2026 ECNP Congress

PS01-1191

Psychometabolic outcomes of incretin-based therapy in a real-world cross-diagnostic psychiatric cohort

Maria Beatrice Rescalli — A. Cuomo, D. Koukouna, P. Carmellini, C. Libri, M. Pinzi, S. Cicali, S. Pardossi, A. Fagiolini · University of Siena, Department of Molecular Medicine- School of Medicine- University of Siena- 53100 Siena- Italy, Siena, Italy

2026 ECNP Congress

Background: Incretin-based therapies, including GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists, are established treatments for obesity and metabolic dysregulation [1]. Translational evidence suggests potential effects on inflammatory, reward and brain–energy pathways, but real-world psychiatric data remain limited [2,3]. This study aimed to characterise 6-month psychometabolic outcomes in a cross-diagnostic psychiatric cohort treated with incretin-based therapy, focusing on body weight, BMI, depressive symptom burden, suicidal ideation and tolerability.

Methods: We conducted a retrospective single-centre longitudinal cohort study within an integrated psychiatric–metabolic pathway. A total of 101 adults with mood-spectrum, psychotic or other psychiatric diagnoses received liraglutide, semaglutide or tirzepatide and were assessed at baseline and after 1, 3 and 6 months. Outcomes included body weight, BMI, change in mean MADRS score, MRS, suicidal ideation and gastrointestinal tolerability. Longitudinal change in continuous outcomes was estimated using covariate-adjusted mixed-effects models; change in suicidal ideation was tested with McNemar.

Results: At baseline patients showed substantial psychometabolic burden (mean age 41.6 years; 64.4% female; BMI 36.0 kg/m²; mean MADRS 21.7; MRS 4.7; suicidal ideation 13.9%). Adjusted month-6 changes were −15.5 kg for body weight (95% CI −16.5 to −14.5), −5.4 kg/m² for BMI, −10.4 points for MADRS (95% CI −11.2 to −9.6) and −2.9 points for MRS; all p<0.001. By month 6, 79.2% of patients had lost ≥10% body weight, 73.3% had dropped at least one BMI class, 43.5% had exited Obesity III and 20.8% had reached normal weight. Mean MADRS score — interpreted here as overall depressive burden across the cross-diagnostic cohort — declined monotonically across the four assessment timepoints, and no patient showed emergent depressive worsening at any visit. Suicidal ideation decreased from 13.9% to 1.0% (13/14 cleared, no de novo cases; McNemar p<0.001), with no suicide attempts and no emergent ideation observed. Gastrointestinal adverse events occurred in 54.5% of patients with no discontinuations. All four continuous outcomes showed large within-subject effect sizes (Cohen’s dz 0.8–2.0), with monotonic improvement across the four timepoints and no plateau or rebound by month 6.

Limitations: This study is limited by its retrospective single-centre design, diagnostic and pharmacological heterogeneity, and limited statistical power for safety outcomes. Importantly, although causality in the observed improvement of psychiatric symptoms cannot be inferred because of the absence of a control group and the concomitant use of psychotropic medications specifically aimed at treating psychiatric symptoms, incretinbased therapy was not associated with psychiatric deterioration in this real-world cohort. No suicide attempts or de novo suicidal ideation were observed, and substantial weight loss occurred despite the frequent use of concomitant psychotropic medications with known weight-promoting liability.

Conclusions: In this retrospective real-world psychiatric cohort, incretin-based therapy was associated with substantial 6-month metabolic improvement and a parallel reduction in mean MADRS score, with no patient showing emergent depressive worsening or new suicidal ideation. These findings support the safety profile of incretin-based therapy in patients with severe psychiatric disorders and motivate prospective controlled studies with formal mediation and biomarker analyses.

References

  1. Wong HJ, Sim B, Teo YH, et al. Efficacy of GLP-1 Receptor Agonists on Weight Loss, BMI, and Waist Circumference for Patients With Obesity or Overweight: A Systematic Review, Meta-analysis, and Meta-regression of 47 Randomized Controlled Trials. Diabetes Care. 2025;48(2):292-300. doi:10.2337/dc24-1678
  2. Chen X, Zhao P, Wang W, Guo L, Pan Q. The Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis. Am J Geriatr Psychiatry. 2024 Jan;32(1):117-127. doi: 10.1016/j.jagp.2023.08.010
  3. Bak M, Campforts B, Domen P, van Amelsvoort T, Drukker M. Glucagon-like peptide agonists for weight management in antipsychotic-induced weight gain: A systematic review and meta-analysis. Acta Psychiatr Scand. 2024; 150(6): 516-529. doi:10.1111/acps.13734