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

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.

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder

“…Furthermore, the importance of mitochondrial energetics in the pathophysiology of BD is increasingly recognized [ 37 , 38 ]. Interestingly, mitochondrial energetics may also play a role in AD associated TEM as recent data reported a significant increase in TEM rates in patients who were exposed to ADs that increase mitochondrial energetics [ 39 ], which would exert a downstream effect in the mTOR and Wnt/ β-catenin signaling pathways [ 35 ]. Importantly, the mTOR/Wnt/β-catenin signaling/pathway and mitochondrial energetics are mechanisms to further investigate in the spectrum of depression improvement from response to emergent mania aligning with the available genetic data.…”

Antidepressant-Associated Treatment Emergent Mania

“…Nonetheless, the time from the start of AD to TEM aligns with the window of vulnerability from a large Swedish registry (N = 3200), which reported a higher risk of TEM in adult BD-I patients treated with AD monotherapy, with the greatest risk occurring during the first 12 weeks of treatment (hazard ratio = 2.83; 95% confidence interval, 1.12–7.19) 36 . This risk period of short-term AD use may involve differences in molecular signaling and/or upregulation of mitochondrial pathways 37 compared with chronic AD exposure 38 . Another potential source of heterogeneity was not controlling for age of BD onset and the total number of prior episodes 10 .…”

Pharmacogenomic Overlap Between Antidepressant Treatment Response in Major Depression & Antidepressant Associated Treatment Emergent Mania in Bipolar Disorder

“…Furthermore, the importance of mitochondrial energetics in the pathophysiology of BD is increasingly recognized 37 38 . Interestingly, mitochondrial energetics may also play a role in AD associated TEM as recent data reported a signi cant increase in TEM rates in patients who were exposed to ADs that increase mitochondrial energetics 39 , which would exert a downstream affect in the mTOR and Wnt/ βcatenin signaling pathway 35 . Importantly, mTOR/Wnt/β-catenin signaling/pathway and mitochondrial energetics are mechanisms to investigate the spectrum of depression improvement (response -emergent mania) aligning with the genetic work.…”