Gut–Brain Axis in Comorbid Constipation and Mood Disorders: Navigating the Efficacy-Tolerability Dilemma Through Emerging Evidence and Future Directions

Abstract

Background

The comorbidity of constipation and mood disorders (anxiety/depression) creates a vicious cycle of symptom superposition and treatment resistance. The persistent “efficacy-tolerability” dilemma—whereby effective treatment for one condition may exacerbate the other—remains unresolved.

Methods

This narrative review is based on a systematic search of PubMed, Embase, and Cochrane Library (2015–2026), focusing on epidemiology, gut-brain axis mechanisms, pharmacotherapy limitations, and emerging strategies. The search formula was: (“constipation” OR “functional constipation”) AND (“mood disorders” OR “anxiety” OR “depression”) AND (“gut-brain axis” OR “microbiota” OR “pharmacotherapy”).

Results

Constipation and mood disorders show a bidirectional association, supported by recent Mendelian randomization studies. Pathogenesis involves central/enteric nervous system dysfunction, microbiota imbalance, and inflammatory mediators. Conventional drugs (eg, selective serotonin reuptake inhibitors [SSRIs], stimulant laxatives) may worsen one condition while treating the other. Preliminary evidence suggests gut-brain axis-targeted therapies—including 5-hydroxytryptamine type 4 (5-HT4) receptor agonists, psychobiotics, and multidisciplinary team models—may improve outcomes, but most findings remain exploratory.

Conclusion

Overcoming the dilemma requires mechanism-oriented drug selection, optimized combination regimens, and individualized management. Future efforts should accelerate multi-target drug trials, multi-omics-based precision models, and multidisciplinary team implementation. The evidence base remains limited, with few large randomized controlled trials specifically targeting the comorbid population. Readers should interpret all quantitative estimates with caution, as they derive from heterogeneous study designs.

Introduction

Chronic constipation is a prevalent functional gastrointestinal disorder, affecting approximately 14% of adults worldwide according to Rome Criteria estimates.¹ Among these individuals, a pooled prevalence of 38–52% also experience comorbid mood disorders such as anxiety and depression,² a rate significantly higher than the 12–18% observed in the general population. This comorbidity establishes a vicious cycle of “symptom superimposition and treatment resistance”. Mood disorders worsen constipation by inhibiting intestinal motility and increasing visceral sensitivity, resulting in patients predominantly presenting with Bristol Stool Scale scores of Type 1–2 (hard stools/ball-shaped stools). Additionally, the incidence of abdominal pain and bloating in these patients is 2.3 times greater than in those with uncomplicated constipation.³ Conversely, the physical discomfort associated with chronic constipation exacerbates emotional disturbances, leading to an 18–25% increase in Hamilton Depression Scale (HAMD) scores and a 20–30% reduction in the response rate to antidepressants.⁴

From a public health perspective, comorbidity presents a significant socioeconomic burden. Data from the European Society of Gastroenterology in 2023 indicate that the annual medical expenditure for patients with comorbid constipation and mood disorders reaches €8900, which is 1.8 times higher than that for patients with uncomplicated constipation. The reconsultation rate due to adverse drug reactions stands at 42%, and the number of work absence days is 3 times greater than that of healthy individuals.⁵ Clinical treatment has long faced the dilemma of “efficacy-tolerability” imbalance—a clinical challenge in which pharmacotherapeutic agents effective for one condition frequently exacerbate the other. While selective serotonin reuptake inhibitors (SSRIs) can enhance mood, 30–45% of patients experience reduced intestinal motility, which exacerbates constipation.⁶ Stimulant laxatives, such as bisacodyl, can provide rapid relief from constipation but may harm the enteric nervous system and worsen anxiety through an imbalance in intestinal microbiota.⁷

Recent breakthroughs in gut-brain axis research have offered new insights into treating comorbidity. Comorbidity involves complex interactions among the central nervous system, enteric nervous system, and intestinal microbiota, mediated by neurotransmitters, inflammatory mediators, and metabolites.^8,9 A recent systematic review by Yu et al (2026) comprehensively summarized the microbiota-gut-brain axis mechanisms underlying chronic constipation and depression comorbidity,⁹ while our manuscript differs by focusing specifically on the pharmacotherapeutic dilemma and the balance between efficacy and gastrointestinal tolerability in clinical decision-making.

We hypothesize that mechanism-oriented drug selection, guided by gut-brain axis principles, can improve the therapeutic index (efficacy/tolerability ratio) in this comorbid population. This article systematically reviews the pathogenesis, current pharmacotherapy status, and optimization strategies for comorbid constipation and mood disorders. It emphasizes balancing efficacy and gastrointestinal tolerability through mechanism-oriented therapeutic regimens, thereby providing valuable references for clinical practice and future research directions.

