Does Dysregulation Of The Indirect Pathway Contribute To The Pathophysiology Of Catatonia Through Neurotransmitter Imbalance?

Abstract

Objective: Catatonia is a complex neuropsychiatric syndrome characterized by motor, cognitive, and emotional disturbances, affecting approximately 7-38% of psychiatric inpatients. Despite its prevalence, it is frequently underrecognized in clinical practice. The objective of this narrative review is to explore the hypothesis that dysfunction of the basal ganglia's indirect pathway-mediated by neurotransmitter imbalances-plays a central role in the pathophysiology of catatonia.

Method: This narrative review synthesized clinical, neuroimaging, and preclinical studies identified through PubMed, Embase, and PsycINFO (1980-April 2025) using terms related to catatonia, basal ganglia pathways, and neurotransmitters. Studies on GABA, dopamine, glutamate, serotonin, and acetylcholine in catatonia or indirect pathway function were included. Findings were conceptually integrated to link neurotransmitter dysregulation with catatonic features, considering age-related effects and circuit models.

Results: Evidence indicates that impaired inhibitory control within the indirect pathway is a core mechanism underlying catatonia. Key findings include reduced GABAergic tone, dopamine D2 receptor dysfunction, glutamatergic hyperactivity, and altered serotonergic and cholinergic modulation. These disruptions collectively contribute to clinical features such as stupor, rigidity, and stereotypies. While benzodiazepines, which enhance GABA-A receptor activity, remain the first-line treatment, preliminary evidence suggests that NMDA antagonists, dopamine agonists, and serotonergic/cholinergic modulators may also offer therapeutic benefits, though these are not yet widely implemented.

Conclusions: By integrating neurocircuit-based models with observed clinical phenomena, this review proposes a unifying framework to understand the neural basis of catatonia. Clarifying the role of indirect pathway dysfunction could support the development of targeted, mechanism-based interventions, ultimately improving recognition and treatment outcomes for this often-debilitating syndrome.

Keywords: GABA; basal ganglia pathways; benzodiazepines; catatonia; dopamine; glutamate; neurotransmitters; pathophysiology; serotonin.

Figure 1.

Pathophysiological and therapeutic insights related to the indirect pathway in catatonia

Figure 2.

This schematic illustrates the key neurotransmitters and receptors involved in the indirect pathway of the basal ganglia