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

Abstract

Functional dyspepsia (FD) is often influenced by psychosocial factors, but high-quality randomized data on the use of neuromodulators is limited. A recent study by Wang et al published in the World Journal of Gastroenterology, which was a single-center, double-blind, placebo-controlled trial, looked at lansoprazole (LPZ) (30 mg daily) combined with low-dose flupentixol-melitracen (FM) (flupentixol 0.5 mg + melitracen 10 mg) in 183 patients with Rome IV FD. This provides important and timely evidence. After two weeks of treatment, the LPZ + FM group showed a significantly higher clinical response rate compared to the LPZ + placebo group (63.0% vs 46.2%; relative risk: 1.42, 95% confidence interval: 1.04-1.93). Patients who received the additional FM had greater and lasting improvements in postprandial distress, quality of life, depressive and anxiety symptoms, and sleep quality. Benefits for Posttraumatic Stress Disorder Scale, Short Form Neck Disability Index, and Patient Health Questionnaire-9 continued through the four-week follow-up. Adverse events were mostly mild (32.6% vs 23.1%), and no serious adverse events occurred. These findings support that short-term, low-dose neuromodulation combined with acid suppression can effectively address both the symptoms and psychosocial factors of FD. Limitations include the study’s single-center design and short treatment duration. Larger, multicenter, and longer trials are needed to confirm long-term effects, optimal dosing, and safety. Nonetheless, this study should encourage clinicians and guideline panels to seriously consider adjunctive neuromodulators as a practical, evidence-based option for certain FD patients.

Key Words: Functional dyspepsia; Lansoprazole; Flupentixol; Melitracen; Prokinetics; Rome IV

Core Tip: Combining lansoprazole (30 mg daily) with low-dose flupentixol-melitracen can effectively address both the symptoms and psychosocial factors of functional dyspepsia. This commentary discusses the potential role of early gut-brain axis modulation, examines the strengths and limitations of current evidence, highlights regulatory and geographic differences in the use of flupentixol-melitracen, and emphasizes the need for large multicenter studies to identify patients most likely to benefit from this therapeutic approach.

TO THE EDITOR

I read with great interest the randomized trial by Wang et al[1] published in the World Journal of Gastroenterology on combining lansoprazole with flupentixol-melitracen (FM) in functional dyspepsia (FD). The results, which show significant improvement in symptoms and quality of life within two weeks of treatment, suggest a potential shift toward early brain and gut management in FD[1]. This raises an important question: Is this “accelerated efficacy” mainly due to central influence on the gut and brain axis, or might it be due to a drug interaction or other non-central effects? I believe exploring this question can help determine if the early use of neuromodulators represents real progress in FD treatment or simply another supplementary therapy.

This study’s design is a significant strength. As a double-blind, placebo-controlled randomized trial, it provides strong evidence on managing FD. Importantly, it measured patient-reported symptom severity and validated quality-of-life scales, capturing meaningful outcomes[1]. The authors state that “this low-dose short-term regimen improved FD symptoms and quality of life within two weeks”, and that the improvements lasted for four weeks after treatment. These patient-focused endpoints enhance the confidence in the findings[1].

However, important limitations affect these strengths. The treatment course was only two weeks, with a four-week follow-up, leaving long-term effects untested. The single center in Shanghai and the likely ethnically similar sample may limit how widely the results can be applied[1]. Additionally, outcomes relied entirely on self-reported symptom scores, raising potential biases. Notably, the authors also call for “future long-term follow-up and multicenter studies” to confirm the regimen’s lasting benefits[1]. In short, while the randomized controlled trial is well-designed, it provides only preliminary evidence; longer and more diverse trials are needed.

FD management varies widely around the world. In Western practice, guidelines first emphasize acid suppression and prokinetics, reserving neuromodulators, particularly low-dose tricyclic antidepressants, for difficult cases (Table 1)[2,3]. For example, a major North American trial found that amitriptyline (50 mg) offered modest symptom relief (53% adequate relief) compared to placebo (40%). In contrast, escitalopram (10 mg) showed no better results than placebo[3]. The 2022 British Society of Gastroenterology FD guidelines also cite moderate-quality evidence for tricyclics like amitriptyline but find no support for selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors in FD[2]. On the other hand, sulpiride, a D2 antagonist, has only weak backing[2]. The FM combination used in this trial is largely unknown outside Asia. In fact, deanxit (flupentixol/melitracen) has never been approved in its home country of Denmark and is not licensed in the United States, United Kingdom, Canada, Japan, Australia, or most of Europe[4]. It was also banned in India and rejected by regulators in the Philippines[4]. Yet, it remains available in parts of Asia and the Middle East. This cross-cultural difference highlights that the FM approach is largely untested by Western standards. Therefore, the current findings must be understood in the context of differing regulatory environments: A treatment widely used (sometimes without caution) in China and Asia but largely unfamiliar and unstudied in Western FD practice.

