2026 ECNP Congress

PS04-4190

FKBP5 rs3800373 genotype is associated with antipsychotic treatment response in a Greek schizophrenia-spectrum cohort

Georgios Papazisis — C. Ntenti, A. Goulas, G. Garyfallos · Aristotle University of Thessaloniki, Laboratory of Clinical Pharmacology- School of Medicine, Thessaloniki, Greece

2026 ECNP Congress

Introduction

Inter-individual variability in antipsychotic treatment response remains a major challenge in psychotic disorders. Genetic variation in stress-related pathways, including FKBP5—a stress-related gene that regulates glucocorticoid receptor sensitivity and the biological response to stress—has been implicated in psychiatric phenotypes1,2,3 and treatment outcomes4,5, however, its role in modulating antipsychotic response remains incompletely understood.

Aims

To investigate whether the FKBP5 rs3800373 polymorphism is associated with clinical response to antipsychotic treatment, and to examine the potential influence of concomitant pharmacological treatments.

Methods

Data from 164 consecutively presenting patients with schizophrenia spectrum disorders at the 2nd Psychiatric Clinic, Aristotle University of Thessaloniki, were analysed in this observational study.

Diagnoses included schizophrenia and related psychotic disorders according to ICD-10 criteria. Treatment response was defined as the corrected percentage change (decrease) in Positive and Negative Syndrome Scale (PANSS), and the change in Calgary Depression Scale scores. Antipsychotic treatment was administered according to clinical need. Genotyping for FKBP5 rs3800373 was performed and analysed under a dominant model (AA vs C allele carriers). Due to non-normal distribution, non-parametric tests (Mann–Whitney and Kruskal–Wallis) were applied. General linear models were used to adjust for age, sex, and concomitant medications. Associations between genotype and treatment allocation were assessed using chi-square tests.

Results

Patients carrying the AA genotype showed significantly greater reduction in PANSS total scores compared to C allele carriers (23.46 ± 15.89 vs 16.17 ± 13.88; Mann–Whitney p = 0.004, effect size r ≈ 0.25). This finding remained significant after adjustment for age, sex, and concomitant pharmacological treatments (p = 0.002, η² ≈ 0.07). In the three-genotype model, a significant overall effect was observed (Kruskal–Wallis p = 0.010), supporting a dose–response relationship. Subscale analyses showed weaker effects (positive symptoms p = 0.048, r ≈ 0.17; general psychopathology p = 0.044, r ≈ 0.17), which did not remain significant after correction for multiple comparisons, while negative symptoms showed no association (p = 0.664).

No significant effects of antipsychotic class were observed. Neither first-generation antipsychotic (FGA; p = 0.051 in adjusted models) nor second-generation antipsychotic (SGA; p = 0.826) treatment was significantly associated with response. Benzodiazepines (p = 0.965), antidepressants (p = 0.105), and mood stabilisers (p = 0.117) also showed no significant effects. No significant interaction between FKBP5 genotype and antipsychotic class was detected (p = 0.970), indicating that the observed genetic effect is independent of treatment type. Although genotype was associated with FGA use (p = 0.017), adjustment for this factor did not alter the main finding.

Conclusions

The FKBP5 rs3800373 polymorphism is associated with antipsychotic treatment response, with AA carriers demonstrating greater clinical improvement. This effect is consistent across analytical approaches and appears independent of pharmacological treatment class. Subscale findings were weaker and did not survive multiple testing correction, suggesting that the primary effect relates to overall symptom reduction. These findings support a role for stress-related genetic mechanisms in treatment response, although replication and functional studies are required to establish clinical relevance.

References

1.Kaul D, Edmond KZ, Czamara D, Martinelli S, Ködel M, Gassen NC, Tao R, Kleinman JE, Hyde TM, Binder EB, Matosin N. FKBP5 splice variant alterations in the human cortex of psychiatric disorders. J Psychiatr Res. 2026 Jun;197:330-339. doi: 10.1016/j.jpsychires.2026.03.016. Epub 2026 Mar 12. PMID: 41849885. 2.Arancibia M, Manterola M, Ríos U, Moya PR, Moran-Kneer J, Bustamante ML. The rs1360780 Variant of FKBP5: Genetic Variation, Epigenetic Regulation, and Behavioral Phenotypes. Genes (Basel). 2025 Mar 11;16(3):325. doi: 10.3390/genes16030325. PMID: 40149476; PMCID: PMC11941772. 3.Stramecki F, Misiak B, Gawęda Ł, Prochwicz K, Kłosowska J, Samochowiec J, Samochowiec A, Pawlak E, Szmida E, Skiba P, Cechnicki A, Frydecka D. The Moderating Role of the FKBP5 Gene Polymorphisms in the Relationship between Attachment Style, Perceived Stress and Psychotic-like Experiences in Non-Clinical Young Adults. J Clin Med. 2022 Mar 15;11(6):1614. doi: 10.3390/jcm11061614. PMID: 35329940; PMCID: PMC8953491. 4.Theodoridou D, Tsiantis CO, Markozannes G, Chondrou V, Vlaikou AM, Karampas A, Georgiou G, Sgourou A, Filiou MD, Syrrou M, Petrikis P. mRNA levels of HPA axis mediators in drug-naïve, first episode psychosis patients before and after antipsychotic treatment. Int J Psychiatry Clin Pract. 2025 Nov;29(4):209-221. doi: 10.1080/13651501.2025.2549306. Epub 2025 Aug 22. PMID: 40844969. 5.Ejiohuo O, Szczepankiewicz A. Genetic Polymorphisms Associated with Lithium Response in Bipolar Disorder: An Integrative Review and In Silico Protein-Protein Interaction Analysis. Pharmaceuticals (Basel). 2026 Mar 20;19(3):511. doi: 10.3390/ph19030511. PMID: 41901356; PMCID: PMC13028772.