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Efficacy of adjunctive mitochondrial modulators for bipolar depression: A comprehensive systematic review and network
Tzu-Rong Peng1, Ming-Chia Lee2, Kazuto Isuzugawa3
1Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Tzu Chi University, Hualien, Taiwan.
Background:
Standard pharmacological treatments for bipolar depression have limitations such as inadequate patient response and adverse effects. Mitochondrial modulators exhibit therapeutic potential for bipolar depression; however, conventional meta-analyses have yielded contradictory results. This network meta-analysis (NMA) evaluated the comparative efficacy of and established a treatment hierarchy of various adjunctive mitochondrial modulators.
Methods:
A systematic literature search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted up to April 2026 to identify double-blind randomized controlled trials (RCTs). We included studies evaluating adjunctive mitochondrial modulators for adult bipolar depression. The primary outcome was the standardized mean difference (SMD) in depressive symptom severity. Frequentist NMA was performed, treatment rankings were based on P-scores, and certainty of evidence was evaluated using the CINeMA framework.
Results:
Twenty-two RCTs were included. The evidence network displayed a classic star-shaped topology anchored by placebo, with no direct head-to-head comparisons among active treatments. Coenzyme Q10 (CoQ10) significantly outperformed placebo with a large effect size (SMD = -1.14, 95% CI: -2.09 to -0.19; P-score = 0.919), though based on a single trial. N-acetylcysteine (NAC) (8 trials) demonstrated a significant, moderate effect (SMD = -0.37, 95% CI: -0.74 to -0.01; P-score = 0.642). The remaining 10 modulators showed no statistically significant differences from placebo. Certainty of evidence was moderate for agomelatine and low to very low across the remaining interventions, including CoQ10.
Conclusions:
Adjunctive CoQ10 and NAC demonstrated the most favorable relative efficacy estimates among evaluated agents. However, given the star-shaped network structure, single-trial evidence for CoQ10, and certainty of evidence ranging from moderate to very low, these findings should be regarded as preliminary and hypothesis-generating rather than definitive evidence of treatment superiority. Adequately powered, direct head-to-head RCTs are necessary to confirm their clinical utility.