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Sensitivity analyses to examine factors contributing to heterogeneity in randomised controlled trials of antidepressants versus placebo in irritable bowel syndrome (IBS)
Source publication
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence for treatment of the condition with antidepressants and psychological therapies is conflicting.
Systematic review and meta-analysis of randomised controlled trials (RCTs). MEDLINE, EMBASE and the Cochrane Controlled Trials Register were searched (up to May 20...
Context in source publication
Context 1
... this appeared to be driven by the TCA arm of one small study, 51 and when this study arm was excluded from the meta-analysis the asymmetry was no longer statistically significant (Egger test, p = 0.07). Sensitivity ana- lyses were conducted (table 3). Treatment effect appeared to be increased in secondary care-based studies, studies that did not state method of generation of the randomisation schedule or method of concealment of allocation, and studies scoring less than 4 on the Jadad scale. ...
Citations
... Between 20% and 30% of people with IBS also have concomitant MDD. About 15% of adult US citizens suffer with irritable bowel syndrome, which also contributes to up to 25% outpatient workload of a gastroenterologist [22,23]. Thus, it is important to prevent IBS among MDD patients at the onset. ...
... Thus, it is important to prevent IBS among MDD patients at the onset. On the other hand, given the coexist of the two diseases, in clinical practice antidepressants including both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are usually used to treat irritable bowel syndrome, the possible pathophysiological mechanisms are alterations in serotonergic signaling or metabolism and disturbance in neurotransmitter-related control of communication between the enteric nervous system and the brain, or called "the brain-gut axis" [22][23][24]. A potential mechanism that could explain the increased risk of IBS associated with MDD involves the activation of the cingulate region of the limbic system in the cerebral cortex. ...
Background
Previous studies have revealed a connection between major depressive disorder (MDD) and irritable bowel syndrome (IBS), but it remains obscure if the two diseases are related causally. Mendelian randomization was utilized in this investigation to ascertain whether MDD contributed to the emergence of IBS.
Methods
To examine possible connections between MDD and IBS, we used two-sample Mendelian randomization (MR) utilizing summary data from genome-wide association studies (GWAS). The Psychiatric Genomics Consortium (PGC) provided information on genetic associations with MDD (cases: 135,458; controls: 344,901). The Medical Research Council Integrative Epidemiology Unit (MRC-IEU) provided information on genetic associations with IBS (cases:10,939; controls:451,994). Inverse Variance Weighted (main analyses), MR-Egger regression, Weighted mode, and Weighted Median were the four MR methods used in this investigation. In addition, we also performed multiplicity and heterogeneity analyses to eliminate possible biases.
Results
In the standard Inverse Variance Weighting (IVW) method, an increased risk of IBS was linked to a genetic susceptibility to MDD (OR: 1.01; 95% CI: 1.006 to 1.014, p = 1.02E-07). In addition, neither significant heterogeneity (IVW Q = 24.80, p = 0.73) nor horizontal pleiotropy (MR Egger p = 0.17; MRPRESSO p = 0.54) were detected in this MR analysis. The bidirectional analysis, however, did not show a genetic link between IBD and MDD ( p steiger <0.01).
Conclusion
A direct causal relationship between MDD and IBS was revealed by Mendelian randomization study, which contributes to the effective clinical management of both diseases.
... In a systematic and meta-analysis study, Ford et al. concluded that antidepressants reduced IBS symptoms in comparison with placebo, and this was independent of their impact on depression, anxiety, and sensory-motor function of the intestine. [23] However, the sample size in most of these studies was not sufficient for meta-analysis. Also, the duration of treatment in this study (six weeks) was shorter than the recommended time (8 to 12 weeks), and there was no follow-up. ...
... [9] Psychological factors are considered to play a role in exacerbation of symptoms in IBS; therefore, antidepressants may be regarded as a type of IBS treatment and can significantly improve the patients' condition. [23] A preliminary study of Duloxetine on the patients with IBS indicated that this drug could result in lowering the pain, disease severity, and anxiety and improving QOL. [22] This could be another reason for the reduction of some symptoms after the use of antidepressants in patients with IBD, such as what was achieved in our study as the effect of 60 mg Duloxetine on symptoms and quality of life in moderate-to-severe IBS. ...
