Metabolic Signatures of Bipolar Disorder Through a Sex-Informed Lens: Emerging Biomarkers for Precision Psychiatry

Bipolar disorder (BD) is a clinically heterogeneous condition for which diagnosis, prognostic assessment, and treatment selection continue to rely predominantly on symptom-based evaluation. Metabolomics offers a promising approach to biomarker discovery by capturing the downstream effects of genetic susceptibility, environmental exposures, lifestyle, disease activity, and pharmacological treatment. Studies using peripheral biofluids, post-mortem brain tissue, and in vivo neurometabolic measures have identified alterations involving lipid metabolism, amino acids, energy production, oxidative stress, one-carbon metabolism, tryptophan–kynurenine pathways, and the gut microbiota-derived metabolome. Reproducibility is limited, and the potential influence of biological sex is frequently neglected or treated merely as a statistical covariate. This narrative review critically examines emerging metabolomic and lipidomic biomarkers in BD through a sex-informed perspective. We discuss their potential applications in differential diagnosis, mood-state characterization, illness staging, prediction of treatment response, and identification of cardiometabolic vulnerability. Particular attention is given to sex hormones, reproductive transitions, body composition, immune–metabolic regulation, circadian biology, and sex-dependent pharmacometabolic effects. Major methodological limitations, including small samples, medication exposure, inconsistent mood-state characterization, and insufficient sex-stratified validation, are also considered. Integrating sex as a biological variable into longitudinal, multi-omic, and clinically deeply phenotyped studies may improve biomarker reproducibility and support more individualized approaches to BD.