Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences

Abstract
The introduction of atypical antipsychotics (AAPs) since the discovery of its prototypical drug clozapine has been a revolutionary pharmacological step for treating psychotic patients as these allow a significant recovery not only in terms of hospitalization and reduction in severity symptoms, but also in terms of safety, socialization and better rehabilitation in the society. Regarding the mechanism of action, AAPs are weak D2 receptor antagonists and they act beyond D2 antagonism, involving other receptor targets which regulate dopamine and other neurotransmitters. Consequently, AAPs present a significant reduction of deleterious side effects like parkinsonism, hyperprolactinemia, apathy and anhedonia, which are all linked to the strong blockade of D2 receptors.
This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them. Furthermore, we propose a continuum spectrum of “atypia” that begins with risperidone (the least atypical) to clozapine (the most atypical), while all the other AAPs fall within the extremes of this spectrum.
Clozapine is still considered the gold standard in refractory schizophrenia and in psychoses present in Parkinson’s disease, though it has been associated with adverse effects like agranulocytosis (0.7%) and weight gain, pushing the scientific community to find new drugs as effective as clozapine, but devoid of its side effects. To achieve this, it is therefore imperative to characterize and compare in depth the very complex molecular profile of AAPs. We also introduce relatively new concepts like biased agonism, receptor dimerization and neurogenesis to identify better the old and new hallmarks of “atypia”.
Finally, a detailed confrontation of clinical differences among the AAPs is presented, especially in relation to their molecular targets, and new means like therapeutic drug monitoring are also proposed to improve the effectiveness of AAPs in clinical practice.
Keywords:
Atypical antipsychotics; Clozapine; Monoamine receptors; Dimerization; Biased agonism; Therapeutic drug monitoring.

Role of funding source
This research was funded by Fondazione ARPA, a non-profit organization founded in 1992 (https://arpa.sidebloom.com) and by Progetti di Ricerca di Ateneo (PRA 2015).
The resources of Fondazione ARPA are aimed towards basic and scientific research, mainly for oncology, transplants and new medical and surgical techniques.
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgements
We would like to express our deepest gratitude to our mentor Prof. Giovanni Umberto Corsini for his guidance, great enthusiasm and precious advices, which has inspired us during all these years in our research.