Background
Irritable bowel syndrome (IBS) is a chronic disease. There are very few studies on the Duloxetine efficacy in improving the gastrointestinal and psychological symptoms, in IBS. The current study attempted to evaluate the effectiveness of Duloxetine in symptoms and quality of life in moderate-to-severe IBS patients.
Materials and Methods
This is a double-blind placebo-controlled clinical trial in which the population is composed of 37 patients with moderate-to-severe IBS in Isfahan from March 2018 to March 2019. For the intervention group, Duloxetine was administered for three months, and the treatment protocol was the same for the control group but using a placebo. The severity of IBS symptoms, quality of life, and negative emotions such as depression, anxiety, and stress were assessed.
Results
Our data showed no significant difference between the two groups of the study for the severity of IBS symptoms (P value = 0.150); however, in the intervention group, it was significantly lower than controls after six, eight, and ten weeks of the intervention (P value = 0.023). Overall evaluation of the quality of life in patients indicated significantly higher quality of life in the Duloxetine group than the control group from the eighth week to the twelfth week after the intervention (P value <0.038). Anxiety and stress in the Duloxetine group were significantly lower than controls after the intervention (P value <0.05).
Conclusion
Duloxetine is probably helpful for reducing anxiety, stress, and the severity of symptoms in IBS patients. It also could increase the quality of life in patients.
... We also looked at studies on the treatment of chronic tension headaches [50,97], migraines [21,26,32,88], and complex conditions such as fibromyalgia [16,24,58,78,86], among others. Non-painful conditions were also studied, such as fibrositis [102], gastrointestinal disorders [35,44,57], post-traumatic stress [104], and nonmotor symptoms of Parkinson's disease [17]. This transformation in the paradigms studied follows its use in clinical practice and seeks to subsidize the long list of uses currently classified as "off-label", as they do not correspond to registration in official agencies [3]. ...
Amitriptyline was first introduced as a medication to treat depression. Over time, this substance has been used to treat other conditions, such as gastrointestinal disorders, fibromyalgia, neuropathic pain, and analgesia, among others. However, there are no published studies that provide a broad view of the possible motivations that have led to changes in the use of amitriptyline. In this study, we have identified the landscape of use for amitriptyline based on knowledge mapping of the 100 most-cited articles about this drug. We searched Web of Science Core Collection without time and language restrictions. We obtained 14,446 results, but we only used the 100 most-cited articles that had amitriptyline as the object of study. We collected the following information from each article: authors, country of the corresponding authors, year of publication, citation count, citation density (number of citations per year), and keywords. In addition, we seek to map in the chosen articles study design and research findings. We found that since 1980, the use of amitriptyline has expanded beyond depression, moving to off-label use to treat a variety of diseases and conditions, including post-herpetic neuralgia, neuropathic pain, primary fibrosis, fibromyalgia, and migraine, can be considered a drug with more clinical applicability than its original clinical indication.
... Pharmacological treatment modalities for IBS target GI receptors and ion channels, peripheral opioid receptor, gut serotonin receptors, and gut microbiota [51] (Figure 2). Selective serotonin reuptake inhibitors and tricyclic antidepressants are effective in numerous IBS cases, suggesting the implication and dysfunction of the central or peripheral serotonergic system in IBS pathophysiology [52,53]. Psychological therapies also appear to be effective treatments for IBS, although there are limitations in the quality of evidence, and treatment effects may be overestimated as a result [54]. ...
Irritable Bowel Syndrome (IBS) is the most common gastrointestinal (GI) disorder in Western populations and therefore a major public health/economic concern. However, despite extensive research, psychological and physiological factors that contribute to the aetiology of IBS remain poorly understood. Consequently, clinical management of IBS is reduced to symptom management through various suboptimal options. Recent evidence has suggested human milk oligosaccharides (HMOs) as a potential therapeutic option for IBS. Here, we review literature concerning the role of HMOs in IBS, including data from intervention and in vitro trials. HMO supplementation shows promising results in altering the gut microbiota and improving IBS symptoms, for instance by stimulating bifidobacteria. Further research in adults is required into HMO mechanisms, to confirm the preliminary results available to date and recommendations of HMO use in IBS.
