Candidate Biomarkers of Bipolar Disorder Progression: Implications for Ketamine and Psychedelic Interventions.

Bipolar depression is the main driver of disability, suicidality, and treatment resistance in bipolar disorder (BD). The neuroprogression hypothesis proposes that repeated mood episodes and related biological disturbances contribute to worsening outcomes over time. Ketamine and psychedelic interventions have emerged as rapid-acting treatments that engage pathways potentially relevant to these processes. This narrative, hypothesis-generating review synthesized evidence on biomarkers of illness progression in BD together with emerging data on ketamine and psychedelic-assisted interventions. A structured but non-systematic search of PubMed/MEDLINE, Scopus, and Web of Science was conducted in December 2025 and February 2026, prioritizing human BD studies, especially longitudinal and staging-based designs, meta-analyses, systematic reviews, and mechanistically relevant preclinical and early-phase clinical studies. Across studies, more advanced BD was associated with abnormalities in inflammatory signaling, neurotrophic regulation, structural and functional neuroimaging, and epigenetic processes. However, findings were heterogeneous, often modest in effect size, and frequently based on cross-sectional designs. Many candidate biomarkers appeared more closely related to current mood state than to cumulative illness progression. Peripheral BDNF and inflammatory markers showed limited specificity, functional neuroimaging findings were largely state-dependent, and epigenetic alterations were focal and context-sensitive rather than uniform. Ketamine and psychedelic compounds modulated several of these same pathways in preclinical models and, to a lesser extent, in human studies, although most mechanistic clinical evidence was derived from unipolar treatment-resistant depression rather than BD. Preliminary bipolar-specific studies, mainly in bipolar II depression, suggest possible feasibility and antidepressant effects of psilocybin- and 5-MeO-DMT-derived interventions under carefully controlled conditions. Current evidence supports dynamic multisystem biological abnormalities in BD but does not yet establish a reliable biomarker framework for staging or neuroprogression. Ketamine and psychedelic interventions are mechanistically relevant, but evidence for true disease modification or clinical downstaging in BD remains indirect. Longitudinal, multimodal, within-subject studies are needed to distinguish state-related changes from cumulative progression and to link biomarker change with meaningful clinical outcomes.