Energetic metabolism in bipolar disorder: from markers to precision therapeutics

Bipolar disorder (BD) is marked by recurrent mood episodes and functional impairment. Growing evidence implicates mitochondrial dysfunction, oxidative stress, and metabolic disturbances as important to its pathophysiology, affecting neuronal signalling, synaptic plasticity, and inflammatory pathways.

This review synthesises current evidence linking energetic metabolism to BD, integrates neuroimaging and peripheral biomarker findings, and discusses emerging therapeutic strategies targeting mitochondrial and metabolic dysfunction.

A systematic search following PRISMA guidelines was conducted across PubMed, MEDLINE, EMBASE, Scopus, and Cochrane Library using 'bipolar disorder', 'energetic metabolism', and 'mitochondria'. Inclusion criteria comprised peer-reviewed human studies, original research, and meta-analyses; paediatric, non-English, dietary, genetic, or comorbidity-focused studies were excluded. Additional manual searches targeted biomarker-specific studies.

Evidence consistently shows impaired oxidative phosphorylation, reduced ATP and phosphocreatine, altered NAD⁺/NADH ratios, and increased oxidative and inflammatory markers in BD. Neuroimaging demonstrates reduced PCr/ATP ratios, elevated lactate, and decreased TCA cycle intermediates, indicating cerebral energy deficits. Peripheral biomarkers: including decreased ETC complex activity, increased MDA and 8-OHdG, altered purinergic enzymes, and elevated mtDNA reflect systemic bioenergetic stress. Emerging interventions targeting mitochondrial cofactors (creatine, CoQ10, carnitine, NAC), metabolic strategies (ketogenic diet), and immunomodulatory or purinergic pathway modulators show promise.

Emerging evidence suggests that systemic bioenergetic dysregulation may contribute to the pathophysiology of BD. Integrating mitochondrial, metabolic, and inflammatory biomarkers with neuroimaging may enable biologically informed patient stratification and precision therapeutics aimed at restoring energetic homeostasis. Large, standardised multicenter studies are required to translate these findings into clinical practice.