Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

Abstract

Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics’ receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na2+ channels at the dopamine at the presynaptic site, dopamine transporter (DAT) involvement as the main regulator of dopamine concentration at synaptic clefts, and the putative role of antipsychotics as chaperones for intracellular D2R sequestration, should be included. These mechanisms expand the fundamental role of dopamine in schizophrenia therapy and may have relevance to considering putatively new strategies for treatment-resistant schizophrenia (TRS), an extremely severe condition epidemiologically relevant and affecting almost 30% of schizophrenia patients. Here, we performed a critical evaluation of the role of antipsychotics in synaptic plasticity, focusing on their canonical and non-canonical mechanisms of action relevant to the treatment of schizophrenia and their subsequent implication for the pathophysiology and potential therapy of TRS.

New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

“…The dopaminergic hypothesis can be summarized as the combination of two main effects: (1) excessive dopamine activity in the mesolimbic pathway (Simpson et al, 2010;Elert, 2014;McCutcheon et al, 2019), specifically in the striatum, disrupts the neurotransmitter balance impairing the functioning of other brain regions involved in cognitive processing; (2) reduced dopamine activity in the mesocortical pathway, connecting the ventral tegmental area (VTA) to the prefrontal cortex (PFC), is linked to both negative symptoms and CIAS (Brisch et al, 2014;Elert, 2014;Slifstein et al, 2015;Simpson and Kellendonk, 2017; Figure 2A). The dual dopamine hypothesis (Elert, 2014; also opens an issue for the functioning of dopaminergic antipsychotics, whose efficacy is largely linked to their affinity for the D2R distributed both in cortical and subcortical regions (Toda and Abi-Dargham, 2007;Howes et al, 2012;de Bartolomeis et al, 2023). Although the dopamine hypothesis is central to SZ, its dysregulation in the striatum and cerebral cortex is just one aspect of the complex pathophysiology of SZ.…”

The Neurobiological Underpinnings of Obsessive-Compulsive Symptoms in Psychosis, Translational Issues for Treatment-Resistant Schizophrenia

“…On the other hand, studies on the serotoninergic system related to hallucinogenic drugs, such as lysergic acid diethylamide [ 144 ], as well as the observation of antipsychotic effects of serotonin–dopamine antagonists, such as clozapine and risperidone, have driven a growing interest in this field as a possible pathophysiological target in schizophrenia [ 145 ]. Growing evidence hypothesizes that psychosis involves neural networks beyond the canonical mesolimbic dopaminergic pathway [ 146 ], including the serotonin and glutamate systems [ 147 ]. Physical and functional interactions between serotonin–glutamate and serotonin–dopamine signaling have been hypothesized to be involved in the pathophysiology of psychosis, relevant for antipsychotic treatment [ 148 ], synaptic plasticity and functional connectivity [ 149 ].…”

“…Several clinical and preclinical studies focus their attention on dopamine–serotonin-glutamate neurotransmission convergence points. Intracellular molecules, as well as receptor heterodimerization, are responsible for integrating different types of signaling in response to extracellular stimuli and drugs [ 146 ].…”

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients

“…The most common prescription drugs are antipsychotics, which control symptoms by affecting dopamine. 8 The goal of drug therapy is to effectively manage symptoms at the optimized dosage possible. 9 First-generation antipsychotics are typical or traditional antipsychotics, such as chlorpromazine, haloperidol, perphenazine, et al, but may cause elevated prolactin levels, affecting libido, mood, menstrual cycles, and breast tissue in both men and women.…”