Toward a Pluralistic Model for the Schizophrenia Spectrum—Dopamine and Beyond

Are schizophrenia-related disorders best explained by a dopaminergic final common pathway or by a pluralistic model of multiple interacting neurochemical mechanisms?Pharmacologic and neuroimaging evidence shows dopaminergic dysregulation in the associative striatum underlying psychosis. Glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and inflammatory mechanisms also underlie psychosis and other psychopathological dimensions; treatment resistance in patients without elevated striatal dopamine synthesis and the antipsychotic efficacy of the muscarinic drug xanomeline support nondopaminergic pathways.A pluralistic model recognizing multiple interacting neurochemical and cellular pathways may better explain schizophrenia heterogeneity and guide biomarker-informed, mechanism-based treatment development.

Corresponding Author: Matcheri S. Keshavan, MD, Harvard Medical School, 75 Fenwood Rd, Boston, MA 02115 (mkeshava@bidmc.harvard.edu).

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