... The prevalence of anxiety and depression increases progressively with the number of coexisting FGID disorders and the frequency and severity of gastrointestinal symptoms (11). Cognitive behavioral therapy and mood-improving medications may help alleviate gastrointestinal symptoms in patients with FGID (12). Anxiety was shown to be an independent predictor of firstepisode FGIDs in a 12-year prospective study, and patients diagnosed with FGIDs also had higher anxiety during followup (13). ...
Objective
The aim of this study was to investigate the characteristics of intestinal flora in patients with functional gastroenteropathy and generalized anxiety disorder (GAD) and the relationship between intestinal flora and psychological factors.
Materials and methods
From March 2020 to December 2020, a total of 35 patients with functional gastroenteropathy and generalized anxiety disorder, 30 healthy controls, 16 patients with functional gastroenteropathy, and 44 patients with generalized anxiety disorder were selected from the Affiliated Hospital of Guizhou Medical University. Fecal samples were collected from each group, and the related psychophysiological factors scales (Hamilton Anxiety Scale, Hamilton Depression Scale, Neurotic Personality Questionnaire, concept of illness questionnaire, Toronto Alexithymia Scale, Severity of Physical Symptoms Scale, and Cognitive Emotion Regulation Questionnaire) were improved. 16S rRNA high-pass sequencing was used to determine the correlation between intestinal flora changes and functional gastroenteropathy with generalized anxiety disorder. Then, the scale and gut microbiota results were analyzed for correlation to determine the correlation between personality traits and gut microbiota.
Results
We found similar intestinal microbiota in patients with functional gastroenterology, generalized anxiety disorder, and functional gastroenteropathy with generalized anxiety disorder. But the relative abundance of Clostridium was significantly increased in patients with functional gastrointestinal disease (FGID) and generalized anxiety. The relative abundance of Haemophilus influenzae was significantly increased in patients with functional gastrointestinal disease without a generalized anxiety disorder. The intestinal microecological composition was significantly correlated with personality traits.
Conclusion
Functional gastrointestinal disease comorbidity GAD may be related to an increase in the relative abundance of Fusobacterium. FGID non-comorbidity GAD may be related to the increased relative abundance of Hemophilus. The increased relative abundance of Fusobacterium and Megamonas is associated with personality traits such as difficulty describing feelings and difficulty identifying feelings, neuroticism, and negative cognition of disease.
... 77 CBT has been evaluated in a variety of chronic pain conditions and has been associated with improvement in pain, physical function, and mood symptoms. [78][79][80][81] Interestingly, CBT modulated connections in pain-processing regions of the brain on functional MRI in patients with endometriosis. 18,82 Careful presentation of this strategy is essential, as many patients with chronic pain conditions may be hesitant to consider "therapy" given prior experiences with pain being dismissed as psychological in origin. ...
Chronic pelvic pain (CPP) is multifactorial in etiology and heterogeneous in presentation. Identification of all pain contributors is essential for successful management. Chronic overlapping pain conditions (COPCs) are a specified group of chronic pain conditions that commonly co-occur in patients. We briefly review individual COPCs and highlight risk factors and mechanisms that appear to be applicable across COPCs. We review evaluation and communication strategies that may help establish a productive therapeutic relationship between clinicians and patients. Management should include treatment of peripheral pain generators as well as co-occurring psychological conditions and central sensitization when present.
... Ces molécules peuvent avoir, de manière indirecte, un effet bénéfique sur les symptômes gastro-intestinaux. En effet, ils peuvent agir au niveau périphérique en (Ford et al., 2009;Ford, Quigley, et al., 2014). Par ailleurs, le bénéfice d'une utilisation à long terme des antidépresseurs pour des indications non psychiatriques n'est à l'heure actuelle pas vérifiée. ...