Methods

Study Design

This is a narrative review that synthesizes the latest evidence on the gut-brain axis mechanisms underlying the comorbidity of constipation and mood disorders (anxiety/depression), current pharmacotherapy limitations, and emerging therapeutic strategies. The review adheres to a systematic literature search approach to ensure the comprehensiveness of included studies, though it does not perform a formal risk-of-bias assessment or meta-analysis. We have explicitly classified this work as a narrative review to accurately reflect its scope and methodology.

Search Terms and Strategy

We systematically retrieved literature from PubMed, Embase and Cochrane Library published between January 2015 and June 2026. All 2026 included references correspond to online ahead-of-print manuscripts. The search formula was as follows: (“constipation” OR “functional constipation”) AND (“mood disorders” OR “anxiety” OR “depression”) AND (“gut-brain axis” OR “microbiota” OR “pharmacotherapy”).

Inclusion criteria: English-language clinical trials, observational population studies, meta-analyses, and mechanistic systematic reviews focusing on human subjects.

Exclusion criteria: case reports, conference abstracts, non-English publications, animal experimental studies lacking human population verification, review letters, commentaries and editorial materials. Animal mechanistic studies were not fully excluded; animal data were only adopted to interpret molecular and neural pathways, and all core clinical conclusions were supported by human population studies.

We manually screened the reference lists of core reviews and landmark studies to capture potentially missed literature. This study follows the standard reporting norms for narrative reviews. Although a systematic literature retrieval framework was adopted to ensure comprehensiveness, no quantitative meta-analysis or formal risk-of-bias assessment was performed. All included evidence was qualitatively synthesized rather than statistically pooled.

Ethical approval was not required for this narrative review. Data sharing is not applicable to this article as no datasets were generated or analyzed.

Current Status and Characteristics of Comorbid Constipation and Mood Disorders

Epidemiological Association

The comorbidity of constipation and mood disorders exhibits a bidirectional predictive characteristic. A recent Mendelian randomization (MR) study by Zheng et al (2025) using UK Biobank and FinnGen data reported that major depression is causally associated with an increased risk of constipation (OR = 1.28, 95% CI: 1.12–1.46).¹⁰ These findings suggest a directionality in the comorbidity that warrants further investigation. However, MR studies have inherent limitations, including potential pleiotropy (where genetic variants affect multiple traits through independent pathways), the reliance on strong instrumental variable assumptions, and the absence of genetic evidence verifying reverse causality from constipation to mood disturbance. The reciprocal correlation is only confirmed by population cohort observations.⁵ A cross-sectional analysis of NHANES data 2005–2010 further reported a significant association: patients with anxiety or depression had a 2.1-fold higher odds of coexisting chronic constipation compared with individuals without mood disorders.⁴ This bidirectional association is particularly pronounced in the elderly population. Comorbid patients aged 60 and above represent 45% of elderly constipation cases. Longer duration of mood disorders has been associated with greater constipation symptom severity, though quantitative estimates vary across studies.

Population distribution reveals distinct patterns in comorbidity. The prevalence rate among women (28.7%) exceeds that of men (19.3%). This disparity may stem from women’s heightened sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis and reduced intestinal serotonin (5-HT) synthesis.¹¹ Furthermore, the incidence of comorbidity among individuals experiencing long-term mental stress, such as medical staff and professionals in high-pressure environments, reaches 35–40%. This rate is 1.7 times higher than that of the general population, underscoring the significant role of psychological stress as a predisposing factor for comorbidity.¹²

Key epidemiological evidence from recent observational and Mendelian randomization studies is summarized in Table 1.

Table 1.

Summary of Key Epidemiological Studies of Comorbidity

Study (Year)	Design	Sample Size	Key Finding	Limitation	Evidence Level	Key References
Zheng et al 2025	Bidirectional MR (UK Biobank, FinnGen)	~500,000	MD causally associated with constipation (OR = 1.28)	No reverse causality found; constipation-specific instruments limited	MR	[10]
Huang et al 2025	Cross-sectional + MR	12,000	38–52% comorbidity prevalence	Cross-sectional design	Cross-sectional / MR	[2]
Yun et al 2024	Population cohort	35,000	Constipation precedes depression by 1–5 years	Observational; residual confounding	Cohort	[5]
Refractory Constipation Study 2025	Retrospective cohort	610	Anxiety, depression, and somatic symptoms independent risk factors for refractoriness (AUC = 0.81)	Retrospective design; single center	Cohort	[13]

Clinical and Economic Burden

The clinical management of patients with comorbid conditions is notably more challenging. Intestinal motility tests indicate that the colonic transit time in these patients is prolonged by 36–45% compared to those with simple constipation. Additionally, the response rate to conventional laxatives decreases by 30%.¹⁴ In comparison to patients with uncomplicated mood disorders, comorbid patients experience a significantly higher rate of gastrointestinal adverse reactions to SSRIs, which may contribute to reduced treatment adherence.¹⁵ A 2025 retrospective analysis of 610 refractory constipation patients found that anxiety (Generalized Anxiety Disorder-7, GAD-7), depression (Patient Health Questionnaire-9, PHQ-9), and somatic symptoms (Patient Health Questionnaire-15, PHQ-15) were independent risk factors for refractoriness, with a predictive model AUC of 0.81, strongly supporting the integration of psychiatric assessment into constipation management.¹³ This treatment resistance directly escalates medical costs. Data from the Agency for Healthcare Research and Quality (AHRQ) in the United States reveal that the average annual hospital stay for comorbid patients is 1.8 times longer than that for patients with single diseases, and the frequency of emergency visits increases by 2.1 times.¹⁶

