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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.

Mitochondria play a critical role in bioenergetics, enabling stress adaptation, and therefore, are central in biological stress responses and stress-related complex psychopathologies. To investigate the effect of mitochondrial dysfunction on the stress response and the impact on various biological domains linked to the pathobiology of depression, a novel mouse model was created. These mice harbor a gene trap in the first intron of the Ndufs4 gene (Ndufs4GT/GT mice), encoding the NDUFS4 protein, a structural component of complex I (CI), the first enzyme of the mitochondrial electron transport chain. We performed a comprehensive behavioral screening with a broad range of behavioral, physiological, and endocrine markers, high-resolution ex vivo brain imaging, brain immunohistochemistry, and multi-platform targeted mass spectrometry-based metabolomics. Ndufs4GT/GT mice presented with a 25% reduction of CI activity in the hippocampus, resulting in a relatively mild phenotype of reduced body weight, increased physical activity, decreased neurogenesis and neuroinflammation compared to WT littermates. Brain metabolite profiling revealed characteristic biosignatures discriminating Ndufs4GT/GT from WT mice. Specifically, we observed a reversed TCA cycle flux and rewiring of amino acid metabolism in the prefrontal cortex. Next, exposing mice to chronic variable stress (a model for depression-like behavior), we found that Ndufs4GT/GT mice showed altered stress response and coping strategies with a robust stress-associated reprogramming of amino acid metabolism. Our data suggest that impaired mitochondrial CI function is a candidate driver for altered stress reactivity and stress-induced brain metabolic reprogramming. These changes result in unique phenomic and metabolomic signatures distinguishing groups based on their mitochondrial genotype.

Corticotropin-releasing factor (CRF) is essentieel bij stressadaptatie en veroorzaakt fysiologische stressresponsen via de hypothalamus-hypofyse-bijnier-as (HHB-as), wat leidt tot een verscheidenheid aan gedragsveranderingen en autonome en endocriene effecten om fysiologische en mentale homeostase te waarborgen (Chrousos & Gold, 1992; Smagin & Dunn, 2000; Vale et al., 1981). Dit gebeurt doordat CRF als neurotransmitter en/of neuromodulator op het centrale zenuwstelsel (CZS) werkt, met de limbische bed-nucleus van de stria terminalis (BST) en de centrale amygdala (CeA) (Deyama et al., 2007; Ji & Neugebauer, 2008) als belangrijke inputgebieden. Door chronische pijn wordt het functioneren van de HHB-as vaak ontregeld. Hierdoor kunnen angststoornissen en depressie optreden, ziekten die regelmatig geassocieerd blijken met een verstoorde werking van limbisch CRF (Arborelius et al., 1999; Blackburn-Munro & Blackburn-Munro, 2001). Recent is de sterke link tussen pijnverwerking en CRF beschreven (Lariviere & Melzack, 2000) en bewijs voor de betrokkenheid van limbisch CRF bij nociceptieve gevoeligheid, ofwel de gewaarwording van pijn, tijdens neuropathische pijn neemt toe (Bomholt et al., 2005; Rouwette et al., 2012a; Ulrich-Lai et al., 2006). Dit review geeft een overzicht van uitkomsten uit recent onderzoek naar hersengebieden die betrokken zijn bij het optreden van neuropathische pijn, waarbij de nadruk ligt op de rol hierbij van CRF. De amygdala, een kern in de temporaalkwab die lijkt te kunnen schakelen tussen nociceptie en analgesie, wordt beschouwd als belangrijk hersengebied voor pijnverwerking.