Schizophrenia is a severe and chronic mental illness that affects approximately 1% of the adult population regardless of one’s gender, ethnicity, or social class. Since the unexpected discovery of the antipsychotic agent Chlorpromazine in the 1950s, and despite the evolution of neuroleptics in subsequent decades, the fundamental treatment of schizophrenia continues to be based on D2 receptor blockade even today. The use of antipsychotics represents a serious public health problem and a major economic cost to society. Although they all act on essentially the same receptors (D2R, D1R, 5-HT1A and 2A), patients differ markedly in their response to treatment and in the occurrence of side effects.
The symptomatology of the disease is highly complex. It is divided into positive (e.g. hallucinations and distortion of reality), negative (e.g. loss of motivation and anhedonia) and cognitive (e.g. concentration and memory difficulties) symptoms. The neuroleptics currently approved as treatment by the Spanish Agency of Medicines manage to palliate, with better or worse results, the positive symptomatology of the disease. However, the negative and cognitive symptoms currently remain pharmacologically orphaned, with Clozapine being the only antipsychotic effective in the cognitive-behavioral recovery of patients. Therefore, there is a compelling need to expand the horizons of pharmacological research and identify new molecular mechanisms associated with antipsychotic action.
The mechanism of action of Clozapine at the cognitive level remains unclear even today, making it imperative to delve deeper into this question in the search for new and more effective therapies for schizophrenia. The main object of study in this present line of research is to clarify whether the mechanism of the pro-cognitive-behavioral action of Clozapine, in a murine model that reproduces the negative and cognitive symptomatology of the pathology, is linked to the modulation of Adamts2 gene expression and its consequences on reelin-dependent physiological processes.