A placebo‐controlled trial of the 5‐HT_1A agonist R‐137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia

Abstract

Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.

Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis

“…In the trial by Braak et al 45 seven (10.3%) of 68 screening failures were due to a mood disorder. Among the other studies, three reported reasons for screening failure and none were due to a mood disorder,25 42 44 and two did not report these data. Detailed characteristics of individual RCTs are provided in table 1.…”

“…We successfully contacted original investigators to seek clarification on study methodology, and hence reduce risk of bias, or to obtain supplementary dichotomous data for nine trials 25 32 33 42–46 48. Three trials used antipsychotic drugs,27 40 41 three trials 5-HT 1A receptor agonists,25 43 44 two trials TCADs,45 46 one trial SSRIs,32 one trial tetracyclic antidepressants,48 one trial serotonin-norepinephrine reuptake inhibitors (SNRIs),33 one trial SSRIs or TCADs,47 and one trial a combination of an antipsychotic drug and a TCAD 42. Ten of the RCTs were at low risk of bias (see online supplementary table S1).…”

“…Six trials screened for, and excluded, individuals with coexistent mood disorders 25 42 44 45 47 48. In the trial by Braak et al 45 seven (10.3%) of 68 screening failures were due to a mood disorder.…”

Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD

“…230 Two larger trials used a parallel design when testing the effects of tandospirone-another 5-HT1A receptor agonist and azapirone derivative-in patients with functional dyspepsia and leave an unclear picture with contradictory results compared to placebo. 231,232 When the same agent was used in patients with IBS and anxiety, the fraction of patients responding with at least 50% decrease in pain was significantly higher than that in the placebo group. 233 A recent meta-analysis of controlled trials in depression showed a relatively high incidence of adverse effects on gastrointestinal function, which could contribute to these discrepancies.…”

Emerging drugs for functional dyspepsia

“…This drug significantly improved total abdominal symptom scores, relieved anxiety and improved quality of life according to the Short Form-8 questionnaire [90]. However, 4-week administration of the fundus-relaxing 5-HT 1A agonist R-137696 failed to significantly improve symptoms or gastric accommodation compared to placebo in a randomized, double-blind, placebo-controlled trial involving 53 patients with FD [91].…”