The impact of comorbidity on patients’ quality of life exhibits a “superimposition effect”. Evaluation using the 36-Item Short Form Health Survey (SF-36) indicates that comorbid patients experience reductions in scores for physical function and role-emotional dimensions by 40% to 60%, respectively. Notably, “social avoidance due to constipation” and “self-isolation stemming from low mood” mutually reinforce each other, leading to a more than 55% decrease in the quality of life scores of comorbid patients compared to healthy individuals.¹⁷

Pathogenesis of Comorbid Constipation and Mood Disorders

Evidence-level annotation: Throughout this section, we explicitly indicate the type of evidence supporting each mechanism: (animal study), (cross-sectional human), (Mendelian randomization), (RCT), etc.

Dysfunction of the Gut-Brain Axis Neural Circuit

Abnormal bidirectional communication between the central and enteric nervous systems serves as the core mechanism of comorbidity. Dense neural connections exist between mood-regulating brain regions (eg, the amygdala and prefrontal cortex) and those controlling intestinal function, including the hypothalamus and brainstem. In animal models of anxiety, optogenetic activation of the amygdala increased corticosterone release and reduced colonic migrating motor complexes by 25–30% [animal].¹⁸ Human correlational studies have shown similar associations between amygdala reactivity (fMRI) and colonic transit time, but causality remains unproven.¹⁹ Concurrently, diminished prefrontal cortex function weakens the inhibition of intestinal sensory signals, leading to a 40% decrease in patients’ pain threshold to intestinal distension.¹⁹ This establishes a vicious cycle of “emotional anxiety—intestinal hypersensitivity—aggravated physical discomfort”.

The enteric nervous system (ENS), often referred to as “the second brain”, serves as an independent regulatory unit that significantly influences comorbidity. In patients with comorbid conditions, alterations in the ratio of cholinergic to noradrenergic neurons have been described, which may contribute to reduced intestinal motility.²⁰ Additionally, the ENS and the central nervous system communicate bidirectionally via the vagus nerve. Metabolites from intestinal microbiota, such as short-chain fatty acids (SCFAs), are transmitted to the central nervous system through the vagus nerve, influencing amygdala activity.²¹ Conversely, emotional disturbances in the central nervous system can inhibit the ENS’s peristalsis regulation through the vagus nerve, further worsening constipation.

Intestinal Microbiota Imbalance and Inflammatory Response

Intestinal microbiota serves as a crucial regulator of the gut-brain axis, and its structural disorder correlates closely with comorbidity. Cross-sectional studies using 16S rRNA sequencing reveal that the α-diversity (Shannon index) of intestinal microbiota in comorbid patients decreases by 28–35%. Additionally, the number of beneficial bacteria, such as Bifidobacterium and Lactobacillus, declines by 30–40%, while the proportion of harmful bacteria, including Escherichia coli and Enterococcus, increases by 25–35%.²² A comprehensive 2026 narrative review on the microbiota-gut-brain axis (MGBA) summarized that gut dysbiosis in comorbid patients is characterized by reduced abundance of butyrate-producing bacteria (Faecalibacterium, Roseburia, Coprococcus), decreased microbial diversity, and enrichment of pro-inflammatory taxa.⁹ This imbalance mediates the onset of comorbidity through five major pathways:

Abnormal Metabolites: The reduction of beneficial bacteria results in a 40% decrease in the production of short-chain fatty acids (SCFAs), specifically butyrate and propionate. This reduction diminishes the expression of intestinal epithelial tight junction proteins, such as occludin and ZO-1, leading to increased intestinal barrier permeability. Consequently, endotoxins, including lipopolysaccharides (LPS), enter the bloodstream, triggering systemic low-grade inflammation. As a result, levels of central inflammatory factors, including IL-6 and TNF-α, increase by 30% to 35%, which subsequently inhibits neurogenesis in the hippocampus and exacerbates depression.²³

Disordered Neurotransmitter Synthesis: Intestinal microbiota produce 5-hydroxytryptamine (5-HT) precursor substances via tryptophan metabolism. In patients with comorbid conditions, the activity of tryptophan hydroxylase in the intestine decreases by 25%, resulting in a 30% reduction in intestinal 5-HT synthesis.²⁴ This reduction weakens intestinal peristalsis and diminishes the supply of 5-HT to the central nervous system, which bidirectionally exacerbates constipation and emotional abnormalities.