Les perturbations de l'axe cerveau-intestin-microbiote font l’objet de nombreuses études afin de mettre au point de nouveaux traitements pour les pathologies intestinales chroniques telles que le syndrome de l’intestin irritable (SII). Dans certains cas, à la suite d’une infection gastro-intestinale par des Entérobactéries et malgré l'élimination de l'agent pathogène, des troubles du transit et des douleurs abdominales chroniques persistent et peuvent favoriser le développement de symptômes anxio-dépressifs. Ceci est alors appelé SII post-infectieux (SII-PI). En développant un modèle préclinique d'infection à Citrobacter rodentium, mes travaux se sont focalisés sur (1) l’étude de l'impact de la cytokine IL-22 sur les symptômes associés au SII-PI, (2) l’étude du métabolisme du tryptophane (Trp), en particulier l'expression d’AhR induite par ses ligands dérivés du microbiote et, (3) l’étude du microbiote et du métabolome fécal sur les troubles de l'homéostasie suite à la résolution d’une infection gastro-intestinale. Ainsi, nous avons montré que le modèle murin d'infection à C. rodentium développe en période post-infectieuse, une hypersensibilité viscérale d’origine colique (HSVC) persistante, un comportement de type anxieux ainsi que des altérations cognitivo-émotionnelles, associés à une dysbiose, une inflammation à bas bruit et à une perméabilité intestinale augmentée montrant qu’il s’agit d’un modèle pertinent pour étudier les mécanismes physiopathologiques du SII-PI. Dans un premier temps, des analyses de métabolomique dirigée ont dévoilé des perturbations fonctionnelles au niveau fécal en phase post-infectieuse. Le métabolisme du Trp est altéré avec une diminution de la voie indole et de l'activité d’AhR ainsi qu’une diminution de la production du tryptophol. La production de la cytokine IL-22 peut être activée par la voie AhR et représente un acteur essentiel de l’homéostasie intestinale. Ainsi l’efficacité de la vectorisation d’IL-22 à l’aide d’une souche de Lactococcus lactis portant un plasmide d'expression eucaryote pour l’IL-22 murine (L. lactisIL-22) a été testée dans ce modèle animal de SII-PI. Le traitement avec L. lactisIL-22 permet d’améliorer les perturbations associées à l’infection par C. rodentium durant la phase post-infectieuse. Nos résultats suggèrent que le ciblage de la voie de signalisation AhR/IL-22 atténue les symptômes du SII-PI en agissant sur l'intégrité de la barrière épithéliale intestinale et les métabolites du Trp dérivés du microbiote. Les études de métabolomique ont été élargies afin d’identifier les perturbations fonctionnelles du microbiote fécal induite par l’infection. Ces travaux ont permis de préciser la physiopathologie du SII-PI et d’identifier de nouvelles cibles thérapeutiques potentielles telle que la voie AhR/IL-22. De plus, le rôle d’autres infections sur les comportements cognitivo-émotionnels de l’hôte a été étudié dans deux modèles animaux. Une infection chronique parasitaire à Blastocystis chez le rat a été utilisé afin de mimer un SII, ainsi qu’une infection chronique aux Escherichia coli producteurs de colibactine (CoPEC), Entérobactéries associées au cancer colorectal (CCR).
... Treatments that target alterations in gut microbiota may be beneficial for patients with IBS [28]. Effective pharmacological therapies for IBS exist, but the duration of most treatment trials is less than 6 months, and so the long-term efficacy of these therapies is unclear [29,30]. ...
Functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, functional constipation, and functional dyspepsia, have had a high prevalence over the past few years. Recent evidence suggests that functional foods and bioactive compounds, such as probiotics and phytochemicals, may have a positive effect in treating the symptoms of the above diseases. In this systematic review study, 32 published studies were selected with the use of comprehensive scientific databases, according to PRISMA guidelines, with emphasis on recent interventional studies that reflect the effect of probiotics and selected phytochemicals on the improvement of FGID symptoms. The bioactive compounds in the selected studies were administered to patients either in capsule form or in enriched food products (yogurt, juice, etc.). According to the results, there is a correlation between the consumption of probiotics and phytochemicals, such as polyphenols, and the relief of symptoms in selected gastrointestinal disorders. Enriching foods that are regularly consumed by the population, such as fruit juices, yogurt, and cheese, with ingredients that may have a positive effect on gastrointestinal disorders, could be a possible novel goal for the management of these diseases. However, further evidence is required for the role of probiotics and phytochemicals in FGIDs to be fully understood.
