[Critical review of mechanisms of action of second-generation antipsychotic drugs].
The advent of second-generation antipsychotics (SGA) in the wake of clozapine, the prototype for atypical antipsychotics, represents a breakthrough in the pharmacologic treatment of schizophrenia. There is growing evidence that most of the SGA can offer advantages over first-generation antipsychotics within the effective dose range, such as improvement in negative symptoms and cognitive impairment, fewer extrapyramidal side effects, and less hyperprolactinemia. However, the essential pharmacological properties that confer the different therapeutic effects of the SGA have remained elusive, and the search for novel antipsychotics without dopamine D2 receptor antagonism has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current predominant theories of mechanisms of action of SGA, including the serotonin-dopamine hypothesis, the "fast-off-D2 theory," and regional specificity. In addition, it focuses on the roles of N-methyl-D-aspartate receptors, dopamine DI receptors, and alpha-adrenergic receptors in the pharmacology of SGA.
Miyamoto
Seiya
S
Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511 Japan. s2miya@marianna-u.ac.jp
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy*
D018687:Antidepressive Agents, Second-Generation; D065127:Dopamine D2 Receptor Antagonists; D011942:Receptors, Adrenergic, alpha; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D003024:Clozapine