Insufficient Vagus Nerve Activation: Reduced colonization of beneficial bacteria diminishes the stimulation of sensory nerve endings in the intestinal mucosa, resulting in a 20–25% decrease in the firing frequency of the vagus nerve.²⁵ This reduction weakens the central nervous system’s regulatory effect on intestinal function, creating a closed loop of “microbiota imbalance—weakened neural signals—ineffective MGBA regulation”.

Immune Pathway Dysregulation: The MGBA also operates through immune pathways, where gut dysbiosis triggers the release of pro-inflammatory cytokines that cross the blood-brain barrier, influencing mood-regulating brain regions.⁹

HPA Axis Hyperactivity: Chronic stress leads to HPA axis overactivation, resulting in elevated cortisol levels that both inhibit intestinal motility and exacerbate depressive symptoms.⁹

Recent evidence has further expanded our understanding of microbiota–brain communication mechanisms. Estrada-Valbuena et al (2026) proposed that microbial extracellular vesicles (MEVs) act as key mediators of microbiota–brain communication by crossing biological barriers and modulating neuroimmune responses, with biologically plausible pathways relevant to mood disorders. This emerging mechanism adds a new dimension to the gut-brain axis framework, suggesting that microbial signals may be transmitted to the central nervous system not only through metabolites and neural pathways but also via nanoscale vesicular carriers.²⁶

To illustrate the interaction among these multiple mechanisms, Figure 1 presents a schematic diagram of the hypothesized pathogenesis.

Figure 1.

Schematic diagram of the bidirectional vicious cycle between chronic constipation and emotional disorders via the microbiota-gut-brain axis. At the gut level, gut microbiota dysbiosis leads to decreased short-chain fatty acids (SCFAs), impaired intestinal barrier function, and enteric nervous system (ENS) imbalance, ultimately slowing colonic motility and causing chronic constipation. These signals are transmitted to the brain through four major pathways: the vagal nerve pathway, immune-inflammatory pathway with elevated IL-6/TNF-α, HPA axis endocrine pathway with increased cortisol, and microbiota-derived metabolic signaling pathway, including microbial extracellular vesicles (MEVs) as emerging mediators of microbiota–brain communication.²⁶ In the brain, these signals induce amygdala hyperactivation and prefrontal cortex inhibition, leading to anxiety and depression-like emotional disorders. Emotional disorders in turn exacerbate gut dysfunction, forming a bidirectional vicious cycle. Solid arrows represent evidence from human studies; dashed arrows represent evidence from animal studies.

Current Status and Dilemmas of Pharmacotherapy for Comorbid Constipation and Mood Disorders

Limitations of Constipation-Treating Medications

Conventional Laxatives

Conventional laxatives are limited by single efficacy and significant long-term risks. Bulk-forming laxatives (eg, calcium polycarbophil) alleviate constipation by increasing stool volume but fail to address mood disorders. Furthermore, 15–20% of patients report abdominal distension and pain, which may heighten anxiety.²⁷ Stimulant laxatives, including bisacodyl, act quickly (within 4–8 hours); however, prolonged use (beyond 8 weeks) may damage enteric nervous system (ENS) neurons and alter gut microbiota composition, as suggested by animal studies,⁷ and may further diminish intestinal motility and potentially contribute to mood disturbances, though clinical evidence in comorbid patients remains limited.²⁸ Osmotic laxatives, such as polyethylene glycol 4000, exhibit fewer adverse reactions (5–10% incidence of abdominal distension), but they fail to regulate intestinal motility and mood. This limitation necessitates their combination with antidepressants, which increases the risk of drug-drug interactions.²⁹

New Prokinetic Agents

Prokinetic agents targeting the gut-brain axis represent a significant advancement, yet they pose tolerability risks. Serotonin 4 (5-HT4) receptor agonists, such as prucalopride, activate both intestinal and central 5-HT4 receptors, suggesting potential dual benefits for motility and mood. However, these agents present dose-dependent adverse reactions, including a headache incidence of 23.5% and diarrhea at 15.2%. Caution is advised when prescribing it to patients with comorbid arrhythmia.³⁰ In contrast, dopamine D2 receptor antagonists, like domperidone, alleviate constipation but do not affect mood. Additionally, long-term use may prolong the QT interval, increasing the risk of cardiac adverse events, necessitating strict electrocardiogram monitoring in clinical practice.³¹

