Efficacy of Antidepressants in Treating Functional Abdominal Pain Disorders in Children: A Meta-Analysis of Randomized Controlled Trials

Abstract

Purpose

Functional abdominal pain disorders (FAPDs) affect 13.5% of children and are challenging to treat owing to their poor quality of life and chronicity. Although antidepressants are potential interventions, the evidence of their efficacy remains inconclusive. This study evaluated the effectiveness of antidepressants in pediatric patients with FAPDs and explored the differences in antidepressant type and treatment duration.

Methods

A systematic review of antidepressant efficacy in pediatric FAPDs was conducted using PubMed, EMBASE, Web of Science, and Cochrane Central databases. Randomized controlled trials (RCTs) comparing antidepressants were included. Subgroup analyses assessed the differences according to the antidepressant type (amitriptyline vs. citalopram) and treatment duration (4 weeks vs. 12 weeks).

Results

Three RCTs with 287 participants met the inclusion criteria. The pooled odds ratio (OR) for clinical response (symptom improvement) was 3.18 (95% confidence interval [CI], 0.67–15.00), which was not statistically significant (p=0.144). Individual ORs were 1.59 (95% CI, 0.76–3.32) for citalopram, 15.55 (95% CI, 7.07–34.20) for amitriptyline, and 1.30 (95% CI, 0.56–2.99) for amitriptyline. Subgroup analysis suggested a numerically higher effect estimate for longer treatment duration; however, the 12-week finding (OR, 15.55; 95% CI, 7.07–34.20), which was derived from a single study, should be interpreted cautiously.

Conclusion

Although antidepressants did not demonstrate statistically significant overall efficacy in pediatric FAPDs, the observed effect estimates suggest a possible therapeutic benefit. Exploratory subgroup analyses indicated that treatment duration might influence symptom improvement; however, these findings were limited by substantial heterogeneity and the small number of trials available. Additional randomized controlled trials are warranted.

INTRODUCTION

Functional abdominal pain disorders (FAPDs) in children are a common and challenging group of conditions characterized by chronic or recurrent abdominal pain without identifiable organic causes. These disorders, including functional dyspepsia, irritable bowel syndrome (IBS), and abdominal migraine, are encompassed by the Rome IV criteria and are thought to involve complex interactions between the central nervous system and the gastrointestinal tract. FAPDs significantly affect the quality of life of the affected children, leading to disruptions in school attendance, social activities, and family dynamics [1]. FAPDs are prevalent among pediatric populations and impose substantial burdens on patients, their families, and healthcare systems because of their chronic and detrimental effects on their quality of life. A comprehensive meta-analysis reported a global pooled prevalence of 13.5% of FAPDs in children aged 4–18 years, with IBS being the most frequently diagnosed subtype at 8.8% [2]. The prevalence of these disorders varies significantly across regions and is influenced by factors, such as sex, with a higher predisposition observed in females (15.9%) than in males (11.5%) [3]. The pathophysiology of FAPDs is multifactorial and has not been fully elucidated. Current evidence suggests that dysregulation of the gut-brain axis, characterized by impaired communication between the central and enteric nervous systems, plays a pivotal role [4].

Additionally, alterations in gastrointestinal motility, leading to delayed or accelerated transit times, contribute to symptom manifestation. Visceral hypersensitivity with increased sensitivity to gastrointestinal stimuli further exacerbates discomfort. Emerging research has also implicated imbalances in the gut microbiota composition as a contributing factor to the development and persistence of these disorders. Although the exact pathophysiology of these conditions is not completely understood, controlling gut-brain dysregulation may be an essential avenue for improvement, particularly in treatment. Antidepressants have been increasingly explored for their potential benefits in the management of pediatric FAPDs. These agents are believed to modulate visceral hypersensitivity and gut-brain axis dysfunction through their effects on central and peripheral pain pathways. Antidepressants, such as low-dose tricyclic antidepressants (TCAs), have been shown to exert analgesic effects independent of their antidepressant properties, making them particularly suitable for patients without comorbid mood disorders. However, the use of antidepressants in pediatric patients is limited by a lack of data on their efficacy compared to that in adults and concerns about long-term safety, tolerability, and potential side effects, including sedation, weight gain, and cardiovascular effects.

This was a meta-analysis and systematic review of the use of antidepressants in children with FAPD to identify the clinical implications of these medications in optimizing treatment to improve symptoms in pediatric patients.

