, Balwinder Singh, Richard S. Pendegraft, Alessandro Miola, Susan L. McElroy, Joanna M. Biernacka, Eva Morava, Tamas Kozicz, Mark A. Frye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Preclinical evidence suggests that antidepressants (ADs) may differentially influence mitochondrial energetics. This study was conducted to investigate the relationship between mitochondrial function and illness vulnerability in bipolar disorder (BD), specifically risk of treatment-emergent mania (TEM). Participants with BD already clinically phenotyped as TEM+ (n = 176) or TEM− (n = 516) were further classified whether the TEM associated AD, based on preclinical studies, increased (Mito+, n = 600) or decreased (Mito−, n = 289) mitochondrial electron transport chain (ETC) activity. Comparison of TEM+ rates between Mito+ and Mito− ADs was performed using generalized estimating equations to account for participants exposed to multiple ADs while adjusting for sex, age at time of enrollment into the biobank and BD type (BD-I/schizoaffective vs. BD-II). A total of 692 subjects (62.7% female, 91.4% White, mean age 43.0 ± 14.0 years) including 176 cases (25.3%) of TEM+ and 516 cases (74.7%) of TEM- with previous exposure to Mito+ and/or Mito- antidepressants were identified. Adjusting for age, sex and BD subtype, TEM+ was more frequent with antidepressants that increased (24.7%), versus decreased (13.5%) mitochondrial energetics (OR = 2.21; p = 0.000009). Our preliminary retrospective data suggests there may be merit in reconceptualizing AD classification, not solely based on monoaminergic conventional drug mechanism of action, but additionally based on mitochondrial energetics. Future prospective clinical studies on specific antidepressants and mitochondrial activity are encouraged. Recognizing pharmacogenomic investigation of drug response may extend or overlap to genomics of disease risk, future studies should investigate potential interactions between mitochondrial mechanisms of disease risk and drug response.

Original languageEnglish
JournalMolecular Psychiatry
StatePublished - 2022

Bibliographical note

Funding Information:
This study was supported, in part, by the J. Willard and Alice S. Marriott Foundation,Thomas and Elizabeth Grainger Fund in Bipolar Disorder Novel Therapeutics and Advanced Diagnostics and the Mayo Clinic Center for Individualized Medicine; none had a role in the design, conduct, analysis, or submission of the study, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Funding Information:
Manuel Gardea-Resendez reports receiving support from the Mayo Foundation during the conduct of the study. MAF has received research support from Assurex Health and Mayo Foundation; received CME Travel and Honoraria from Carnot Laboratories and has Financial Interest/Stock ownership/Royalties with Chymia LLC. SLM reports receiving personal fees for advisory boards and/or consultation from Idorsia, Levo, Novo Nordisk, Sunovion, and Takeda; receiving grant support from Jazz, Janssen, Novo Nordisk, Otsuka, and Sunovion; and receiving payments from Johnson & Johnson for being an inventor on US Patent 6 323 236 B2. Francisco Romo-Nava was supported in part by NIH grant K23MH10503. NAN was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. MLP was supported in part by CONICYT/ANID grants FONDECYT Regular 1181365, FONDEF ID19I10116 and Basal Funding for Scientific and Technological Center of Excellence, IMPACT, #FB210024. Miguel Prieto reports receiving personal fees for advisory board from Janssen. SJT was supported in part by a NHMRC grant (1160472). AM reports receiving support from the Mayo Foundation during the conduct of the study.

Publisher Copyright:
© 2022, The Author(s).


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