Pluralistic Model Proposed for Schizophrenia Spectrum: Beyond Dopamine

Key Points

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.

Study Snapshot

Type: Narrative review (expert synthesis)
Data sources: Neuroimaging, postmortem, genetic, pharmacologic challenge, clinical trial, and animal model studies (1980–2025)
Key finding: Dopamine hyperactivity is not a universal final common pathway; a pluralistic model better accounts for heterogeneity and treatment resistance.
Citation: Keshavan MS et al. JAMA Psychiatry. 2026. PMID: 42418174.

Introduction

For decades, the dopamine hypothesis has dominated the understanding of schizophrenia spectrum disorders (SRD). However, a comprehensive narrative review published in JAMA Psychiatry challenges this framework, advocating for a pluralistic model that incorporates multiple neurochemical and cellular pathways.

Evidence Summary

According to the review, positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, a finding that predicts response to dopamine D2 receptor antagonists. Yet approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. The authors highlight growing evidence for contributions from glutamatergic, GABAergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes such as oxidative stress, mitochondrial dysfunction, and neuroinflammation.

A pivotal example is the efficacy of xanomeline-trospium, a muscarinic M1/M4-preferring agonist that lacks direct D2 receptor antagonism, which suggests that nondopaminergic mechanisms can reduce psychotic symptoms.

Clinical Implications

The pluralistic model implies that future treatment development may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes, requiring targeted therapies rather than a one-size-fits-all dopamine-centric approach.

Expert Perspectives

The authors conclude that “dopamine dysregulation is unlikely to be a universal final common pathway across symptom domains.” They argue that a pluralistic model—recognizing multiple interacting neurochemical and cellular processes—may better account for the heterogeneity seen in SRD and for past translational failures.

Bottom Line

This comprehensive review suggests a paradigm shift toward a pluralistic understanding of schizophrenia spectrum disorders, with direct implications for future treatment development, patient stratification, and clinical trial design.