MATERIALS AND METHODS

Search strategy

The meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched randomized controlled trials (RCTs) published in English that were comparative studies reporting antidepressant efficacy in pediatric patients diagnosed with FAPD. PubMed, Embase, and the Cochrane Library databases (search undertaken by NW Kim, Medical Library, Yonsei University of Korea) were searched for RCTs from database inception to May 2023. The keywords/subject headings included “functional abdominal pain disorders,” “functional dyspepsia,” “antidepressant,” and “antidepressant use.” Search strategies were developed according to the indices of various databases and were based on the MEDLINE strategy. The detailed search strategies are provided in the Supplementary Material. In addition to the electronic search via databases, we manually searched for additional relevant studies from the lists of references in the articles retrieved from the electronic search method.

Data extraction and study selection

The citations and abstracts of all retrieved studies were downloaded to the EndnNote X8.1 citation management software (Thomson Reuters). After removing duplicate titles and abstracts, the retrieved articles were independently reviewed by two authors (YJ Kim and SH Park). The full texts of relevant articles were checked against the inclusion criteria, and any discrepancies or issues were resolved by consensus.

In the meta-analysis, the inclusion criteria were as follows: (1) RCTs, (2) studies on pediatric patients, and (3) confirmation of the number of patients whose symptoms improved according to the drug. Studies were excluded if they were available only as abstracts, reviews, case reports, studies without raw data available for retrieval, duplicate publications, non-English publications, crossover study designs, studies without a control group, or data from a single experiment. Data without a mean value for the outcomes between the two groups were also excluded. The following variables were extracted: (a) authors, (b) year and language of publication, (c) treatment duration, (d) treatment regimen, and (e) outcome (symptom improvement).

Study outcomes

This meta-analysis aimed to evaluate symptom improvement following antidepressant treatment in children with FAPDs. The effects of antidepressant treatment on children according to the type of antidepressant (amitriptyline vs. citalopram) were also evaluated. In addition, we sub-analyzed the outcomes according to treatment duration (4 weeks vs. 12 weeks).

Statistical analysis

Meta-analysis was performed using the R program 4.0.0. We used a random-effects model to account for between-study variation and calculated odds ratios (ORs) and 95% confidence intervals (CIs) as the main pooled metrics. We calculated the following outcomes using the OR and 95% CI: (a) pooled odds ratio of clinical response (symptom improvement) to antidepressants versus placebo, (b) odds ratio of clinical response according to the type of antidepressant, and (c) odds ratio of clinical response according to treatment duration. The analysis employed the Inverse Variance Method for weighting individual studies, with the DerSimonian-Laird estimator used to calculate tau² (between-study variance). Confidence intervals for tau² and tau were estimated using the Jackson method. Heterogeneity across studies was assessed using Cochran’s Q test and I² statistic. Q tests revealed the significance of heterogeneity, whereas I² quantified the percentage of the total variation due to heterogeneity. High heterogeneity (I²>75%) indicated considerable variation between studies; therefore, the pooled estimates were interpreted with caution.

RESULTS

Study selection

Three RCTs were included in the meta-analysis after screening 1,186 records. These studies assessed the efficacy of antidepressants in children with FAPDs. The analyzed studies included two types of antidepressants, citalopram and amitriptyline, with a treatment duration of 4 or 12 weeks. The characteristics of the eligible studies are summarized in Table 1. In the three included RCTs, 287 participants were identified (antidepressants: 167; placebo: 120). The included studies investigated two specific antidepressants, citalopram and amitriptyline [5,6,7]. Both amitriptyline studies reported mild adverse effects, whereas the citalopram study highlighted a higher frequency of drowsiness and dry mouth in the antidepressant group than in the placebo group.

Table 1. Study characteristics.

Study	Drug & dosage	Treatment duration	Observation period	ITT group size	PP group size	Symptom improvement (ITT)	Symptom improvement (PP)	Secondary outcomes	Adverse effects
Roohafza et al. [5], 2014	Citalopram: 10 mg/d (wk 1), 20 mg/d (4 wk)	4 wk	12 wk	59 (Citalopram), 56 (Placebo)	43 (Citalopram), 43 (Placebo)	40.6% (Citalopram), 30.3% (Placebo)	55.8% (Citalopram), 39.5% (Placebo)	Depression, anxiety, somatization, CGI scores	Citalopram group: Drowsiness (37.2%), dry mouth (44.1%), dizziness, nausea; 5 participants discontinued due to adverse effects.
Seetharaman et al. [6], 2022	Amitriptyline: 10 mg (<35 kg), 25 mg (>35 kg)	12 wk	15.8 mo (mean)	82 (Amitriptyline), 86 (Placebo)	75 (Amitriptyline), 74 (Placebo)	76% (Amitriptyline), 14.9% (Placebo)	76% (Amitriptyline), 14.9% (Placebo)	Quality of life, analgesic use	Amitriptyline group: Minor adverse events (25.3%) included mild somnolence and gastrointestinal discomfort; no major events reported.
Saps et al. [7], 2009	Amitriptyline: 10 mg (<35 kg), 20 mg (>35 kg)	4 wk	4 wk	46 (Amitriptyline), 44 (Placebo)	43 (Amitriptyline), 40 (Placebo)	59% (Amitriptyline), 53% (Placebo)	63% (Amitriptyline), 57.5% (Placebo)	Depression, anxiety, somatization, coping	Amitriptyline group: Mild adverse events (fatigue, rash, headaches); no serious adverse events reported. Adverse events occurred within the first 2 wk of treatment.

