Translating preclinical findings in clinically relevant new antipsychotic targets: focus on the glutamatergic postsynaptic density. Implications for treatment resistant schizophrenia

There is a growing interest in new molecular targets for antipsychotic therapy. Multiple signal transduction systems have been recently implicated in the pathophysiology of schizophrenia. However, the weight of each specific mechanism remains controversial. A need for a more vigorous approach to the pharmacotherapy of schizophrenia arises from the bedside: about 30-40% of patients do not respond to antipsychotic therapy. Postsynaptic Density (PSD) proteins have recently attracted attention for their role in signal transduction modulation and for their potential implication in psychosis and cognition. The involvement of PSD in the pathophysiology of schizophrenia is supported by post mortem studies, preclinical animal models, modulation by antipsychotics, and association of PSD genes with schizophrenia in GWAS. Taken together, these studies underline the role of PSD modulation, its effects on striatal function and its relationship with motor, executive- and cognitive-like functions suggesting a potential role of PSD proteins as a potential target of novel intervention in the treatment of refractory psychosis