Tailored Treatment of Functional Dyspepsia With Nortriptyline: A Multicenter, Double-Blind, Placebo-Controlled Trial

BACKGROUND & AIMS: Low-dose tricyclic antidepressants may be effective for patients with functional dyspepsia (FD), although high-quality randomized controlled trials (RCTs) are limited. We aimed to investigate the efficacy of nortriptyline in an escalating low-dose regimen vs placebo in participants with FD following a genotype-guided pre-selection based on cytochrome P450 2D6 (CYP2D6), the primary enzyme responsible for nortriptyline metabolism. METHODS: We conducted a multicenter, RCT of patients with FD in primary, secondary, and tertiary care. Sixty-nine participants were randomly assigned to nortriptyline (weeks 1-2: 10 mg; weeks 3-4: 25 mg; weeks 5-12: 50 mg) vs placebo for a 12-week treatment. The primary outcome was clinical response based on a decrease in FD symptoms of at least 30% compared with baseline, in 50% of the last 10 weeks of the treatment period. RESULTS: The primary outcome showed no significant difference in response for nortriptyline compared with placebo (45% vs 58%; odds ratio [OR], 0.574; 95% confidence interval [CI], 0.211-1.560; P = .276). There was no significant difference in adverse events between the nortriptyline and placebo group. Nortriptyline plasma levels were significantly higher in responders compared with non-responders (13.0 μg/L; interquartile range [IQR], 12.0-16.0 vs 9.0 μg/L; IQR, 8.0-10.5; P = .003). The belief to have received nortriptyline showed a higher response rate than the belief to have received placebo (77% vs 36%; OR, 11.439; 95% CI, 2.138-61.201; P = .004). CONCLUSIONS: Nortriptyline was not more effective than placebo in reducing FD symptoms in participants pre-selected based on CYP2D6 genotype, although a biological effect of nortriptyline could not be ruled out. However, effects related to participants' belief appeared to be stronger. CLINICALTRIALS: gov, Number, NCT03652571.