ITT: intention-to-treat, PP: per-protocol, CGI: clinical global impression.

Overall meta-analysis on the efficacy of antidepressants

Three studies (k=3) were included in the meta-analysis (Fig. 1). The individual ORs reported by these studies were as follows: Roohafza et al. [5] demonstrated an OR of 1.59 (95% CI, 0.76–3.32), Seetharaman et al. [6] reported a higher OR of 15.55 (95% CI, 7.07–34.20), and Saps et al. [7] found an OR of 1.30 (95% CI, 0.56–2.99). The pooled OR for symptom improvement with antidepressant use was 3.18 (95% CI, 0.67–15.00), based on a random-effects model (Fig. 2). This pooled effect did not reach statistical significance (z=1.46, p=0.144), indicating that no statistically significant overall benefit was demonstrated when all studies were collectively analyzed. Heterogeneity among the studies was high, with an I² of 91.5% and Q=23.41 (p<0.0001). The between-study variance (tau²) was estimated to be 1.72, reflecting considerable variability in effect sizes across the included studies. Differences in study characteristics, such as antidepressant type and treatment duration, may have contributed to the observed variability in effect estimates (Fig. 3).

Fig. 1. Study selection process.

Fig. 2. Forest plot of clinical response (symptom improvement) comparing antidepressants and placebo in pediatric functional abdominal pain disorders.

OR: odds ratio, CI: confidence interval.

Fig. 3. Meta-analysis heterogeneity assessment.

Subgroup analysis by antidepressant type

Subgroup analysis according to the antidepressant type showed differences in efficacy between citalopram and amitriptyline, although these differences were not statistically significant (Fig. 4). Citalopram was assessed in one study [5], which reported an OR of 1.59 (95% CI, 0.76–3.32), suggesting no significant symptom improvement compared to the control group. Amitriptyline was evaluated in two studies [6,7], which reported an OR of 15.55 (95% CI, 7.07–34.20) and 1.30 (95% CI, 0.56–2.99), respectively. The pooled OR for amitriptyline was calculated as 4.51 (95% CI, 0.40–51.39) using a random-effects model, but the heterogeneity was substantial (I²=94.4%), indicating variability in the reported efficacy across these studies. Despite the observed differences in the odds ratios between the two antidepressants, the test for subgroup differences was not statistically significant (Q=0.65, p=0.4214). This suggests that the overall efficacy of antidepressants in treating functional abdominal pain disorders in children may not differ substantially between citalopram and amitriptyline, although further studies are required to confirm this observation given the high variability and limited number of included trials.

Fig. 4. Subgroup analysis of clinical response (symptom improvement) according to antidepressant type (amitrip-tyline vs. citalopram).

OR: odds ratio, CI: confidence interval.

Subgroup analysis by treatment duration

Subgroup analysis based on treatment duration revealed differences in effect estimates between shorter and longer treatment periods. For studies with a 4-week treatment duration, the pooled OR was 1.45 (95% CI, 0.84–2.53), indicating no statistically significant improvement in symptoms (Fig. 5). By contrast, the 12-week treatment subgroup, which was informed by a single study, showed a higher odds ratio for symptom improvement (OR, 15.55; 95% CI, 7.07–34.20). Although the test for subgroup differences was statistically significant (Q=23.28, p<0.0001), this finding should be interpreted with caution because the 12-week result was derived from a single study. Accordingly, any apparent differences in the treatment duration should be interpreted cautiously and considered exploratory.

Fig. 5. Subgroup analysis of clinical response (symptom improvement) according to treatment duration (4 wk vs. 12 wk).

OR: odds ratio, CI: confidence interval.

DISCUSSION

The results of this meta-analysis showed that antidepressant treatment in pediatric patients with FAPD did not demonstrate statistically significant efficacy. However, the magnitude of the observed effect estimates, and exploratory subgroup analyses suggest that treatment duration may be a clinically relevant factor influencing outcomes, with numerically greater symptom improvement observed with longer treatment durations. These findings should be interpreted cautiously given the limited number of studies and substantial heterogeneity.