Gastrointestinal Adverse Reactions of Mood Disorder-Treating Medications

Antidepressants serve as the cornerstone of mood disorder treatment; however, poor gastrointestinal tolerability poses a significant challenge in managing comorbidities. A comprehensive 2025 network meta-analysis of 196 RCTs (57,162 patients) systematically compared the gastrointestinal adverse effect profiles of 21 antidepressants. Compared with placebo, 15 antidepressants had significantly higher odds ratios for constipation, including amitriptyline, clomipramine, reboxetine, and duloxetine. Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and escitalopram fall at the mid-range of constipation risk among antidepressants. Notably, diarylurea antidepressants (eg, levomilnacipran) and vilazodone carry a higher risk of inducing nausea and vomiting, whereas trazodone, agomelatine, and mirtazapine tend to be better tolerated regarding gastrointestinal adverse effects. Among SSRIs, paroxetine, which possesses mild anticholinergic activity, exhibits a higher constipation incidence (approximately 32–40%), whereas escitalopram shows relatively lower rates (approximately 18–25%). Therefore, for comorbid patients, among SSRIs, escitalopram may be better tolerated from a gastrointestinal perspective. Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, demonstrate a more pronounced mood-enhancing effect and may be effective for anxiety, but their gastrointestinal adverse reaction rates remain notable.⁶ Tricyclic antidepressants (TCAs), such as amitriptyline, are among the most prone to inducing constipation, with a significantly higher risk compared to SSRIs, and are therefore infrequently prescribed for patients with comorbid constipation and mood disorders.

Table 2 summarizes the comparative risk of constipation and other gastrointestinal adverse events associated with different classes of antidepressants, along with clinical considerations for patients with comorbid constipation and mood disorders.

Table 2.

Gastrointestinal Adverse Effect Profiles of Common Antidepressants Based on Network Meta-Analysis

Antidepressant Class	Specific Agents	Constipation Risk (vs Placebo)	Other GI Effects	Clinical Consideration for Comorbidity
TCAs	Amitriptyline, Clomipramine	Higher risk (OR > 2.5)	Dry mouth, dyspepsia	Avoid in comorbid constipation
NRI / NaSSA	Reboxetine, Mirtazapine	Moderate–higher (reboxetine) / lower (mirtazapine)	Dry mouth, weight gain	Mirtazapine preferred (~13% incidence, but post-hoc data)
SSRIs (higher risk)	Paroxetine, Fluoxetine	Moderate (~1.5–2.0)	Nausea, diarrhea (fluoxetine)	Use with caution; consider alternatives
SSRIs (lower risk)	Escitalopram, Sertraline	Lower–moderate (~1.2–1.5)	Diarrhea (sertraline)	Escitalopram may be better tolerated
SNRIs	Duloxetine, Venlafaxine	Moderate–higher (duloxetine)	Nausea, anorexia	Monitor GI effects
Atypical	Trazodone, Agomelatine	Lower (better tolerated)	Minimal	Potential alternative for selected patients

Complexity of Drug-Drug Interactions

In the treatment of comorbidity, drug-drug interactions exacerbate the “efficacy-tolerability” dilemma. At the pharmacokinetic level, osmotic laxatives, such as polyethylene glycol, may accelerate gastrointestinal transit, theoretically reducing the absorption of some SSRIs, which could affect mood outcomes, though the clinical significance requires further study. It is theoretically possible that accelerated transit could reduce absorption of certain SSRIs, but no clinical data are available specifically in comorbid patients. Conversely, stimulant laxatives, such as senna leaf extracts, may alter gut enzyme activity, potentially affecting the metabolism of concurrently administered medications.³²

At the pharmacodynamic level, drug effects can produce either antagonistic or additive outcomes. In theory, combining selective serotonin reuptake inhibitors (SSRIs) with 5-HT4 receptor agonists could overstimulate intestinal 5-HT4 receptors, potentially increasing gastrointestinal motility. The combination of anticholinergic antidepressants, such as amitriptyline, with anticholinergic laxatives may synergistically inhibit intestinal peristalsis, leading to aggravated constipation. Furthermore, long-term use of SSRIs may alter the intestinal microbiota composition, which could have downstream effects on mood regulation via the MGBA, adding another layer of complexity in managing comorbid patients.³²

To illustrate this clinical challenge: consider a 55-year-old female patient with moderate depression (HAMD 22) and chronic constipation (Bristol Type 1, <3 spontaneous bowel movements/week). Initiating sertraline 50 mg daily improved her mood within 4 weeks (HAMD reduced to 14) but worsened her constipation (no bowel movement for 5 days, requiring emergency laxative use). Adding bisacodyl provided relief but caused abdominal cramping that exacerbated her anxiety. This case exemplifies the efficacy-tolerability dilemma—effective mood treatment came at the cost of worsened gastrointestinal symptoms and reduced quality of life. Such scenarios underscore the importance of carefully weighing gastrointestinal tolerability when selecting antidepressants for comorbid patients and of monitoring potential interactions when combining gastrointestinal and psychiatric medications. The following section reviews emerging strategies to address these limitations.

Optimization Strategies to Overcome the Efficacy-Tolerability Dilemma

Mechanism-Oriented Drug Selection

Drug Selection Based on Symptom Priority and Individual Characteristics

The treatment of comorbidity adheres to the principle of “symptom stratification and individualized matching”. Table 3 provides a structured overview of key therapeutic interventions with their evidence classification for the comorbid population.

Table 3.

