Polyunsaturated fatty acids and psychotic disorders: integrating mechanistic, genetic, and clinical evidence

Polyunsaturated fatty acids (PUFAs), including omega-3 (n-3) and omega-6 (n-6) essential fatty acids, play critical roles in brain development and function, serving as precursors to a wide range of bioactive lipid mediators involved in immune and inflammatory signaling. Emerging evidence implicates PUFA dysregulation in schizophrenia and bipolar disorder, severe psychiatric conditions that remain incompletely treated by current therapeutics. In this review, we first outline the biological roles of PUFAs relevant to neurodevelopment and psychiatric risk, with particular emphasis on their interactions with synaptic, immune, and stress-related risk pathways impinging on neurodevelopment. We synthesize preclinical evidence showing how altered PUFA availability influences neurobiological and behavioral phenotypes relevant to psychosis, alongside human observational, epidemiological, genomic and lipidomic studies that implicate disrupted PUFA metabolism in schizophrenia and bipolar disorder. Finally, we evaluate clinical trials of n-3 PUFA supplementation, considering both its therapeutic potential and current limitations. Together, we highlight PUFA metabolism as a mechanistic bridge linking neurodevelopment, immune function, and psychiatric risk, and as a potential target for future therapeutic strategies.