Letter to the Editor: Adjunctive low-dose flupentixol-melitracen with lansoprazole rapidly improves functional dyspepsia - implications from a randomized, double-blind trial

Table 1 Guideline-based functional dyspepsia management by country

Country	First-line FD therapy	Neuromodulators (examples)	Position in algorithm	Guideline
United States	Helicobacter pylori test-and-treat; then PPI trial if negative or after eradication. Empiric PPI is standard first-line therapy	TCAs (e.g. low-dose amitriptyline) recommended if PPI fails; prokinetics also in algorithm. SSRIs not specifically endorsed	Neuromodulators are used after first-line (i.e. second line)	ACG/CAG Dyspepsia Guideline (United States, 2017)[8]
United Kingdom	PPI (e.g. pantoprazole) ± prokinetic (e.g. domperidone, metoclopramide) first-line. Trial of PPI is standard; prokinetics may be added especially for PDS	TCAs (amitriptyline) recommended for refractory FD; SSRIs/SNRIs not shown effective	Neuromodulators (TCAs) are reserved for non-responders (second line)	British Society of Gastroenterology Gut 2022 FD Guideline (United Kingdom, 2022)[2]
China	EPS: PPI first line; PDS: Prokinetic first-line. Helicobacter pylori eradication recommended if positive. Dietary adjustment also emphasized	Neuromodulators effective for refractory FD or FD with anxiety/depression (no specific agent singled out)	Used in refractory or overlap cases (i.e. later-line)	2022 China Expert Conference on the Diagnosis and Treatment of Functional Dyspepsia
Japan	Acid suppression (PPI or H2RA) and prokinetics (acetylcholinesterase inhibitor acotiamide) are first line. Kampo herbal rikkunshito is also first-line therapy	Anxiolytics/antidepressants (e.g. low-dose benzodiazepines or antidepressants) used second-line; no specific SSRIs/TCA detailed in guideline	Neuromodulators are second-line, after acid suppression/prokinetic therapies	JSG Clinical Practice Guideline (Japan, 2021)[9]
India	EPS: PPI first-line, prokinetic (itopride) second-line, neuromodulators third line; PDS: Prokinetic first-line, prokinetic + PPI, neuromodulators third line; EPS-PDS overlap: Prokinetic + PPI first-line, neuromodulators second-line. Helicobacter pylori testing and eradication if positive is emphasized	Indian experts note TCAs (e.g. amitriptyline), mirtazapine, SSRIs may help in EPS/refractory cases	Neuromodulators are second line/third line, after acid suppression/prokinetic therapies	Proposed India FD Algorithm (2024)[10]
Brazil	PPI (acid suppression) for pain-predominant FD; Helicobacter pylori eradication recommended for infected patients. Prokinetics helpful for motility symptoms	TCAs (amitriptyline) or trazodone for refractory FD, especially if insomnia/anxiety present	Neuromodulators are second-line, used when PPI (and prokinetics) fail	Brazilian Consensus/Practice Guideline, 2012 JF Machado
France	Test-and-treat Helicobacter pylori; PPI for symptom relief (especially pain). No other pharmacologic therapy reached consensus efficacy. Dietary/Lifestyle advice also used	No specific neuromodulator recommendation in consensus (PPI only reached consensus)	Neuromodulators not defined in consensus; would be used only by clinical judgment (likely later-line)	UEG/ESNM European FD Consensus (2021) (no French-specific guideline)[11]
Germany	First-line: Herbal phytotherapy (STW-5/Iberogast or peppermint/caraway oil). Helicobacter pylori eradication if positive. Acid suppression (PPI/H2) if prominent acid symptoms	Second-line: Low-dose TCAs (amitriptyline, nortriptyline), mirtazapine, and sulpiride (SSRIs not preferred)	Neuromodulators are second-line after first-line herbs/acid therapy	DGNM S1 Leitlinie (Germany, 2025)[12]
South Africa	Lifestyle/diet changes; empiric PPI trial (6-8 weeks) for low-risk FD. Non-invasive Helicobacter pylori test-and-treat is recommended	Not specified in SAGES guidance; neuromodulators (e.g. TCAs) are considered only if symptoms persist despite above	Neuromodulators would be used late (refractory FD), not in initial algorithm	SAGES Dyspepsia Guidance (South Africa, 2025)[13]

FD: Functional dyspepsia; TCA: Tricyclic antidepressants; SSRI: Selective serotonin reuptake inhibitors; ACG: American College of Gastroenterology; CAG: Canadian Association of Gastroenterology; PPI: Proton pump inhibitor; PDS: Posttraumatic Stress Disorder Scale; SNRI: Serotonin-norepinephrine reuptake inhibitors; EPS: Epigastric pain syndrome; H2RA: Histamine 2 receptor antagonist H2; UEG: Upper endoscopy; ESNM: European Society of Neurogastroenterology and Motility; DGNM: Digestive Neurogastroenterology and Motility; SAGES: Society of American Gastrointestinal and Endoscopic Surgeons.