Etiopathogenic Models of Psychosis Spectrum Illnesses Must Resolve Four Key Features.

Etiopathogenic models for psychosis spectrum illnesses are converging on a number of key processes, such as the influence of specific genes on the synthesis of proteins important in synaptic functioning, alterations in how neurons respond to synaptic inputs and engage in synaptic pruning, and microcircuit dysfunction that leads to more global cortical information processing vulnerabilities. Disruptions in prefrontal operations then accumulate and propagate over time, interacting with environmental factors, developmental processes, and homeostatic mechanisms, eventually resulting in symptoms of psychosis and disability. However, there are 4 key features of psychosis spectrum illnesses that are of primary clinical relevance but have been difficult to assimilate into a single model and have thus far received little direct attention: 1) the bidirectionality of the causal influences for the emergence of psychosis, 2) the catastrophic clinical threshold seen in first episodes of psychosis and why it is irreversible in some individuals, 3) observed biotypes that are neurophysiologically distinct but clinically both convergent and divergent, and 4) a reconciliation of the role of striatal dopaminergic dysfunction with models of prefrontal cortical state instability. In this selective review, we briefly describe these 4 hallmark features and we argue that theoretically driven computational perspectives making use of both algorithmic and neurophysiologic models are needed to reduce this complexity and variability of psychosis spectrum illnesses in a principled manner.