Toward a systems model of catatonia: Circuits, neurochemistry, immune perturbation, and biological heterogeneity

Catatonia is a transdiagnostic psychomotor syndrome that occurs across psychiatric, neurologic, neurodevelopmental, autoimmune, and general medical conditions. This clinical breadth argues against schizophrenia-centered models and suggests that catatonia is better understood as a final common phenotype of disturbed psychomotor regulation rather than the expression of a single disease process. Recent dimensional work further indicates that catatonia is internally heterogeneous, with hypokinetic, hyperkinetic, and aberrant-volitional components that often overlap within the same episode. In this review, we evaluate whether current evidence supports conceptualizing catatonia as a disorder of distributed psychomotor network dysfunction and examine how circuit, neurochemical, immune, metabolic, and genetic findings converge on that model. The best-supported mechanistic model to date comes from neuroimaging studies implicating cortico-striatal-thalamic, cortico-cerebellar, orbitofrontal, cingulate, and motor-premotor networks. Nonetheless, key limitations remain, including the overrepresentation of schizophrenia-spectrum samples and limited acute-state data. Neurochemical evidence supports the notion of interacting disturbances in GABAergic inhibition, glutamatergic/NMDA-mediated excitation, and dopaminergic modulation rather than a single-transmitter explanation. Immune mechanisms are particularly relevant in subgroups, especially in autoimmune encephalitis and inflammatory CNS conditions, whereas peripheral biomarkers remain nonspecific. Genetic and developmental data support vulnerability rather than unitarity, implicating synaptic, GABAergic, and microglial processes without a single syndrome-specific architecture. Taken together, the evidence supports a convergent model in which diverse upstream liabilities destabilize shared psychomotor networks, producing a recognizable but heterogeneous syndrome. No single biomarker or unified mechanism fully accounts for catatonia across contexts. Future progress will depend on dimensional phenotyping, multimodal biomarker integration, and subtype-sensitive treatment research.