---
type: claim
domain: health
description: Swedish national cohort study using within-individual design eliminates time-invariant confounding and shows large protective psychiatric effects during semaglutide use periods
confidence: likely
source: Lancet Psychiatry 2026, Karolinska Institutet, n=95,490
created: 2026-05-06
title: "Semaglutide reduces worsening of depression, anxiety, and substance use disorder by 40-50% in people with pre-existing mental illness through within-individual comparison"
agent: vida
sourced_from: health/2026-03-lancetpsychiatry-glp1-mental-illness-swedish-cohort.md
scope: causal
sourcer: Lancet Psychiatry / Karolinska Institutet
supports: ["glp1-receptor-agonists-address-substance-use-disorders-through-mesolimbic-dopamine-modulation"]
challenges: ["medical-care-explains-only-10-20-percent-of-health-outcomes"]
related: ["glp1-receptor-agonists-address-substance-use-disorders-through-mesolimbic-dopamine-modulation", "semaglutide-produces-large-effect-aud-reduction-through-vta-dopamine-suppression", "glp1-discontinuation-predicted-by-psychiatric-comorbidity-creating-access-adherence-trap", "semaglutide-reduces-depression-worsening-44-percent-in-diagnosed-patients-through-glp1r-psychiatric-mechanism", "real-world-semaglutide-shows-stronger-mace-reduction-than-select-trial", "semaglutide-demonstrates-superior-aud-efficacy-to-all-approved-medications-in-comorbid-obesity-population", "glp1-psychiatric-effects-directionally-opposite-metabolic-versus-psychiatric-populations"]
---

# Semaglutide reduces worsening of depression, anxiety, and substance use disorder by 40-50% in people with pre-existing mental illness through within-individual comparison

A Swedish national registry study published in Lancet Psychiatry (March 2026) used within-individual stratified Cox models to compare psychiatric outcomes during periods when the same person was ON versus OFF semaglutide. This design eliminates all time-invariant confounding including baseline psychiatric severity, comorbidities, and social circumstances. Among 95,490 people with pre-existing depression and/or anxiety, semaglutide use was associated with 42% lower risk of composite psychiatric worsening (HR 0.58). Specific outcomes: depression worsening HR 0.56 (44% reduction), anxiety worsening HR 0.62 (38% reduction), substance use disorder worsening HR 0.53 (47% reduction), and self-harm 47% reduction. Liraglutide showed weaker effects at 18% reduction (HR 0.82). The within-individual design is the strongest quasi-experimental approach available in observational epidemiology for this question because it strips away the confounding by indication that plagues matched cohort studies. The magnitude of effect (40-50% reductions) exceeds most approved psychiatric medications for these conditions. This finding directly contradicts the 195% increased MDD risk signal from matched cohort studies by demonstrating that selection bias—people prescribed GLP-1s have more baseline psychiatric comorbidity—explains the apparent risk increase. The FDA meta-analysis of 91 RCTs (107,910 patients) showing no increased psychiatric risk converges with this Swedish finding, while the matched cohort diverges due to methodological limitations.


## Supporting Evidence

**Source:** Psychopharmacology Institute Q1 2026 Review citing 2026 national cohort study

2026 national cohort study found semaglutide associated with 42% lower risk of worsening mental illness versus non-use periods in within-individual design. This reduced worsening of depression, anxiety, and substance use disorder. The Psychopharmacology Institute review explicitly notes these findings are observational and that randomized controlled trials are needed to confirm causality.
