Rethinking the Dopamine Hypothesis: Upstream Circuits and Muscarinic Treatment in Psychosis

CONFERENCE REPORTER

Dopamine was central to the pathophysiology of psychosis, but it probably represented a downstream effect rather than the intrinsic problem, according to Jose Rubio, MD, PhD. For decades, evidence had implicated excess dopamine synthesis in the striatum of patients with psychosis, particularly those with schizophrenia. Rubio said the primary dysfunction more likely arose upstream of the dopamine synapse, in circuits such as excessive glutamatergic input to the midbrain dopamine neurons and dysregulation of the balance between GABA and glutamate in the cortex. Understanding of these mechanisms evolved in several directions over the decades, Rubio said.

Dopamine appeared most relevant to psychosis specifically rather than to the full syndrome of schizophrenia. Rubio proposed that dopamine signaled relevant information and helped differentiate neutral from salient stimuli; in psychosis, aberrant dopamine discharge unpaired from relevant stimuli produced a sense that everything was relevant. Antipsychotics that blocked D2 receptors were effective because they countered this aberrant salience, but they did not address the upstream dysfunction, which also left cognitive deficits and negative symptoms unexplained.

Imaging studies using different modalities repeatedly found a group-level association between treatment resistance and intact dopamine function, and between treatment response and excess dopamine, although Rubio cautioned that the relationship was not absolute.¹ Some investigators reasoned that D2 blockers failed when symptoms arose from a nondopaminergic mechanism, but Rubio said understanding of these relationships still had a long way to go.

Muscarinic agents acted on that upstream dysfunction, ultimately decreasing dopamine release. Through M1 receptors, Rubio said, "they may normalize the excitation inhibition balance in the cortex so that those cortical neurons that go to the midbrain are not firing excessively." M4 receptors acted subcortically and probably made dopaminergic neurons less excitable, reducing dopamine synthesis. By either mechanism, the net effect was a decrease in the amount of dopamine released, according to Rubio. Rubio considered the effect of these drugs on cognition and negative symptoms reasonably well established, noting that "other drugs like the muscarinics they have an effect on cognition and negative symptoms in a way that the other drugs don't."²

Dr Rubio is an assistant professor of psychiatry at the Zucker School of Medicine at Hofstra University.

References

1. Demjaha A, Murray RM, McGuire PK, et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry. 2012;169(11):1203-1210.

2. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.