[Aripiprazole as dopamine partial agonist model: Basic concepts and clinical impact]

Area of Science:

• Neuropharmacology
• Psychiatry

Background:

• Third-generation antipsychotics, exemplified by aripiprazole, represent a paradigm shift from traditional D2 antagonist medications.
• Their action is based on partial agonism at dopamine D2 receptors, a distinct mechanism from first- and second-generation antipsychotics.

Purpose of the Study:

• To review the pharmacological concepts of D2 partial agonism, functional selectivity, and biased ligands.
• To explore the implications of aripiprazole's D2 partial agonism on D2 supersensitivity.
• To discuss the clinical and preclinical relevance of these mechanisms in psychosis, schizophrenia, and addiction.

Main Methods:

• Review of pharmacological literature on antipsychotic mechanisms.
• Analysis of D2 receptor pharmacology, including partial agonism and antagonism.
• Examination of studies on D2 supersensitivity and its modulation by antipsychotics.
• Discussion of functional selectivity and biased ligand concepts.

Main Results:

• Aripiprazole's D2 partial agonism distinguishes it from older antipsychotics.
• D2 partial agonists, like aripiprazole, do not induce D2 supersensitivity and can reverse existing supersensitivity.
• This property has significant clinical implications for treating first-episode psychosis and refractory schizophrenia.
• Animal models suggest D2 supersensitivity may exacerbate addictive behaviors.

Conclusions:

• D2 partial agonism is a key feature of third-generation antipsychotics like aripiprazole.
• The ability to modulate D2 supersensitivity offers therapeutic advantages in psychiatric disorders.
• Understanding functional selectivity may pave the way for designing novel, fourth-generation antipsychotics.