Schizophrenia: Mechanism of Action of Current and Novel Treatments

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Antipsychotics are effective for managing the positive symptoms of schizophrenia. When prescribing these agents, clinicians should consider pharmacokinetics, pharmacodynamics, and the interaction between the drug and the individual patient’s unique genetics, age, disease variables, and environment. All antipsychotics are D2 receptor-antagonists; however, only 1 of the 6 dopamine pathways in the brain is implicated in psychosis. Dopamine blockade in the other pathways can cause a wide range of side effects, and unfortunately, a medication cannot target only 1 dopamine pathway. Therefore, other strategies, such as agents that also act at other neurotransmitter systems, could be used to balance D2 blockade in the other 5 pathways. Aiming at a novel treatment target, N-methyl-d-aspartate (NMDA) receptors, may also help to mediate the downstream release of dopamine as well as other neurotransmitters, such as glutamate and γ-aminobutyric acid (GABA), which are thought to be involved in the pathophysiology of schizophrenia. Because noncompetitive NMDA receptor agonists, such as ketamine and phencyclidine (PCP), induce schizophrenia-like positive, negative, and cognitive symptoms, dysfunctional NMDA receptor-mediated neurotransmission in the glutamate pathway may underlie the pathogenesis of schizophrenia.

From the Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry, Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead; and Behavior Health Services, North Shore-Long Island Jewish Health System, New Hyde Park, New York (Dr Kane); and the Recognition and Prevention Program (RAP), The Zucker Hillside Hospital, Glen Oaks; the Department of Psychiatry and Molecular Medicine, Hofstra-North Shore-Long Island Jewish School of Medicine, Hempstead; and the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York (Dr Correll).’ ‹