A Polyunsaturated Fatty Acid (PUFA) Theory of Schizophrenia

I present a theory of schizophrenia (SZ) that mechanistically explains its etiology, symptoms, pathophysiology, and treatment. SZ involves the chronic release of membrane polyunsaturated fatty acids (PUFAs) and their utilization for the synthesis of stress-induced plasticity agents such as endocannabinoids (ECBs). The causal event in SZ is prolonged stress during a sensitive period, which can induce prolonged and heritable changes. The physiological effect of the released PUFAs and their products is to disconnect neurons from their inputs and promote intrinsic excitability. I show that these effects can explain the positive, negative, cognitive, and mood symptoms of SZ, as well as the mechanisms of many known triggers of psychosis. The theory is supported by overwhelming evidence addressing lipids, immunity, ECBs, neuromodulators, hormones, neurotransmitters, and cortical parameters in SZ. It explains why antipsychotic drugs are effective against positive symptoms, and why they do not affect the other symptoms. Finally, I present promising treatment directions implied by the theory, including some that are immediately available.