Toward a Pluralistic Model for the Schizophrenia Spectrum-Dopamine and Beyond.

Abstract

Importance Dopaminergic dysregulation has been considered the final common pathway for pathophysiology of schizophrenia and related disorders (SRD). However, this model does not adequately explain treatment resistance, cognitive impairment, negative symptoms, and marked biological heterogeneity across patients. Objective To examine whether SRD are best conceptualized as resulting from a final common dopaminergic pathway or from several partially independent neurochemical mechanisms and to evaluate the implications of these models for treatment development. Evidence Review Neuroimaging, postmortem and genetic investigations, pharmacologic challenge paradigms, clinical trials, and animal models published between 1980 and 2025 were synthesized. Studies were identified through expert knowledge and targeted searches of PubMed and related databases. Systematic reviews, meta-analyses, and multimodal convergent findings were emphasized. Evidence was appraised qualitatively with attention to consistency, specificity, and translational relevance. Findings Positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, which predicts response to dopamine D2 receptor antagonists. However, approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. Increasing evidence implicates glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes including oxidative stress, mitochondrial dysfunction, and neuroinflammation. The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes. Conclusions and Relevance Dopaminergic hyperactivity may be a key mechanism for core psychotic symptoms in many patients, but it is unlikely that dopamine dysregulation is a universal final common pathway across symptom domains. A pluralistic model-recognizing multiple interacting neurochemical and cellular processes-may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes.