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. 2023 Mar;28(3):1020-1026.
doi: 10.1038/s41380-022-01888-x. Epub 2022 Dec 13.

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

Manuel Gardea-Resendez #  1   2 , Brandon J Coombes #  3 , Marin Veldic  1 , Susannah J Tye  1   4 , Francisco Romo-Nava  5 , Aysegul Ozerdem  1 , Miguel L Prieto  1   6   7 , Alfredo Cuellar-Barboza  2 , Nicolas A Nunez  1 , Balwinder Singh  1 , Richard S Pendegraft  3 , Alessandro Miola  1   8 , Susan L McElroy  5 , Joanna M Biernacka  1   3 , Eva Morava  9   10 , Tamas Kozicz  9   10   11 , Mark A Frye  12
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Antidepressants that increase mitochondrial energetics may elevate risk of treatment-emergent mania

Manuel Gardea-Resendez et al. Mol Psychiatry. 2023 Mar.

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Global effect of antidepressants on mitochondrial respiratory chain complexes.
A Schematic overview of the mitochondrial electron transport chain (ETC), a cluster of protein complexes and electron transporters in the inner mitochondrial membrane that generate ATP. The electrons generated during the oxidation of NADH and FADH2, in complexes I and II, respectively, are transported through coenzyme Q (CoQ), complex III (CIII), cytochrome C (Cyt C) and complex IV (CIV or COX). As electrons are transferred through the chain, energy is released to pump protons (H+), generating an electrochemical gradient across the membrane. Finally, in complex V (CV), also known as ATP synthase, the electrochemical gradient is used to catalyze the production of ATP from ADP. B Summary of the global effect of the investigated antidepressants and their effect on each complex of the ETC [22] based on preclinical studies [–59]: A green box with an upward arrow indicates an increase in the activity of the specific complex after exposure to an antidepressant, a blue box with a downward arrow indicates a decrease in the activity of the specific complex after exposure to an antidepressant and a yellow box with a “~” sign indicates no effect observed. Abbreviations: CI Complex I, NADH:ubiquinone oxidoreductase, NADH reduced nictotinamide adenine dinucleotide, NAD+ nictotinamide adenine dinucleotide, CII Complex II, succinate-coenzyme Q reductase, CoQ coenzyme Q, FADH reduced flavin adenine dinucleotide, FAD flavin adenine dinucleotide, CIII Complex III, coenzyme Q – cytochrome c reductase, Cyt C cytochrome C, CIV Complex IV, cytochrome C oxidase, CV Complex V, ATP synthase, ADP adenosine diphosphate, ATP adenosine triphosphate.
Fig. 2
Fig. 2. Increased rates of TEM+ with antidepressants that increase mitochondrial function.
Rates of treatment-induced mania with antidepressants that increase (Mito+) were two times more frequent than with those that decrease (Mito−) mitochondrial function [TEM+ Mito+ = 24.7%; TEM+ Mito− = 13.5%; OR = 2.21; p = 0.000009].
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