Antidepressants are commonly prescribed for patients with functional dyspepsia. However, the effect of tricyclic antidepressants on satiation and gastric emptying remains unclear, and there are no data for tetracyclic compounds. To compare the effects of nortriptyline (maximum dose: 50 mg daily) and mirtazapine (30 mg daily) vs placebo on gastric emptying, gastric satiation and postprandial symptoms after a nutrient load in healthy volunteers. Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 14 days of nortriptyline (n = 13), mirtazapine (n = 13), or placebo (n = 14) in healthy volunteers. Validated methods were used to study gastric emptying ((13)C-octanoate) and satiation postnutrient drink test. The three arms were comparable with regard to age, gender, body mass index and hospital anxiety/depression scale. There were no statistically significant effects of mirtazapine or nortriptyline on gastric emptying compared to placebo (P = 0.34). Maximum tolerated volume was similar on drug and placebo (P = 0.56). Aggregate symptom score 30 min postmaximum tolerated volume after nutrient drink challenge on placebo was 132 (+/-21), vs 165 (+/-21) on mirtazapine, and 126 (+/-21) on nortriptyline 50 mg respectively (P = 0.28). Tricyclic and tetracyclic antidepressant agents do not appear to have significant effects on gastric motor or satiation postnutrient challenge in healthy individuals at the doses tested.