Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence
Vawter M, Rollins B, Ling M, Hjelm B, Sequeira A, Myers RM, Barchas JD, Lee FS, Schatzberg AF, Akil H, Watson SJ, Bunney WE
American College of Neuropsychopharmacology. 2017.
Background: Previous reports of mitochondrial dysfunction in the brain from subjects with schizophrenia (SZ) and bipolar disorder (BD) have shown decreased protein and transcript levels for mitochondrial genes, primarily those related to Complex I, the first protein assembly of the electron transport chain. However, in vitro results have suggested the antipsychotic and antidepressant drugs used to treat these psychiatric disorders may be fully or partially responsible for these mitochondrial dysfunctions.
Methods: We measured mitochondrial Complex I activity in postmortem brain tissue in parallel with measures of antipsychotic and antidepressant medications to gain a clearer understanding of these observed alterations. We additionally measured mitochondria DNA (mtDNA) copy number and the heteroplasmy rate of the 4,977 bp “common deletion” in the same samples. The aggregated protein concentration of Complex I was evaluated in brain tissue homogenate from the dorsolateral prefrontal cortex (DLPFC) of three groups (SZ, BD, and controls) and was used to standardize concentrations in the subsequent Complex I activity assay. Finally, regression analyses were performed to test for the effects of disease and psychiatric medications on Complex I activity while controlling for important covariates such as age, sex, and pH.
Results: Complex I activity was significantly decreased by 45% in SZ compared to controls (p = 0.02) after adjusting for relevant covariates while no significant difference was found in BD. Additionally, two analyses of case only (SZ and BD) were conducted to evaluate the effect of drugs and age at disease onset. First, Complex I activity was significantly decreased (p = 0.01) in pooled cases that had detectable psychotropic medications and drugs compared to pooled cases that did not have detectable levels in toxicological assays. Second, subjects with an age of onset in teens (with no detectable psychotropic medications) showed significantly decreased (po0.05) Complex I activity compared to subjects with an adult age of onset. Additionally, both SZ and BD groups displayed significant increases (po0.05) of mtDNA copy number in the DLPFC compared to controls. Despite the observed differences in mtDNA copy number, the mitochondria common deletion burden was not significantly altered in SZ or BD, but this metric did have a significant and positive correlation with age in the brain (po0.01).
Conclusions: The present study suggests that in chronic patients with SZ and BD there is a significant reduction in mitochondrial activity particularly in subjects that had taken recent antipsychotic or antidepressant medications. One proxy indicator of illness severity, age at onset, showed that subjects with a younger age of onset showed more reduction in Complex I activity than adult onset cases. Present data show an increase in copies of mtDNA in SZ and BD, a surrogate for the actual numbers of mitochondria in the brain. These results support prior studies showing that antipsychotic or antidepressant treatments can lead to mitochondrial hypofunction and suggest that drugs which target improvement in mitochondrial function may be a beneficial therapeutic strategy for some SZ and BD patients with an early age of onset. The negative toxicology results of postmortem brain is an indicator of the absence of acute treatment, we cannot conclude that those patients were never exposed to psychiatric medications. Further studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independently of longer term medication effects in subjects that later develop a psychiatric illness.