Blood-based biomarkers in ketamine treatment: A blueprint for translational drug development in mood disorders

Over the past two decades, the N-methyl-d-aspartate receptor antagonist ketamine has emerged as a transformational, rapid-acting therapy for both unipolar and bipolar depression-particularly in treatment refractory cases. However, its specific mechanism of action remains unclear. Furthermore, although repeatable neuroimaging-based and electrophysiological biomarkers of treatment response to ketamine have been identified, they cannot provide specific molecular targets with which to advance precision psychiatry with rapid-acting antidepressants. This review explores blood-based biomarkers of ketamine response with an eye towards elucidating ketamine's intricate and varied antidepressant effects. Key findings indicate that ketamine modulates inflammatory, neurotrophic, and metabolic systems, and these changes are reflected in altered levels of biomarkers such as interleukin-6, brain-derived neurotrophic factor (BDNF), and plasma d-serine. Notably, the relationship between therapeutic efficacy and ketamine's metabolites, such as (2R,6R)-hydroxynorketamine, highlights the potential for metabolite-guided strategies and reciprocal translational research. In addition, the rapid temporal dynamics of biomarkers, particularly BDNF and inflammatory cytokines, underscore their potential as tools for monitoring treatment response and developing novel therapeutics. Despite these advances, limitations persist, including heterogeneous methodologies and small sample sizes across studies. The field requires a paradigm shift towards integrated biosignatures, combining multi-system biomarkers (i.e., neuroimaging, electrophysiological, and sleep biomarkers) with clinical outcomes. Such an approach has the potential to refine patient stratification, enhance drug development, and improve treatment monitoring.