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

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 symptoms severity, 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.