... Similarly, another trial with 193 patients also found that depression was not associated with fullness but had a positive association with abdominal pain, which is the main symptom of EPS. Although antidepressants including tricyclic antidepressants and selective serotonin reuptake inhibitors have been used for irritable bowel syndrome [21], their efficacy in FD management is very uncertain. A multicenter, randomized, placebo-controlled trial with 292 subjects found that antidepressants appeared to benefit some patients with ulcer-like (painful) FD, not dysmotility-like FD, and patients with delayed gastric emptying do not respond to these drugs [7]. ...
Background:
Postprandial distress syndrome (PDS) is accompanied by a high incidence of mood disorder. Acupuncture is an effective method in relieving dyspepsia symptoms; however, the impact of psychological status on acupuncture for PDS remains mysterious.
Methods:
This secondary analysis of a multicenter, randomized controlled trial aims to evaluate the influence of anxiety and depression on acupuncture for PDS. 138 patients received the same acupuncture treatment and were followed up until week 16. The 2 primary outcomes were the response rate based on overall treatment effect and the elimination rate of all 3 cardinal symptoms after 4 weeks of treatment.
Results:
Of 114 patients, 31 were anxiety patients and 83 were nonanxiety patients or 32 were depressive patients and 82 were nondepressive patients. The response rate and elimination rate at week 4 were 77.4% and 9.7% in anxiety patients versus 84.3% and 27.7% in nonanxiety patients, respectively (P = 0.388; P = 0.041). No significant difference was noted in the response rate (P = 0.552) and elimination rate (P = 0.254) at week 4 between nondepressive and depressive patients. There was no significant intergroup difference in the response rate and elimination rate between non-mood-disorder and mood disorder patients (P > 0.05) during the 12-week post-treatment follow-up, except for the response rate at week 8 (P < 0.05).
Conclusion:
The effect of acupuncture on response rate was similar for both non-mood-disorder and mood disorder patients. However, anxiety but not depression had a negative influence on the elimination rate, especially in postprandial fullness.
... Currently, more attention is being paid to the treatments for the psychological problems of IBD patients [11,12]. A range of psychological therapies is now used as part of the combined clinical treatment in many settings [33,34]. Such treatments may effectively alleviate symptoms such as anxiety and depression as well as improve physical symptoms in patients with inflammatory bowel disease [35]. ...
... Stress level Two studies (134 participants in total) reported participants' stress levels after the intervention, one reported effectiveness (P = 0.04) [49], the other did not (P = 0.34) [50]. Four studies (334 participants in total) reported the stress level of participants at follow-up [50,51], and two reported effectiveness (P = 0.04 [34]; P < 0.01 [46]). However, Mikocka-Walus's study reported that the stress level of the control group also fell statistically (P = 0.01) [46]. ...
Objective
Cognitive behavioral therapy (CBT) is now included in the treatment of patients with inflammatory bowel disease (IBD) in many settings. However, different clinical trials report different outcomes without consensus. This study aims to evaluate the impact of CBT on the mental state, quality of life and disease activity of patients with IBD.
Design
Systematic review.
Methods
This systematic review searched eligible studies from 1946 to December 8, 2019, in MEDLINE, EMBASE, CINAHL, Cochrane library, ClinicalTrials.gov, PsycINFO, Web of Science for eligible randomized controlled trials (RCT).
Results
Among the initial identified 1807 references, 11 studies met inclusion criteria. CBT was shown to improve patient's quality of life and reduce the level of depression and anxiety post-intervention but was not sustained. Evidence is not enough for the effect of CBT on disease activity, or C-reactive protein level.
Conclusions
CBT has shown short-term positive psychological effects on IBD patients, but there is insufficient evidence for sustained physical and psychological improvements of IBD patients.
PROSPERO registration : CRD42019152330.
