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CHANGES IN DEPRESSIVE SYMPTOMS WITH TIRZEPATIDE IN INDIVIDUALS WITH MODERATE-TO-SEVERE METHAMPHETAMINE USE DISORDER

Virgilio Garza — Amrita Ghose1, Teresa Slettebo1, Nandini Jha1, Elizabeth Dedrick1, Snoben Kuruvila1, Manish Jha1 1The University of Texas Southwestern Medical Center

2026 ASCP Annual Meeting

Background

Individuals with moderate-to-severe methamphetamine use disorder (MtUD) often report depressive symptoms. In a recent publication (Jha et al. 2025 Journal of Clinical Psychiatry), we found that over 75% of individuals with MtUD enrolled in an RCT experienced mild-to-moderate severity of depression. Furthermore, improvement of depressive symptoms were associated with greater likelihood of subsequent reduction in methamphetamine use. Here, we evaluate the change in depressive symptoms with tirzepatide, a dual agonist of glucagon-like peptide 1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR), in individuals with moderate-to-severe MtUD. With the emerging interest in tirzepatide and similar medications as potential treatments for substance use disorders, findings of this report may inform their broader effect on mental health-related outcomes in individuals with MtUD.

Methods

Individuals with moderate-to-severe MtUD who participated in an open-label trial of 32-week-long treatment with tirzepatide for a weight-related indication (NCT06745128) were included. Self-report symptoms of depression were assessed with the 16-item Quick Inventory of Inventory of Depressive Symptomatology Self-Report version (QIDS-SR) at baseline (i.e., prior to first injection) and weekly thereafter during the 32-week treatment period. Repeated measures mixed model analyses were used to measure changes in QIDS-SR domains.

Results

Of the 35 individuals enrolled, 25 had a QIDS-SR score > 5 (indicating mild or greater symptoms severity) and were included in this report [16 females/9 males; mean (standard deviation, SD) age = 44.6 (8.2) years]. Mean (SD) QIDS-SR score at baseline was 10.2 (3.55). There was a significant reduction in depressive symptoms (Bonferroni adjusted p < 0.05) after 5 weeks of treatment [estimate(β)= -4.5, standard error (SE)= 1.11, p < 0.0001] which persisted during the entirety of treatment period. Numerically maximal improvement was noted after 20 weeks of treatment (β= -6.0, SE= 1.14, p < 0.0001). At week 20, 48% of those with a baseline QIDS-SR score of > 5 met criteria for both response (defined by at least a 50% score reduction) and remission (defined by attaining a score of five or lower). In addition, 8% of individuals met criteria for remission but not response, and 8% of individuals met criteria for response but not remission.

Conclusions

In this first study of a dual GLP-1R/GIPR agonist in individuals with moderate-tosevere MtUD, we observed marked reduction in depressive symptoms with 5 mg/week or higher doses of tirzepatide. These improvements persisted for the entirety of treatment period and were observed before meaningful weight reductions were observed. Future placebo-controlled trials are needed to validate these findings.