A group of senior schizophrenia researchers has synthesised neuroimaging, postmortem, genetic, pharmacological challenge and trial evidence from 1980 to 2025 to ask whether the schizophrenia spectrum is one dopaminergic disease or several partly independent ones. Their answer is the second.
The case rests on things clinicians already see. Positive psychotic symptoms do track raised presynaptic dopamine in the associative striatum, and that predicts response to D2 antagonists. But about a third of patients are treatment-resistant and show no rise in striatal dopamine synthesis capacity at all — they are not under-dosed, they are differently ill. Glutamatergic, GABAergic, serotonergic, cholinergic, endocannabinoid and opioidergic systems are all implicated, alongside oxidative stress, mitochondrial dysfunction and neuroinflammation. The clinching pharmacological argument is that xanomeline-trospium, a muscarinic M1/M4-preferring agonist with no direct D2 antagonism, reduces psychotic symptoms.
For practice this reframes what non-response means. Escalating a D2 antagonist in a patient who never had raised striatal dopamine synthesis is not a trial of adequate treatment; it is a category error that buys side effects. It also explains why clozapine remains the only reliable answer in resistance, and why the arrival of a non-dopaminergic mechanism matters beyond its own efficacy figures.
The practical limit is that no biomarker yet tells you which patient you are facing at first presentation. The review is explicit that biomarker-informed stratification is the work ahead, not a tool available now.
- Treat persistent non-response after two adequate antipsychotic trials as a different illness state, not a dosing problem
- Move to clozapine on schedule rather than cycling a third D2 antagonist
- Record negative symptoms and cognition separately from positive symptoms — they do not share the dopaminergic mechanism
- Follow the availability and cost of muscarinic agents in India before discussing them with families
- Do not offer polygenic or imaging stratification; it does not yet exist clinically
Why it matters
It undercuts the reflex to push the dose in non-response, and gives a mechanistic reason why some patients were never going to answer a D2 blocker.
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