Key Therapeutic Interventions – Evidence Classification for Comorbid Population

Intervention	Target	Classification	Key Supporting Evidence	Major Limitations for Comorbid Use	Key References
Osmotic laxatives (PEG)	Constipation only	Established	RCTs in constipation	No mood effect	[29]
SSRIs (escitalopram)	Mood disorders	Established	Large RCTs in MDD	May worsen constipation in subset of patients	[6]
Mirtazapine	Mood + minimal constipation	Established for mood (preferred in comorbid)	RCTs; 2024 tolerability data	Weight gain, sedation	[33]
Prucalopride	Constipation + possible mood benefit	Promising (requires study in comorbidity)	Emulated target trial (n > 13,500)	No dedicated RCT in comorbid patients	[34]
Bifidobacterium probiotics	Both (exploratory)	Investigational	RCT in healthy adults; pilot in IBS	Mixed results; limited evidence in comorbid constipation	[35,36]
GLP-1 receptor agonists	Mood (potential) + weight	Investigational	Large meta-analysis (n = 107,860)	May cause/worsen constipation; no direct evidence in comorbidity	[37]
MDT model	Care delivery	Promising	One RCT	Single site; requires replication	[38]
Matrine nanoparticles	Both (exploratory)	Preclinical	Preclinical study	No human data; requires clinical validation	[39]

For patients with predominant mood symptoms and mild constipation (Mood-predominant phenotype), it is advisable to prioritize antidepressants that minimally impact intestinal motility. Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), is particularly suitable in this context. Mechanistically, mirtazapine acts as a potent antagonist at 5-HT2 and 5-HT3 receptors, accounting for its low rate of gastrointestinal side effects compared to SSRIs. Clinical data from tolerability analyses indicate that mirtazapine is associated with a constipation incidence of only approximately 13%, which appears lower than that associated with many SSRIs and TCAs.³³ However, mirtazapine is associated with significant weight gain (mean 2–3 kg over 8 weeks) and dose-related sedation (lower doses ≤15 mg are more sedating), which may limit its use in individuals with obesity or those requiring high daytime alertness. In such cases, alternative options such as bupropion or low-dose escitalopram combined with a prokinetic agent may be considered.

For patients with predominant constipation and mild mood symptoms (Constipation-predominant phenotype), it is preferable to use medications that may benefit both intestinal motility and mood. Prucalopride, a highly selective 5-HT4 receptor agonist, is licensed for chronic idiopathic constipation and has shown promising effects on cognition in individuals with remitted depression.⁴⁰ Recent evidence from an emulated target trial using electronic health records (n > 13,500) found that prucalopride prescription for constipation was associated with a reduced incidence of depression compared to alternative anti-constipation agents (HR = 0.84, 95% CI: 0.73–0.96 for lubiprostone; HR = 0.85, 95% CI: 0.75–0.97 for linaclotide).³⁴ These findings suggest a potential mood-protective effect of 5-HT4 receptor agonism, though confirmatory randomized controlled trials in the comorbid population are still needed.

For patients with balanced symptom severity (Mixed phenotype), combination strategies may be appropriate. One approach involves initiating low-dose escitalopram (5–10 mg) combined with prucalopride (1–2 mg), with careful titration based on both mood response and bowel function. Another option is bupropion (150–300 mg) combined with an osmotic laxative such as polyethylene glycol, as bupropion has a relatively low gastrointestinal side effect profile.

Special populations necessitate enhanced safety considerations. For patients with comorbid intestinal microbiota imbalance, the combined use of Bifidobacterium quadruple viable tablet may improve constipation outcomes and may indirectly address associated negative emotions, though large-scale trials are required.⁴¹

Drug Screening Based on Side Effect Profiles

When selecting drugs, it is essential to evaluate their effects on intestinal function and microbiota. Among antidepressants, bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI), exhibits a relatively low incidence of gastrointestinal adverse reactions. In clinical trials, the incidence of constipation with bupropion is approximately 8% to 13%, lower than that observed with many SSRIs.⁴² A systematic review and meta-analysis supports the use of bupropion as an effective sole or coprescribed antidepressant, with comparable effectiveness to other antidepressants.⁴³

Synergistic and Efficacy-Enhancing Combined Medication Regimens

Emerging Combination Approaches

Combination regimens targeting both intestinal and mood improvement are an important area of investigation. A clinical trial is currently ongoing to evaluate whether the addition of prucalopride to escitalopram can improve treatment response in patients with major depressive disorder, although results are not yet available.⁴⁴ Preclinical studies have provided the mechanistic rationale for such combination strategies. However, clinicians should be aware of potential pharmacodynamic interactions: combining SSRIs with 5-HT4 agonists could theoretically overstimulate intestinal 5-HT4 receptors, potentially leading to diarrhea or abdominal cramping in some patients.

