Obesity Pillars · Published 2026-07-14 · DOI 10.1016/j.obpill.2026.100302
Spencer Nadolsky, Summer Kessel, Zachary A. Krumm, Grant M. Tinsley
Introduction: Glucagon-like peptide-1 receptor agonists (GLP1RAs) have demonstrated substantial efficacy for obesity and metabolic disease treatment, with emerging evidence suggesting effects on reward-processing pathways and motivated behaviors. Although reductions in food craving and addictive behaviors may be beneficial, some patients anecdotally report diminished motivation and anhedonia-like symptoms during high-dose therapy. This case series highlights a potentially underrecognized neurobehavioral effect associated with high-dose tirzepatide and explores clinical management strategies. Case presentation: Three female patients with obesity treated with high-dose tirzepatide (15 mg·week−1) reported reduced motivation, emotional “flatness,” or loss of interest in exercise and previously enjoyable activities despite successful weight loss. Two patients had no prior history of mood disorders, while one patient had a history of depression and anxiety. Symptoms were described as distinct from depressive episodes and emerged after prolonged treatment at or near maximal dosing. One patient independently noted symptom improvement after temporary discontinuation and dose reduction surrounding a medical procedure. Interventions and outcomes: All patients underwent tirzepatide dose reduction to 10 mg·week−1 or lower. Two patients experienced marked improvement in motivation and enjoyment of daily activities after dose reduction alone. One patient required adjunctive bupropion therapy, which produced additional symptomatic improvement. Re-escalation of the tirzepatide dose in one patient resulted in recurrence of symptoms without additional weight loss benefit, whereas subsequent dose reduction restored motivation while maintaining weight-loss outcomes. Across all cases, symptom improvement occurred alongside continued weight maintenance or further weight reduction. Conclusion: This case series suggests that anhedonia-like symptoms may occur in a subset of patients receiving high-dose tirzepatide, potentially related to GLP1RA-mediated modulation of mesolimbic dopaminergic pathways. Clinicians should consider monitoring for changes in motivation and reward perception during treatment, particularly at higher doses. Dose reduction, with or without adjunctive dopaminergic therapy such as bupropion, may alleviate symptoms while preserving therapeutic benefits.
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Nadolsky, S., Kessel, S., Krumm, Z., et al. (2026). Resolution of anhedonia-like symptoms in patients treated for obesity with tirzepatide: A three-case series. Obesity Pillars. https://doi.org/10.1016/j.obpill.2026.100302