Identifying treatments that will benefit patients with TRS remains a significant challenge. Our understanding of personalized treatment response and resistance to medication is limited by an inability to accurately pinpoint the individual genetic, cellular and neural circuit drivers of psychoses. Investigations of neuronal ensembles and cortical networks at the micro-scale level are not possible using the clinical diagnostic and macro-scale imaging tools that are currently available. Moreover, inconsistent clinical definitions of positive, negative or cognitive symptom-specific differences in TRS lead to ambiguous treatment guideline recommendations and a wide variation in clinical approaches to treat TRS in practice. Different phenotypes of psychoses may respond to different targeted treatments that are cellular or neural circuit-specific, but at present we do not have the ability to identify the appropriate targeted therapies for different TRS phenotypes.