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

The treatment of major depressive episodes in bipolar disorder (BD) is underdeveloped, leading to frequent antidepressant (AD) use despite limited evidence. This practice is concerning because ADs can increase the risk of mania, known as antidepressant-induced mania (AIM), treatment-emergent mania (TEM+), or cycle acceleration. The consequences of mania—increased energy expenditure, impulsivity, poor judgment, psychosis, and loss of insight—can lead to serious consequences. Meta-analyses show a significant increase in switch rate with AD use in bipolar depression. Clinical factors associated with TEM+ include younger age, female sex, mixed symptoms, and BD type. Mitochondrial dysfunction, characterized by reduced expression of electron transport chain (ETC) genes and impaired ATP production, is implicated in BD pathophysiology. Suboptimal mitochondrial function (SMF) contributes to various illness vulnerabilities, including relapse risk. Preclinical studies show that antidepressants differentially alter ETC complex activity. Some ADs increase mitochondrial respiration, potentially contributing to mania. This study used data from the Mayo Clinic Bipolar Disorder Biobank to investigate whether ADs increasing mitochondrial activity are associated with higher TEM+ rates.

The introduction thoroughly reviews existing literature on the use of antidepressants in bipolar disorder, the risk of treatment-emergent mania (TEM+), and the role of mitochondrial dysfunction in the pathophysiology of bipolar disorder. It cites numerous studies supporting the link between antidepressants and mania, highlighting the clinical factors associated with TEM+, and the evidence for mitochondrial dysfunction as a key element in the neurobiology of BD. The review also lays the groundwork for the study by pointing out the differential effects of antidepressants on mitochondrial function, drawing from preclinical research demonstrating that certain antidepressants can increase mitochondrial respiration. This literature review effectively contextualizes the research question and justifies the rationale behind the study.

This retrospective study utilized data from the Mayo Clinic Bipolar Disorder Biobank, including patients with a history of antidepressant exposure and clinical outcome measures. The biobank, established in 2014, contains biological samples and clinical data from patients meeting criteria for bipolar disorder or schizoaffective bipolar disorder. TEM+ was defined as a manic/hypomanic episode within 60 days of starting or increasing an AD dose. TEM– controls had ≥60-day AD exposure without a manic/hypomanic episode. Antidepressants were classified as Mito+ (increasing mitochondrial function) or Mito– (decreasing mitochondrial function) based on a preclinical review. The study included 952 subjects (176 TEM+, 516 TEM–). Generalized estimating equations (GEEs) were used to compare TEM+ rates between Mito+ and Mito– ADs, adjusting for age, sex, and BD type. Chi-squared tests and two-sample t-tests assessed differences in other variables.

The study identified 952 subjects with previous exposure to Mito+ and/or Mito– antidepressants (62.7% female, 91.4% White, mean age 43.0 ± 14.0 years). TEM+ participants were significantly younger than TEM– participants (40.6 ± 13.8 vs. 43.8 ± 13.9; p = 0.019). There were no significant differences in BD type between groups. After adjusting for age, sex, and BD type, TEM+ was significantly more frequent with Mito+ antidepressants (24.7%) than Mito– antidepressants (13.5%; OR = 2.21; p = 0.000009).

This study provides the first clinical investigation into the relationship between antidepressant-induced mitochondrial energetics changes and the risk of treatment-emergent mania. The finding that TEM+ is twice as common with Mito+ antidepressants aligns with some clinical evidence suggesting increased mood switch risk with certain ADs. The study's strengths include its hypothesis-driven classification of antidepressants based on mitochondrial energetics, the use of clinician-defined TEM+, and adjustment for known risk factors. Limitations include the retrospective nature of the assessment, lack of data on age at TEM+ onset, and inability to control for concurrent psychotropic use or other factors influencing mitochondrial function. Future prospective studies are needed to address these limitations and explore the complex interactions between mitochondrial function, antidepressants, and TEM+.

This retrospective study indicates a strong association between antidepressants that increase mitochondrial energetics and a higher incidence of treatment-emergent mania in individuals with bipolar disorder. This novel classification of antidepressants based on their effect on mitochondrial function warrants further investigation. Future prospective studies should examine the mechanisms underlying this relationship and explore the potential for personalized treatment strategies based on individual mitochondrial profiles.

The retrospective design limited the ability to control for several factors, including age at TEM+ onset and concurrent medication use. The classification of antidepressants as Mito+ or Mito– was based on a preclinical review, and the generalizability of these preclinical findings to human populations may be limited. The study didn't account for lifestyle factors, comorbid conditions, or other variables that might impact mitochondrial activity and risk for TEM+. Future prospective studies with larger, more diverse populations are needed to validate these findings and address these limitations.