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

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 vs. BD-II). A total of 952 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 continuums but mechanism of action, but additionally based on mitochondrial energetics. Future prospective clinical studies specific antidepressant selections and disease risk, therefore should investigate potential interactions with mitochondrial mechanisms of disease risk.

Manuel Gardea-Resendez, Brandon J. Coombes, Marin Velidic, Susannah J. Tye, Francisco Romo-Nava, Asygul Ozeroglu, Miguel L. Prieto, Alfredo Cuellar-Barboza, Nicolas A. Nunez, Balwinder Singh, Richard S. Pendergraft, Alessandro Miola, Susan L. McElroy, Joanna M. Biernacka, Eva Morava, Tamas Koczi, Mark A. Frye