Another combination under investigation involves probiotics and SSRIs. A 2024 randomized, double-blind, placebo-controlled trial (n = 120) in healthy adults with high mental stress, insomnia, and constipation found that Bifidobacterium breve 207–1 significantly increased GABA levels, suppressed HPA axis hormones, and improved sleep quality, though significant mood-modulating efficacy was not observed.³⁵ A separate pilot study in IBS patients (n = 35) reported that Bifidobacterium longum NCC3001 improved depression scores and decreased amygdala activation, with these effects correlated with increased butyric acid levels.³⁶ Collectively, these findings suggest that certain Bifidobacterium strains may offer promise as adjunctive therapies in comorbid conditions, but large-scale confirmatory trials are needed.

Adverse Reaction Antagonism Regimens

Combination strategies targeting adverse drug reactions can enhance tolerability. For patients experiencing aggravated constipation from selective serotonin reuptake inhibitors (SSRIs), the addition of a prokinetic agent such as prucalopride may theoretically counteract the intestinal inhibitory effects, though clinical evidence in the comorbid population remains limited at present.

The evidence level, clinical effects and limitations of major therapeutic interventions for this comorbid population are classified and summarized in Table 3.

New Research Progress and Future Prospects

New Drug Development Directions

Gut-Brain Axis Multi-Target Drugs

GLP-1 receptor agonists are an emerging area of research in neuropsychiatry. These medications, widely used for obesity and diabetes, have recently been evaluated for their psychiatric safety and potential mood effects. A 2025 meta-analysis of 80 double-blind placebo-controlled RCTs (107,860 patients) examining GLP-1 receptor agonists (including semaglutide) found that these medications were not associated with an increased risk of psychiatric adverse events or worsening of depressive symptoms compared to placebo. The study further reported improvements in mental health-related quality of life, restrained eating, and emotional eating behaviors, providing reassurance regarding the psychiatric safety profile of GLP-1 receptor agonists.³⁷ However, real-world studies have also noted a significant risk of gastrointestinal adverse effects, including nausea (up to 44%) and constipation (25–33%). Given that constipation is a known gastrointestinal side effect of GLP-1 receptor agonists, their role in the specific comorbid population of constipation and mood disorders remains unclear and requires dedicated investigation. The constipation risk associated with these agents may limit their utility in patients already suffering from chronic constipation, and clinicians should exercise caution when considering GLP-1 RAs in this population.

Multi-target drug development targeting serotonin receptors continues to advance. Preclinical studies of 5-HT1A/5-HT4 dual receptor modulators have shown the potential to simultaneously alleviate anxiety and enhance intestinal motility, but these agents remain in early-stage development and have not yet been evaluated in clinical trials for the comorbid population of interest.

Nanoparticle-based delivery systems represent another promising frontier. Liu et al (2025) demonstrated that matrine nanoparticles improved functional constipation and associated depressive behavioral disorders by modulating the gut-brain axis in preclinical models. This approach highlights the potential of nanotechnology to enhance the bioavailability and targeted delivery of bioactive compounds with dual effects on gastrointestinal and mood symptoms, though clinical translation in the comorbid population requires further investigation.³⁹

Intestinal Microbiota-Targeted Drugs

Microbiota-targeted therapies offer promise for the comorbid population. Psychobiotics—probiotics that confer mental health benefits through the gut-brain axis—are gaining attention. The MGBA facilitates communication through neural pathways (vagus nerve), immune pathways (cytokines), endocrine pathways (HPA axis), and metabolic pathways (SCFAs, neurotransmitter precursors). Microbiota-targeted interventions, including psychobiotics, prebiotics, and dietary modifications, have shown preliminary efficacy but remain at an early stage of clinical validation.⁹

Butyrate supplementation has been investigated as a potential intervention to enhance intestinal barrier function and exert anti-inflammatory effects. A 2024 randomized controlled trial in IBS patients found that Bifidobacterium longum NCC3001 increased butyric acid levels, which correlated with lower anxiety and depression scores and decreased amygdala activation (p < 0.05),³⁶ suggesting that butyrate might serve as a biochemical marker linking microbial metabolism with beneficial effects on the gut-brain axis. However, this study was conducted in non-constipation IBS patients, and its generalizability to the comorbid constipation-mood disorder population requires confirmation.

Innovation in Treatment Concepts

Application of Precision Medicine

Multi-omics technology advances the treatment of comorbidities from an “empirical” to a “precision” approach. By detecting the 5-HTTLPR polymorphism of the serotonin transporter gene (SLC6A4), researchers may predict patients’ responses to selective serotonin reuptake inhibitors (SSRIs). Patients carrying the S allele exhibit a higher incidence of intestinal adverse reactions to SSRIs, suggesting a preference for alternative medications such as mirtazapine and bupropion.⁴⁵ Additionally, by identifying microbiota imbalances through 16S rRNA sequencing, clinicians could potentially tailor treatments, though this approach remains largely investigational.