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.

Mechanistically, the FM combination likely targets the gut-brain axis in FD. Flupentixol, a thioxanthene antipsychotic, blocks dopamine D1 and D2 receptors, which can unexpectedly increase synaptic dopamine through autoreceptor blockade[5]. Melitracen, a tricyclic antidepressant, inhibits the reuptake of norepinephrine and serotonin. Together, these drugs can quickly enhance central monoamine activity[5]. In fact, FM has been shown in randomized controlled trials to relieve anxiety and depression in medical patients within two weeks, achieving an 86.7% gastrointestinal symptom remission rate with few side effects[5]. By reducing central anxiety and alertness, FM likely raises visceral pain thresholds, addressing key aspects of FD’s pathophysiology (visceral hypersensitivity)[2]. Dopamine antagonism may also have peripheral effects; D2 blockade, as seen with metoclopramide or domperidone, can improve gastric motility or lessen nausea. However, unlike domperidone, flupentixol crosses the blood-brain barrier, making its gastrointestinal effects less certain. Importantly, FM was used here at very low doses, minimizing side effects. This likely improved tolerability and adherence. Indeed, a related trial of FM in China found that a two-week FM regimen provided similar symptomatic benefits to a four-week therapy while significantly reducing antidepressant discontinuation syndrome and achieving higher medication possession ratios[6]. In other words, short courses of FM may offer both effectiveness and better patient compliance.

The implications of these findings could significantly change FD management. Traditionally, gastroenterologists have followed a stepwise approach: Starting with dietary changes, Helicobacter pylori treatment, and acid blockade, then adding prokinetics, and only considering neuromodulators later. This study suggests a more integrated approach - using brain-directed therapy early for moderate to severe FD. This matches recent expert opinions which state that neuromodulators and even psychological therapies are underused in FD, and many experts support their earlier introduction for patients with significant symptoms[7]. Just as care for irritable bowel syndrome has shifted toward early neuromodulation, we need to explore whether FD patients could also benefit from prompt gut-brain intervention. Since up to 60% of difficult FD cases have anxiety or depression[2], an early trial of a gut-brain modulator could address fundamental illness drivers rather than simply blocking acid.

In conclusion, this trial should motivate further action in the field. I suggest three urgent priorities: (1) Conduct large-scale international multicenter randomized controlled trials of FM and similar gut-brain combinations in FD. These must meet strict reporting standards, like CONSORT or CONSORT-CHM for herbal and combination therapies. Wang et al[1] call for “multicenter studies” to confirm their results, and such trials could establish broader applicability across diverse groups and healthcare settings; (2) Investigate FM’s effects on visceral hypersensitivity and biological markers. For instance, evaluate gastric sensitivity, accommodation, and emptying, along with neural pain processing or inflammation markers, before and after FM therapy. Previous work shows that amitriptyline and escitalopram do not alter gastric emptying or satiety, suggesting their benefits are sensory rather than motor. Similar studies with FM could determine whether its benefits come from changes in brain-gut connections. Long-term follow-up is also necessary to see if FM’s early improvements lead to sustained remission or just postpone symptoms; and (3) Define which patients are best suited for early neuromodulation. Not every FD patient needs a psychotropic medication. I recommend targeting those with moderate to severe symptoms (for example, Rome IV Posttraumatic Stress Disorder Scale symptoms of two or more on initial questionnaires) or clear psychosocial elements, who are more likely to show visceral hypersensitivity and benefit from brain-gut therapy. Dividing patients (as was done for ulcer-like vs dysmotility-like FD) will clarify who gains the most from adding FM early.

In summary, Wang et al’s trial[1] points toward a promising shift away from the traditional stepwise model toward a combined brain-gut treatment approach for FD. Whether this reflects true neuromodulation or another productive mechanism, it sparks an important conversation. These areas must be rigorously examined through collaborative research, ensuring that patients with FD receive the most effective, evidence-based care available.