2026 ECNP Congress

PS03-3210

Anticholinergic burden in schizophrenia: associations with symptoms, cognition, and thought disorder

Gabriele Pezzullo — F. Iannotta, C. Ceparano, C. Ricci, A. Catina, D.M. Walter, A. de Bartolomeis, F. Iasevoli · University of Federico II Naples, Department of Neurosciences- Reproductive and Dental Sciences, Napoli, Italy

2026 ECNP Congress

Introduction

Anticholinergic burden reflects cumulative exposure to medications with anticholinergic properties [1]. In schizophrenia, this exposure may derive from the intrinsic anticholinergic activity of some antipsychotics, which differs substantially across agents, and may be further amplified by adjunctive medications used to manage motor, behavioral, or sleep-related symptoms [2]. Although these treatments may be clinically useful, excessive anticholinergic exposure may paradoxically worsen neuropsychiatric functioning [1,3]. Previous research has mainly focused on cognition, whereas associations with psychopathological severity, symptom dimensions, and thought/language disorder remain less explored [3,4].

Aims

We examined associations between anticholinergic burden, psychopathological severity, cognition, thought/language disorder, and treatment-resistant schizophrenia-related differences.

Methods

The sample included 96 patients with schizophrenia: 51 non-treatment-resistant and 45 treatment-resistant schizophrenia (TRS) patients. Anticholinergic burden was quantified using the Anticholinergic Cognitive Burden scale (ACB). Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) total/subscales/five-factor dimensions. Cognition was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS); thought/language disorder with the Thought and Language Disorder Scale (TALD). Analyses used R/RStudio. Multivariable models adjusted for age, sex, education, IQ, illness duration, and antipsychotic dose. Cognitive models additionally adjusted for overall psychopathological severity. ACB was modeled continuously and by tertiles; generalized additive models examined non-linear associations. Holm-corrected p<0.05 was considered significant.

Results

Higher ACB was associated with PANSS total severity, B = 2.88, β = 0.283, p = 0.0423, and PANSS negative symptoms, B = 1.41, β = 0.431, p = 0.00143. In five-factor PANSS, ACB was associated with negative symptoms, B = 1.33, β = 0.437, p = 0.00355, and disorganization, B = 0.529, β = 0.353, p = 0.00508. Tertiles suggested a burden gradient: high versus low burden was associated with greater five-factor negative symptoms, B = 7.24, β = 1.11, p = 0.0108, and disorganization, B = 3.41, β = 1.06, p = 3.91×10⁻⁴; medium versus low burden with disorganization, B = 2.14, β = 0.666, p = 0.0243. Generalized additive models further supported a non-linear association between anticholinergic burden and disorganization, edf = 2.01, p = 0.0047, suggesting a steeper increase at low-to-moderate burden levels. TRS showed higher five-factor disorganization, B = 2.39, β = 0.372, p = 0.00102, and negative symptoms, B = 4.86, β = 0.372, p = 0.00444. These differences were attenuated after ACB adjustment: disorganization, B = 1.65, β = 0.258, p = 0.0893; negative symptoms, B = 2.88, β = 0.221, p = 0.142. Higher ACB was also associated with poorer BACS Symbol Coding, B = −0.140, β = −0.290, p = 0.0352, and higher TALD total score, B = 1.38, β = 0.244, p = 0.0144.

Conclusions

These findings suggest that anticholinergic burden in schizophrenia is associated not only with cognitive performance, but also with psychopathological severity, particularly negative symptoms and disorganization. The attenuation of TRS-related differences after accounting for anticholinergic burden suggests that part of the clinical severity observed in TRS patients may overlap with medication-related anticholinergic exposure. Systematically considering cumulative anticholinergic load may support a more conscious pharmacological choice, balancing symptomatic benefits against potential effects on cognition, disorganization, and overall clinical severity.

References

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  2. Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, McKinzie DL. Muscarinic mechanisms of antipsychotic atypicality. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2003;27(7):1125–1143. doi:10.1016/j.pnpbp.2003.09.008.
  3. Vidal N, Roux P, Urbach M, Belmonte C, Boyer L, Capdevielle D, et al. Comparative analysis of anticholinergic burden scales to explain iatrogenic cognitive impairment in schizophrenia: results from the multicenter FACE-SZ cohort. Frontiers in Pharmacology. 2024;15:1403093. doi:10.3389/fphar.2024.1403093.
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