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

Int J Mol Sci. 2023 Mar 21;24(6):5945. doi: 10.3390/ijms24065945.

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.

Keywords: Homer; PSD-95; antipsychotics; dopamine; glutamate; postsynaptic density; synaptopathy; treatment-resistant schizophrenia.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Antipsychotic Agents* / pharmacology
  • Antipsychotic Agents* / therapeutic use
  • Dopamine / therapeutic use
  • Humans
  • Schizophrenia* / drug therapy
  • Schizophrenia, Treatment-Resistant
  • beta-Arrestins

Substances

  • Antipsychotic Agents
  • Dopamine
  • beta-Arrestins

Grants and funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Andrea de Bartolomeis MD PhD is a full-time employee at the University of Naples “Federico II”; Giuseppe de Simone MD is enrolled in the Residency Program of Psychiatry at the University of Naples “Federico II”; Licia Vellucci MD is enrolled in the Residency Program of Psychiatry at the University of Naples “Federico II” and Clinical and Experimental Medicine PhD candidate at the Department of Medical and Translational Sciences, the University of Naples “Federico II”; Benedetta Mazza MD is enrolled in the Residency Program of Psychiatry at the University of Naples “Federico II”; Annarita Barone MD is Neuroscience PhD candidate at the Department of Neuroscience, University of Naples “Federico II”, and Mariateresa Ciccarelli MD is Neuroscience PhD candidate at the Department of Neuroscience, University of Naples “Federico II”.