Emmerzaal Tim L, Jacobs Leah, Geenen Bram, Verweij Vivienne, Morava Eva, Rodenburg Richard J, Kozicz Tamas
Department of Anatomy, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Eur J Neurosci. 2021 May;53(9):2986-3001. doi: 10.1111/ejn.14901. Epub 2020 Jul 21.
Antidepressants have been shown to influence mitochondrial function directly, and suboptimal mitochondrial function (SMF) has been implicated in complex psychiatric disorders. In the current study, we used a mouse model for trait SMF to test the hypothesis that chronic fluoxetine treatment in mice subjected to chronic stress would negatively impact brain bioenergetics, a response that would be more pronounced in mice with trait SMF. In contrast, we hypothesized that chronic ketamine treatment would positively impact mitochondrial function in both WT and mice with SMF. We used an animal model for trait SMF, the Ndufs4 mice, which exhibit 25% lower mitochondrial complex I activity. In addition to antidepressant treatment, mice were subjected to chronic unpredictable stress (CUS). This paradigm is widely used to model complex behaviours expressed in various psychiatric disorders. We assayed several physiological indices as proxies for the impact of chronic stress and antidepressant treatment. Furthermore, we measured brain mitochondrial complex activities using clinically validated assays as well as established metabolic signatures using targeted metabolomics. As hypothesized, we found evidence that chronic fluoxetine treatment negatively impacted brain bioenergetics. This phenotype was, however, not further exacerbated in mice with trait SMF. Ketamine did not have a significant influence on brain mitochondrial function in either genotype. Here we report that trait SMF could be a moderator for an individual's response to antidepressant treatment. Based on these results, we propose that in individuals with SMF and comorbid psychopathology, fluoxetine should be avoided, whereas ketamine could be a safer choice of treatment.
抗抑郁药已被证明可直接影响线粒体功能，而线粒体功能欠佳（SMF）与复杂的精神疾病有关。在本研究中，我们使用了一种特质SMF小鼠模型，以检验以下假设：在遭受慢性应激的小鼠中，长期使用氟西汀治疗会对脑生物能产生负面影响，这种反应在具有特质SMF的小鼠中会更明显。相比之下，我们假设长期使用氯胺酮治疗会对野生型和具有SMF的小鼠的线粒体功能产生积极影响。我们使用了一种特质SMF动物模型，即Ndufs4小鼠，其线粒体复合物I活性降低了25%。除了抗抑郁药治疗外，小鼠还遭受了慢性不可预测应激（CUS）。这种模式被广泛用于模拟各种精神疾病中表现出的复杂行为。我们测定了几个生理指标，作为慢性应激和抗抑郁药治疗影响的代理指标。此外，我们使用临床验证的检测方法测量了脑线粒体复合物活性，并使用靶向代谢组学确定了代谢特征。如我们所假设的，我们发现有证据表明长期使用氟西汀治疗会对脑生物能产生负面影响。然而，这种表型在具有特质SMF的小鼠中并未进一步加剧。氯胺酮对两种基因型的小鼠脑线粒体功能均无显著影响。在此我们报告，特质SMF可能是个体对抗抑郁药治疗反应的一个调节因素。基于这些结果，我们建议，对于患有SMF和共病精神病理学的个体，应避免使用氟西汀，而氯胺酮可能是一种更安全的治疗选择。
