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Toward a Pluralistic Model for the Schizophrenia Spectrum-Dopamine and Beyond.
Matcheri S Keshavan1, Henry A Nasrallah2, Anissa Abi-Dargham3
1Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
JAMA Psychiatry
|July 8, 2026
Summary
Dopamine dysregulation may explain some schizophrenia symptoms, but a pluralistic model is needed to address treatment resistance and patient heterogeneity. Future treatments require biomarker-informed approaches for better outcomes.
Area of Science:
- Neuroscience
- Psychiatry
- Pharmacology
Background:
- Schizophrenia and related disorders (SRD) pathophysiology has been linked to dopaminergic dysregulation.
- This model inadequately explains treatment resistance, cognitive deficits, negative symptoms, and patient heterogeneity.
Purpose of the Study:
- To determine if SRD result from a single dopaminergic pathway or multiple neurochemical mechanisms.
- To evaluate the implications for developing new treatments for SRD.
Main Methods:
- Synthesis of neuroimaging, genetic, postmortem, and clinical data (1980-2025).
- Inclusion of systematic reviews, meta-analyses, and multimodal findings.
- Qualitative appraisal of evidence for consistency, specificity, and translational relevance.
Main Results:
- Positive psychotic symptoms correlate with increased striatal dopamine, predicting response to D2 antagonists.
- Approximately one-third of patients show treatment resistance and normal dopamine synthesis.
- Evidence implicates glutamatergic, GABAergic, serotonergic, and other systems, alongside non-neurotransmitter processes.
Conclusions:
- Dopaminergic hyperactivity is key for some psychotic symptoms but not a universal pathway.
- A pluralistic model accounting for multiple interacting mechanisms better explains SRD heterogeneity.
- Novel treatment development may rely on biomarker stratification and mechanism-based trials.
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