Purinergic signaling and energetic metabolism in bipolar disorder: From pathophysiology to precision therapeutics

Bipolar disorder (BD) is a chronic psychiatric illness marked by recurrent manic and depressive episodes, with substantial disability and high comorbidity. Emerging evidence highlights purinergic signaling and cellular energy metabolism as convergent, interdependent drivers of BD pathophysiology. Purines-particularly adenosine and ATP-function dually as intracellular energy substrates and extracellular signaling molecules regulating neuroinflammation, neurotransmission, and redox balance. Dysregulation of purinergic pathways, including P2 × 7 receptor overactivation, elevated uric acid, and reduced neuroprotective adenosine, interacts with mitochondrial dysfunction-characterized by impaired oxidative phosphorylation, ATP depletion, increased reactive oxygen species, and redox imbalance-to form a pathological feedback loop. This bioenergetic-purinergic axis underlies mood cycling: mania reflecting bioenergetic upregulation with purinergic hyperactivity, and depression representing bioenergetic downregulation with purinergic hypoactivity. Biomarkers such as uric acid, xanthine dehydrogenase and adenosine deaminase activity, phosphocreatine, ATP levels, and oxidative stress indices demonstrate phase-dependent alterations and hold promise for diagnosis, prognosis, and treatment monitoring. Therapeutic opportunities extend beyond conventional mood stabilizers to include xanthine oxidase inhibitors (e.g., allopurinol), P2 × 7 antagonists, adenosine modulators, and mitochondrial-supportive agents (e.g., creatine, carnitine, CoQ10, N-acetylcysteine). Integration of omics profiling, advanced neuroimaging, and biomarker-guided stratification may enable precision psychiatry approaches tailored to individual metabolic-inflammatory phenotypes. This integrative model reframes BD as a systemic disorder of cellular energetics and purinergic signaling, offering novel mechanistic targets and guiding the development of personalized, phase-specific interventions to improve long-term outcomes.