Background: The dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in major depression includes hyperactivity and reduced feedback inhibition. Atrial natriuretic peptide (ANP) is able to reduce the HPA-axis response to stress and has an anxiolytic effect in rodents and humans. We hypothesized that patients with depression would have an attenuated N-terminal proANP (NT-proANP) response to acute exercise compared to healthy controls. Secondly, we aimed to assess the effect of antidepressants on NT-proANP response to acute exercise. Methods: We examined 132 outpatients with mild to moderate depression (ICD-10) and 44 healthy controls, group matched for age, sex, and BMI. We used an incremental bicycle ergometer test as a physical stressor. Blood samples were drawn at rest, at exhaustion, and 15, 30, and 60 min post-exercise. Results: The NT-proANP response to physical exercise differed between depressed subjects and healthy controls (group x time; F-4,F-162.9 = 10.92; p < 0.001). The increase from rest to VO2max was 0.98 (SD 0.8) and 1.96 nmol/l (SD 1.1), respectively, for depressed subjects and healthy controls (mean diff: 0.98 nmol/l; 95% CI 0.7-1.3; t = 6.63; df = 170; p < 0.001). The increase in NT-proANP from rest to peak VO2max was 1.27 (SD 1.0) and 0.84 nmol/l (SD 0.6), respectively, for unmedicated and medicated patients (mean diff: 0.42 nmol/l; 95% CI 0.1-0.8; t = 2.56; df = 128; p = 0.01). Conclusion: We observed an attenuated NT-proANP response to acute physical stress in depressed patients. Antidepressants were associated with an independent suppressive effect on the NT-proANP response. (c) 2010 Elsevier Ltd. All rights reserved.