# Do GLP-1 Drugs Cause Depression or Anxiety? The Trials Say No, the Records Say Yes Pooled STEP trial data found PHQ-9 depression scores better on semaglutide than placebo (difference -0.56). A matched cohort reported psychiatric disorders at 2.02 instead. Publisher: This GLP Editorial Team Canonical: https://thisglp.com/research/do-glp1-drugs-cause-depression Updated: 2026-10-26 Published: 2026-09-17 [← Research](https://thisglp.com/research) Safety # Do GLP-1 Drugs Cause Depression or Anxiety? The Trials Say No, the Records Say Yes Randomized trials found depression scores slightly better on semaglutide than placebo. Health records report the opposite, and the comparison group explains most of the gap. [This GLP Editorial Team](https://thisglp.com/about)September 20267 min readUpdated September 2026 Records above the line, randomized trials below · 1.0 · records: depression · records: anxiety · records: any psychiatric · trials: worsening · The trials found worsening LESS likely, not more. **Research, not medical advice.** This GLP is independent and educational. Nothing here is a substitute for individualized care from a licensed clinician, and reading it creates no doctor–patient relationship. Talk to your own provider before starting, stopping, or changing any medication, peptide, or therapy. See our [methodology](https://thisglp.com/methodology) and [terms](https://thisglp.com/terms). ## Key takeaways - Randomized trials found the opposite of what health records show. Pooled across STEP 1, 2 and 3, depression scores were slightly better on semaglutide than placebo. - Participants on semaglutide were less likely to shift into a worse depression category, at odds of 0.63 (95% CI 0.50 to 0.79). - A matched cohort in Korean hospitals reported higher rates instead: psychiatric disorders 2.02, anxiety 2.39, depressive disorder 3.42. - The cohort's comparison group was people who never started the drug — and starting one means more clinical contact, which means more recorded diagnoses. The two study designs point in opposite directions, and the reason is the comparison group. The randomized evidence is reassuring and narrow; the observational evidence is alarming and confounded. This site reads that split the same way in [what pooling does to psychiatric risk estimates](https://thisglp.com/research/semaglutide-psychiatric-risk-pooling). For the drug-specific question, the [tirzepatide anxiety and depression evidence](https://thisglp.com/research/can-tirzepatide-cause-anxiety) separates clinical-trial findings from medical-record associations. ## What the randomized trials found A post hoc analysis pooled the STEP 1, 2 and 3 trials — 3,377 participants — plus 304 from STEP 5 [\[1\]](https://thisglp.com/research/do-glp1-drugs-cause-depression#ref-1). Depression was measured with the PHQ-9 and suicidal ideation with the Columbia-Suicide Severity Rating Scale. Baseline scores were 2.0 and 1.8, which is no or minimal symptoms. At week 68 they were 2.0 on semaglutide and 2.4 on placebo, an estimated treatment difference of -0.56 with an interval from -0.81 to -0.32. Participants on semaglutide were also less likely to move into a more severe PHQ-9 category, at odds of 0.63. One percent or fewer of participants reported suicidal ideation or behavior, with no difference between groups. Who those trials excluded The paper's own title says it: people without known major psychopathology. Anyone with significant existing mental illness was not enrolled, so these results do not speak to that group. A reassuring number from a trial that screened out the people most at risk is a reassuring number about everyone else. This site set out the same population problem in [the mortality gap in serious mental illness](https://thisglp.com/research/a-mortality-gap-in-serious-mental-illness). ## What the health records found A multicenter cohort across 13 South Korean hospitals compared 2,357 semaglutide and 6,953 liraglutide initiators against propensity-matched people who started neither [\[2\]](https://thisglp.com/research/do-glp1-drugs-cause-depression#ref-2). Hazard ratios against matched people who did not start a GLP-1 drug. | Outcome | Semaglutide | Liraglutide | | --- | --- | --- | | Psychiatric disorders overall | 2.02 (1.30–3.14) | 1.66 (1.36–2.03) | | Anxiety disorder | 2.39 (1.22–4.71) | 1.68 (1.45–1.96) | | Depressive disorder | 3.42 (1.51–7.74) | 1.51 (1.14–2.00) | | Gastrointestinal dysmotility | 3.91 (1.42–10.82) | — | Hazard ratios against matched people who did not start a GLP-1 drug. 13 South Korean hospitals, 2018–2025 Read the widths. An interval from 1.42 to 10.82 is compatible with a small effect and an enormous one, and the two largest point estimates are the two least precise. The liraglutide figures, drawn from three times as many initiators, are smaller and tighter. ## Why the designs disagree Someone who starts a weight-management drug has usually just seen a doctor, is being monitored, and is often distressed about their weight. Their matched non-initiator is not necessarily doing any of those things. Higher recorded rates of anxiety and