Nortriptyline Found Ineffective for Functional Dyspepsia in Placebo-Controlled Trial
A recent study published in the journal of Clinical Gastroenterology and Hepatology found that nortriptyline did not significantly reduce symptoms of functional dyspepsia (FD) when compared to placebo, which indicated no clear therapeutic benefit for this condition.
Low-dose tricyclic antidepressants have long been considered a potential treatment option for FD with persistent upper abdominal discomfort without an identifiable structural cause. However, solid evidence from high-quality randomized controlled trials has been limited. A new multicenter study now adds nuance to this debate, suggesting that patient expectations may play a larger role in symptom improvement than the drug itself.
This trial investigated whether nortriptyline could reduce FD symptoms when patients were pre-selected based on their cytochrome P450 2D6 (CYP2D6) genotype. CYP2D6 is the main enzyme responsible for metabolizing nortriptyline, and the genotype-guided approach was designed to optimize drug exposure while minimizing side effects.
A total of 69 participants with FD, recruited across primary, secondary, and tertiary care settings, were randomly assigned to receive either nortriptyline or placebo over a 12-week period. The nortriptyline dose was gradually increased from 10 mg in weeks one and two, to 25 mg in weeks three and four, and finally to 50 mg from week five through week twelve. The primary outcome focused on meaningful clinical response, defined as at least a 30% reduction in FD symptoms compared with baseline during at least half of the final 10 weeks of treatment.
The main results showed no statistically significant advantage of nortriptyline over placebo. Clinical response occurred in 45% of patients receiving nortriptyline, compared with 58% in the placebo group. Statistical analysis indicated that this difference was not significant, suggesting that nortriptyline did not outperform placebo in reducing FD symptoms in this genetically pre-selected population.
The frequency and type of adverse events were similar between the nortriptyline and placebo groups, indicating that the low-dose, step-up regimen was generally well tolerated. Measurements of nortriptyline plasma concentrations showed that patients who responded to treatment had significantly higher drug levels than non-responders.
The participants who believed they were receiving nortriptyline reported a much higher response rate than those who believed they were on placebo, regardless of their actual treatment assignment. This strong association highlights the powerful role of expectation and perception in symptom-driven conditions like FD. Overall, while nortriptyline was not more effective than placebo overall, the study illuminates that a potential dose–response signal at higher plasma levels, and an even stronger influence of patient belief.
Source:
Bosch, D. H., Beckers, A. B., Snijkers, J. T. W., Bosman, M. H., Winkens, B., Muris, J. W. M., de Wit, N., Brouwers, J. R., van Hee, K., Clemens, C. H. M., Haarhuis, B. J. T., Witteman, B. J. M., Masclee, A. A. M., & Keszthelyi, D. (2026). Tailored treatment of functional dyspepsia with nortriptyline: a multi-center, double-blind, placebo-controlled trial. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association. https://doi.org/10.1016/j.cgh.2026.01.013
