Human induced pluripotent stem cells (hiPSCs) in schizophrenia: Modelling the disease and the treatment response

Abstract

Response to drug treatment is under the sophisticated control of complex signalling pathways and gene regulatory networks. Indeed, drug-induced modulation of dysregulated gene expression and altered synaptic plasticity are critical steps for the successful treatment of neuropsychiatric disorders. Among the antipsychotic drugs, clozapine (CLZ) is widely considered to be the most effective medication for the treatment of schizophrenia. However, due to its high risk for severe side effects, CLZ use is currently restricted to patients who do not respond to other antipsychotics. Nonetheless, up to 20% of patients are considered nonresponders to CLZ treatment. The mechanism of action underlying CLZ's exceptional clinical efficacy in SCZ is not fully understood. In this context, in vitro molecular and functional assessment of patient-derived glutamatergic and GABAergic neurons’ properties are mandatory to reveal the mechanisms underlying CLZ responsiveness and might mirror the clinical response. Here, we will describe the generation of hiPSCs from SCZ patients, classified based on their response to conventional treatments, to CLZ or total resistance to every treatment. These patient-specific hiPSCs have been converted into enriched cortical glutamatergic neurons and parvalbumin-positive GABAergic interneurons populations that are under inspection to reveal phenotypic and molecular/pharmacological aspects correlating with patient-specific responsivity pattern to CLZ treatment. These results might help to unveil the molecular basis of treatment response profiles that can be exploited to predict response to antipsychotic drugs and that might help to develop personalized treatments, more individually tailored and less hazardous.Disclosure of interestThe authors have not supplied their declaration of competing interest.