depression in a group with more clinical contact can reflect more diagnosis rather than more disease. Matching on baseline variables does not remove that, because the contact happens after matching. This site set the general problem out in [the trials and the records disagreeing on Alzheimer's](https://thisglp.com/research/do-glp1-drugs-help-alzheimers), where the same shape appears with the signs reversed. A randomized trial removes the problem by construction: both arms are in the same study, seen on the same schedule, assessed with the same instrument. That is why the PHQ-9 result carries more weight here than the hazard ratios, despite the hazard ratios being larger and louder. ## When the comparison is another drug A Medicare target trial emulation removed the never-started group [\[3\]](https://thisglp.com/research/do-glp1-drugs-cause-depression#ref-3). It matched adults aged 66 or older with type 2 diabetes who started a GLP-1 against people starting another diabetes drug. Against DPP-4 inhibitors, across 13,711 matched pairs, the depression hazard ratio was 0.90 (0.82 to 0.98). Against SGLT2 inhibitors, across 14,665 pairs, it was 1.07 (0.98 to 1.18). Same drug class, same outcome, and the comparator decided the direction. A 2026 meta-analysis pooled trials, cohorts and pharmacovigilance studies of semaglutide [\[4\]](https://thisglp.com/research/do-glp1-drugs-cause-depression#ref-4). The pooled risk ratio for depression was 1.25, with an interval from 0.95 to 1.65. Anxiety came in at 1.22 (0.93 to 1.60). Heterogeneity was extreme, at an I² of 98 percent. The authors call the result an absence of detected risk, not proof of no risk. ## What is still open The authors of the cohort add their own caveat: semaglutide-associated vision impairment and liraglutide-associated hepatic impairment lost significance in some sensitivity analyses. And nobody has run a randomized trial in people with established serious mental illness, which is the group a reader worrying about this is most likely to belong to. Until somebody does, the honest position is narrow. The drug has not been shown to worsen mood in people without a psychiatric history, and it has not been properly tested in people with one. The adjacent question of motivation is in [a secondary finding on motivation](https://thisglp.com/research/motivation-in-depression-a-secondary-finding). ## Frequently asked Do GLP-1 drugs cause depression? Randomized trials say no. Pooled across STEP 1, 2 and 3, PHQ-9 depression scores were slightly better on semaglutide than placebo, and participants were less likely to shift into a worse category. Why do some studies report higher rates? Those are health-record studies comparing people who started the drug against people who did not. Starting one usually means more clinical contact, and more contact means more recorded diagnoses. Does the comparison group change the answer? Yes. In older Medicare patients with type 2 diabetes, the depression hazard ratio for a GLP-1 was 0.90 against DPP-4 inhibitors and 1.07 against SGLT2 inhibitors. Only the first was statistically significant. What about suicidal thoughts? In the pooled trials, one percent or fewer of participants reported suicidal ideation or behavior, with no difference between semaglutide and placebo. Does this apply if I already have depression? Not directly. The randomized analysis covered people without known major psychopathology, so it does not speak to anyone with established serious mental illness. No trial has tested that group properly. ## Sources 1. \[1\] Wadden TA, Brown GK, Egebjerg C, Frenkel O, Goldman B, Kushner RF (2024). Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials JAMA Internal Medicine. [PMID 39226070](https://pubmed.ncbi.nlm.nih.gov/39226070/) 2. \[2\] Park J, Kim JH, Kim YS, Lim G, Song HJ, Rhee SY (2026). GLP-1 Receptor Agonists for Weight Loss and Risk of Major Safety Outcomes: A Multicentre Cohort Study Diabetes, Obesity and Metabolism. [PMID 42410329](https://pubmed.ncbi.nlm.nih.gov/42410329/) 3. \[3\] Tang H, et al. (2025). Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes : A Target Trial Emulation Study Annals of Internal Medicine. [PMID 39993315](https://pubmed.ncbi.nlm.nih.gov/39993315/) 4. \[4\] Bhaduri G, et al. (2026). Burden and Risk of Depression in Patients Receiving Semaglutide: A Systematic Review and Meta-Analysis Clinical Obesity. [PMID 42584177](https://pubmed.ncbi.nlm.nih.gov/42584177/) ## More in Safety - [ Medication list · Check combinations · Fluid loss · Changes kidney risk · Pharmacist · Choose a safe option ### Can You Take Ibuprofen With Ozempic? Check Kidney and Stomach Risks ](https://thisglp.com/research/can-you-take-ibuprofen-with-ozempic) - [ 1.9% · Placebo · 8.5% · Ozempic 0.5 mg · 8.8% · Ozempic 1 mg ### Does Ozempic Cause Diarrhea? Rates, Timing, and When to Call ](https://thisglp.com/research/does-ozempic-cause-diarrhea) - [ Sit down · Prevent a fall · Check context · Glucose and fluids · Get help · Severe symptoms ### Does Ozempic Cause Dizziness? What to Check First ](https://thisglp.com/research/does-ozempic-cause-dizziness)