Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside

Dear Colleagues,

Schizophrenia is among the most debilitating causes of morbidity worldwide, with a progressively worsening course. The WHO stated that schizophrenia should be treated by integrated therapeutic strategies, including pharmacological and non-pharmacological interventions, both considered mandatory to cure these patients efficaciously. The mainstay of pharmacological treatment of schizophrenia is the class of Antipsychotic agents, which comprises several chemically unrelated compounds. However, all antipsychotics (with the possible exception of clozapine) share a variable degree of action as dopamine D2 receptor blockers. Despite this common mechanism of action, antipsychotics exert molecular actions on multiple dopaminergic and non-dopaminergic receptors. The relevance to the therapeutic efficacy of these actions, as well as their molecular consequences, are largely unknown. Also, the molecular effects triggered by antipsychotics after their interaction with target receptors have been only limitedly characterized.  

The lack of in-depth data on antipsychotic molecular action is a major cause of relevant clinical challenges since currently available antipsychotics suffer from several limitations in the treatment of schizophrenia. According to some estimations, approximately 30% of all schizophrenia patients have positive symptoms that are unresponsive or only minimally responsive to antipsychotics. The so-called negative symptoms, which include several distinct pathological phenotypes, as well as cognitive dysfunctions in schizophrenia patients are not ameliorated by current antipsychotics. Also, it has been suggested that antipsychotics may cause iatrogenic worsening and/or occurrence of negative or cognitive symptoms. Unfortunately, these symptoms are those maximally associated with long-term disability in schizophrenia patients and pharmacological therapeutic strategies addressing them are among the most relevant unmet need of schizophrenia clinics. As a further consideration, antipsychotics are burdened from multiple side effects, that in part stem from their therapeutic mechanism of action but, in many other cases, derives from the action on receptor targets that are not strictly necessary for their efficacy against psychotic symptoms.

All these considerations indicate the urge to gain more insights into the molecular mechanism of actions of currently available antipsychotics and to unravel other mechanisms of action, even including the possibility of sharp paradigmatic changes, e.g., using small molecules; gene therapy; or acting on post-receptor or non-receptor neuronal sites.

The Special Issue, “Mechanisms of Antipsychotic Action: from the researcher bench to the patient bedside” of the International Journal of Molecular Sciences will include a selection of research papers and reviews about various aspects of the molecular and cellular biology of antipsychotics. In addition, studies on molecules able to modulate various aspects of synaptic signaling, and their possible use in the treatment of psychotic diseases will also be considered.

Dr. Felice Iasevoli
Guest Editor

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