Pluralistic Model Proposed for Schizophrenia Spectrum: Beyond Dopamine

Dopaminergic hyperactivity in the associative striatum is strongly linked to positive psychotic symptoms and predicts response to D2 antagonists.
Approximately one-third of patients with treatment resistance show no increase in striatal dopamine synthesis capacity.
Emerging evidence implicates glutamatergic, GABAergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as oxidative stress, mitochondrial dysfunction, and neuroinflammation.
The efficacy of xanomeline-trospium—a muscarinic M1/M4-preferring agonist lacking direct D2 antagonism—demonstrates that nondopaminergic mechanisms can reduce psychotic symptoms.
Neurochemically distinct subgroups may cut across overlapping clinical phenotypes, supporting a pluralistic rather than a single final common pathway model.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Dopaminergic hyperactivity in the associative striatum is strongly linked to positive psychotic symptoms and predicts response to D2 antagonists.
Approximately one-third of patients with treatment resistance show no increase in striatal dopamine synthesis capacity.
Emerging evidence implicates glutamatergic, GABAergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as oxidative stress, mitochondrial dysfunction, and neuroinflammation.
The efficacy of xanomeline-trospium—a muscarinic M1/M4-preferring agonist lacking direct D2 antagonism—demonstrates that nondopaminergic mechanisms can reduce psychotic symptoms.
Neurochemically distinct subgroups may cut across overlapping clinical phenotypes, supporting a pluralistic rather than a single final common pathway model.

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