Multidisciplinary Team (MDT) Model

The “Gastroenterology + Psychiatry + Nutrition” MDT model has been validated for effectiveness in clinical practice. In the model tested by Basnayake et al,³⁸ the team met biweekly for 60 minutes, with gastroenterologists performing colonic transit tests and anorectal manometry, psychiatrists administering HAMD/GAD-7 scales and adjusting antidepressants, and dietitians providing high-fiber (25–30 g/d) and probiotic supplementation. Primary outcomes were the proportion of patients achieving ≥50% reduction in PAC-SYM score and ≥30% reduction in HAMD score at 12 weeks. Clinical data indicate that the MDT model may increase the treatment response of comorbid patients, though the exact magnitude of benefit varies across studies.³⁸ Future efforts should focus on further establishing the MDT approach and developing long-term follow-up management systems.

Beyond pharmacotherapy, non-pharmacological interventions play an important adjunctive role. Cognitive-behavioral therapy (CBT) has been shown to reduce anxiety and depression symptoms in patients with functional gastrointestinal disorders and may improve constipation-related quality of life. Mindfulness-based stress reduction (MBSR) and gut-directed hypnotherapy have also demonstrated benefits in reducing visceral hypersensitivity and improving bowel symptoms. Regular physical exercise, particularly moderate aerobic activity, can enhance intestinal motility and improve mood through endorphin release and microbiota modulation. Dietary interventions, including increased soluble fiber intake (psyllium, oats), adequate hydration, and consumption of fermented foods containing probiotics, may support both gastrointestinal function and mental health through modulation of the gut microbiota. These non-pharmacological approaches should be integrated into the MDT care model as complementary strategies.

Conclusion

The primary therapeutic challenge in managing comorbid constipation and mood disorders is the imbalance between efficacy and tolerability. This dilemma arises because conventional medications typically target a single mechanism, overlooking the complex interactions within the gut-brain axis. Addressing this challenge requires mechanism-oriented drug selection, optimized combination regimens, and individualized management approaches.

Limitations of the Current Evidence Base

Nearly all studies cited in this review are either (i) animal studies, (ii) cross-sectional or observational human studies, or (iii) small open-label trials without adequate control groups. No large (n > 200) randomized controlled trial has specifically tested any gut-brain-axis-targeted intervention in patients with the specific comorbidity of constipation and mood disorders. Many of the quantitative claims in the literature—including precise response rates for combination therapies—derive from small or uncontrolled studies and have not been independently replicated. Therefore, our recommendations should be viewed as hypothesis-generating and directions for future research rather than established clinical guidelines.

Future Perspectives

Future research should focus on three key directions. First, well-designed randomized controlled trials with adequate sample sizes are urgently needed to evaluate gut-brain-axis-targeted interventions specifically in the comorbid constipation-mood disorder population. Second, researchers should utilize multi-omics technology to construct a “mechanism-target-drug” matching model aiming toward precision treatment. Third, large-sample longitudinal studies are necessary to identify early warning markers for comorbidity, including intestinal microbiota characteristics and inflammatory factor levels. Additionally, further promotion of the MDT model and integration of multidisciplinary resources—including dietary counseling, CBT, and physical activity programs—are essential to enhance the clinical prognosis and quality of life for patients with comorbidities.

Funding Statement

This work was supported by the Health Commission of Mianyang City (Grant No. 2024078).

Declaration of AI Use

During the manuscript preparation, multiple artificial intelligence tools were utilized to assist with linguistic polishing, English translation, and conceptual schematic drawing. We hereby confirm that all content in this manuscript is original and all cited data are accurate. The AI tools adopted in this work are as follows: Doubao (Version 13.3.0) for text polishing, English translation and auxiliary drawing; DeepSeek for academic text sorting and expression optimization; Meitu Xiuxiu (Version 12.9.0) for image editing and post-processing; WPS for the production of mechanism diagrams and table layout. All authors have fully reviewed the service agreements of the above AI tools, and verify that all AI-generated texts and graphics comply with the publication standards of academic journals. We guarantee that we hold complete legal publication rights for all AI-assisted textual and visual materials, and have obtained all necessary authorization for journal submission. All authors take full responsibility for the integrity of the full manuscript and the accuracy of all references. Original versions of all figures and the complete prompt records applied to generate AI content are properly archived by the authors for potential review inspection upon journal request.

Abbreviations

5-HT, Serotonin; ENS, Enteric nervous system; FGIDs, Functional gastrointestinal disorders; GLP-1, Glucagon-like peptide-1; HAMD, Hamilton Depression Scale; HPA axis, Hypothalamic-pituitary-adrenal axis; MDT, Multidisciplinary team; MEVs, Microbial extracellular vesicles; MGBA, Microbiota-gut-brain axis; MR, Mendelian randomization; PAC-SYM, Patient Assessment of Constipation-Symptom; SCFAs, Short-chain fatty acids; SNRIs, Serotonin-norepinephrine reuptake inhibitors; SSRIs, Selective serotonin reuptake inhibitors; TCAs, Tricyclic antidepressants.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests in this work.