When antidepressants are initiated with careful consideration of the risk–benefit profile and close monitoring of adverse effects, a longer treatment duration may be beneficial in selected patients. Bahar et al. [8] found significant improvements in the quality of life and symptom reduction in adolescents with IBS treated with amitriptyline for 13 weeks, suggesting that continued treatment may improve outcomes, especially in conditions that overlap with FAPD, such as IBS [8]. The Teitelbaum study reported that low-dose TCAs significantly improved the long-term symptoms in pediatric patients. The study demonstrated an average of more than 10 months of symptom relief, with the treatment effects maintained significantly after drug discontinuation [9]. The 2025 European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN/NASPGHAN) guidelines conditionally suggest amitriptyline for children with IBS and FAP-NOS, although the certainty of evidence is low. The guidelines also emphasize that psychopharmacological therapies should be prescribed cautiously by experienced clinicians [3].

While the exact pathophysiology of pediatric FAPD is not completely understood, recent evidence suggests that dysregulation of gut-brain interactions, altered gastrointestinal motility, visceral hypersensitivity, and gut dysbiosis play a role in the development and persistence of the disorder. Given the multiple etiologies involved, a careful treatment strategy is required. Treatment strategies for pediatric FAPD have evolved into a multidisciplinary approach that emphasizes non-pharmacologic interventions alongside pharmacotherapy. Cognitive behavioral therapy, dietary modifications such as low-FODMAP diets, and probiotics have shown promise in alleviating symptoms and improving outcomes. In particular, increased interest in the gut-brain axis has led to the investigation of novel therapies that target microbiome modulation and neuromodulation. Many studies have emphasized that nonpharmacologic treatments should be prioritized, suggesting the need for a biopsychosocial approach to address the multifaceted nature of FAPD through a comprehensive approach that includes counseling and reassurance [10]. When these nonpharmacologic treatments fail to produce clinical improvement, a variety of medications are selected on a patient-by-patient basis. Antidepressants are classified as neuromodulators for the treatment of pediatric functional FAPD, with drugs such as amitriptyline and citalopram being the most commonly used. These medications act on the central nervous system to regulate pain sensation and reduce the frequency and intensity of abdominal pain [3]. Antidepressants minimize visceral and central hypersensitivity, which are key pathological mechanisms of FAPD [11]. A significant advantage of antidepressants is that they can simultaneously relieve physical pain and psychological symptoms [12]. As FAPD is often accompanied by mental health problems such as anxiety and depression, antidepressants can be a treatment option as part of a multifaceted treatment approach for these patients [11].

The use of antidepressants for these conditions requires a cautious approach, as antidepressant use can be associated with side effects. Common side effects include dry mouth, drowsiness, weight gain, and constipation, and some patients may experience insomnia or mood swings early in the course of treatment [13]. Therefore, antidepressants are generally well tolerated in pediatric patients but require close monitoring for side effects. Regular monitoring during treatment is essential, and a strategy that begins with a low dose and gradually increases it is recommended. Concerns about the psychological effects of psychotropic medications on children have also hindered the widespread use of antidepressants, and the lack of evidence has been limited by the difficulty of conducting studies in children compared with adults. Antidepressants may be promising treatment options for pediatric patients with refractory or severe disease progression. The Rome IV criteria for functional dyspepsia highlight that low-dose tricyclic antidepressants, such as amitriptyline and imipramine, are often considered for refractory cases, despite the lack of convincing data. However, the heterogeneity of FAPD, as defined by the Rome IV criteria, makes it difficult to generalize treatment outcomes because the treatment response may vary depending on the FAPD subtype, comorbidities, and individual patient factors. Accordingly, the current evidence supports a cautious and individualized approach rather than definitive conclusions regarding efficacy.

The limitations of this meta-analysis include the small number of studies and considerable heterogeneity between studies. Future studies should explore the optimal duration of antidepressant treatment, compare the efficacy and safety profiles of different classes of antidepressants, and incorporate patient-reported outcomes and quality-of-life measures for a more comprehensive assessment of treatment effectiveness. Additionally, studies that identify the predictors of treatment responses, such as specific FAPD subtypes or psychosocial factors, may enable personalized treatment approaches.

This meta-analysis demonstrates the potential role of antidepressants as therapeutic options for pediatric FAPD. While the lack of statistically significant overall efficacy, high variability in treatment responses, and concerns regarding safety and tolerability necessitate cautious use, the findings suggest that a longer treatment duration may be associated with symptom improvement in selected cases, although the available evidence remains limited. Differences between antidepressant classes were not statistically significant; however, further research is needed to tailor treatments based on patient-specific characteristics and symptom profiles. Current guidelines prioritize non-pharmacological strategies and recommend antidepressant use only in carefully selected cases. Nevertheless, antidepressants may be a possible component of FAPD management in a multidisciplinary approach for refractory or chronic cases. Further high-quality large-scale studies in children are required to better inform future clinical practice.