Given the vast clinical heterogeneity of major mental illness, Akira Sawa, from John Hopkins University School of Medicine, advocated careful patient stratification when selecting cohorts for hiPSC-based disease modeling. He argued that traditional Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 1994) diagnosis does not provide enough neurobiologically relevant information for patient recruitment for basic research and proposed that other criteria such as clinical longitudinal assessment, neuropsychology examination, brain imaging, and correlation between intermediate phenotypes and disease-related genetic polymorphisms should be considered. By screening olfactory NPCs obtained from a larger clinical cohort of patients with SZ and bipolar disorder (BD) with psychotic features, he identified those patients with reduced phosphorylation (pS713) of disrupted in schizophrenia 1 (DISC1), independent of clozapine treatment, and selected them for further hiPSC-based characterizations. Reduced (pS713) DISC1 phosphorylation was replicated in hiPSC neurons, and levels of p713-DISC1 correlated to neuropsychological and anatomical changes, highlighting the importance of patient stratification in complex neuropsychiatric diseases. He proposed that such clinical phenotype-based stratification of the subjects for hiPSC research could also be applied for unique subsets of SZ and mood disorders, such as psychotic depression and rapid-cycling BD.
