2026 ECNP Congress

PS03-3053

The relationship between drug-induced Parkinsonism observed in patients with schizophrenia and serum levels of GDNF family ligands

Koray Hamza Cihan — Y. Kır, T. Özdemir Tekeli, S. Elgün Ülkar, M.Ç. Aydemir · Ankara University School of Medicine, Department of Psychiatry, Ankara, Türkiye

2026 ECNP Congress

Introduction: Drug-induced parkinsonism (DIP) in schizophrenia may reflect a biologically distinct vulnerability rather than a purely pharmacological effect. GDNF family ligands (GFLs) — GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN) — regulate dopaminergic neuron survival and plasticity [1]. Despite the established trophic role of GFLs in dopaminergic circuits, their peripheral levels in DIP-complicated schizophrenia (SCZ) remain unexplored. We tested whether GFL profiles identify a distinct DIP subgroup within schizophrenia.

Methods: This cross-sectional, case-control study included 159 participants in three groups (n=53 each): schizophrenia with DIP, schizophrenia without DIP, and healthy controls. All patients met DSM-5 criteria for schizophrenia. DIP was assessed using the Simpson–Angus Scale, and akathisia and tardive dyskinesia were excluded using standard clinical scales. Psychopathology was evaluated with validated rating scales. Serum GDNF family ligand levels were measured using sandwich ELISA. Statistical analyses comprised Kruskal–Wallis tests with Bonferroni post-hoc comparisons, MANCOVA with BMI as covariate (Pillai’s Trace), and Spearman correlations with Benjamini–Hochberg FDR correction.

Results: All GFLs differed significantly between groups (Kruskal–Wallis, all p ≤ .005). NRTN and ARTN were reduced across all schizophrenia patients, indicating a generalized trophic deficit. In contrast, GDNF and PSPN showed a selective reduction in the DIP subgroup, distinguishing it from both non-DIP schizophrenia and controls. BMI-adjusted MANCOVA confirmed a strong group effect (Pillai’s Trace = .303, F(8,306) = 6.830, p < .001, partial η² = .152). BMI exerted no independent effect on GFL levels. Within-patient MANCOVA controlling for BMI and disease duration yielded a significant multivariate group effect (p = .030), though individual between-group differences were not significant after covariate adjustment. Disease duration was a significant negative predictor of GDNF (p = .021), NRTN (p = .032), and PSPN (p = .011) with small-to-moderate effect sizes.

Discussion: The observed GFL pattern suggests a dual mechanism: a generalized trophic deficit in schizophrenia, reflected by reduced NRTN and ARTN, and a selective GDNF-related vulnerability underlying DIP. This pattern is consistent with disease-level dopaminergic trophic impairment in schizophrenia [2]. In contrast, GDNF reduction aligns with its role in nigrostriatal maintenance and extrapyramidal pathophysiology [3], and may indicate impaired compensatory capacity under dopaminergic blockade. These findings raise the possibility that DIP reflects not only drug exposure but also intrinsic vulnerability of dopaminergic trophic regulation in a subset of patients with schizophrenia. The identification of disease duration as a negative predictor of GDNF, NRTN, and PSPN further supports progressive depletion of dopaminergic trophic reserve with illness chronicity.

Conclusion: Selective GDNF reduction identifies a biologically distinct DIP vulnerability in schizophrenia. GFL reductions in SCZ present a clinically stratified pattern: NRTN and ARTN are broadly reduced regardless of motor phenotype, whereas GDNF reduction is specific to the DIP subgroup. Disease chronicity independently predicts trophic reserve decline. Panel-based GFL assessment, integrated with clinical context, represents a promising translational biomarker framework in schizophrenia research.

References

  1. Ducray, A., Krebs, S. H., Schaller, B., Seiler, R. W., Meyer, M., & Widmer, H. R., 2006. GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon. Brain research 1069(1), 104-112.
  2. Ricci V, De Berardis D, Martinotti G, Maina G., 2025. Glial derived neurotrophic factor and schizophrenia spectrum disorders: a scoping review. Curr Neuropharmacol 23(5).
  3. Vaiman EE, Shnayder NA, Khasanova AK, et al., 2022. Pathophysiological mechanisms of antipsychotic-induced parkinsonism. Biomedicines 10(8):2010.