Calum D. Moulton

Background: Although depressive symptoms are highly prevalent in IBD based on questionnaire estimates, the prevalence of stringently diagnosed depression in IBD is unclear. This is important because higher‐intensity treatments for depression are only recommended in this subgroup. Methods: We searched PubMed, Web of Science, Embase and PsycINFO to June 8, 2026 for studies reporting prevalence of depressive disorders in IBD diagnosed using structured or semi‐structured clinical interviews. Random‐effects meta‐analyses were used to estimate the prevalence (with 95% CIs) of depressive disorders among patients with IBD. Current major depressive disorder (MDD) was the primary outcome and current dysthymia, any current or lifetime depressive disorder were secondary outcomes. Odds ratios (ORs) with 95% CIs were calculated to compare prevalences between Crohn's disease (CD) and ulcerative colitis (UC). Subgroup analyses by region, interview type, diagnostic criteria and diagnostic instrument were performed. Results: Thirteen reports from 12 independent studies (1159 patients and 10 countries) were included. The pooled prevalence of current MDD in IBD was 13% (95% CI, 4%–32%; I ² = 94.1%). Pooled prevalence estimates were 4% for current dysthymia, 18% for any current depressive disorder and 30% for any lifetime depressive disorder. There were no significant differences between CD and UC across all depressive disorder outcomes. Conclusions: Clinically diagnosed depressive disorders appear to be highly prevalent in IBD. However, estimates should be interpreted cautiously given the small number of studies and substantial heterogeneity. These findings support improved identification and treatment of depressive disorders in IBD care.

Background: Major depressive disorder (MDD) is highly prevalent in inflammatory bowel disease (IBD) and associated with poor IBD outcomes. However, there have been no randomised controlled trials (RCTs) of any antidepressants in patients with MDD and IBD. Methods: We conducted a multi-centre, parallel-group, double-blind, feasibility RCT of mirtazapine against placebo in patients with comorbid IBD and MDD. Participants were randomised evenly to mirtazapine 30mg (n=38) or matched placebo (n=38) at night. After 4 weeks, the dose was increased to 45mg mirtazapine or 2 placebo capsules if there was <20% improvement in depression. Primarily we assessed trial recruitment, follow-up, adherence and overall acceptability. Using linear mixed models and intention to treat analysis, we estimated treatment effects on depression, anxiety, fatigue, sleep and GI symptoms. Findings: Of 76 patients randomised, mean age 40 years (SD 12·3), 84% had Crohn's disease, 59% were male, 25% of non-white ethnicity, and 75% were prescribed advanced IBD therapies. The trial demonstrated all feasibility parameters and only minor modifications were indicated for trial adherence and medication adherence. At week 12, there was a large signal of benefit on depression favouring mirtazapine using the Quick Inventory of Depressive Symptomatology-16 (adjusted mean difference [aMD] = -4·13 [Cohen d = -1·10; 95% CI, -1·66 to -0·54]) and moderate-to-large reduction in anxiety using the Generalised Anxiety Disorder-7 questionnaire (aMD = -2·87; d = -0·65; 95% CI, -1·14 to -0·15). There were no serious adverse reactions. Interpretation: We conducted the first antidepressant RCT in comorbid IBD and major depression and found that the trial was highly feasible. Despite most patients having difficult-to-treat IBD and depression, we found a very strong signal of benefit for depression and anxiety. These findings require replication in a confirmatory trial.

Fatigue is highly prevalent in inflammatory bowel disease (IBD) and is associated with poor quality of life, often persisting despite improvement in mucosal disease. This clinical primer aims to provide an overview of IBD-related fatigue and its management, particularly for clinicians who lack access to a broad multidisciplinary team. We discuss the clinical presentation and epidemiology of IBD-related fatigue and potential underlying mechanisms, such as nutritional deficiencies and dysfunction of the gut-brain axis. We outline key screening tools, which can be easily used to identify severe fatigue, such as the IBD Fatigue Assessment Scale. We then outline a treatment algorithm for IBD-related fatigue, encompassing (1) identification of severe fatigue and appropriate screening tools; (2) addressing overt inflammatory, nutritional and other biomedical causes; (3) patient-led management of activity levels, including avoidance of ‘all-or-nothing’ behaviour and strategies to improve sleep hygiene and increase drivers of sleep; (4) medical management of sleep difficulties that have persisted despite non-pharmacological strategies and (5) using alerting medications such as modafinil and low-dose aripiprazole in refractory cases. We outline practical considerations in prescribing modafinil, including its dosing, common side effects and groups in whom caution is needed. We then discuss reassessment following treatment response or non-response. Finally, we outline key unmet needs for IBD-related fatigue research, such as better understanding of the clinical phenotype of fatigue, its underlying mechanisms and suggestions for novel interventional studies.

Disorders of gut–brain interaction (DGBI) are common clinical presentations in gastroenterology. Central gut–brain neuromodulator medications have an increasingly important role in the management of DGBI. However, gastroenterologists often lack confidence in prescribing central neuromodulators and typically lack access to specialist psychiatric support. This review aims to provide a practical guide to the prescribing of key central neuromodulator medications. We first suggest a positive dialogue for discussing DGBI, covering concepts such as visceral hypersensitivity, central sensitisation and psychological maintaining mechanisms, providing the context for prescribing central neuromodulators. We then outline general points about antidepressants, such as response time, medication switches, mitigating discontinuation symptoms and nocebo effects in DGBI. Next, we review key central gut–brain acting neuromodulators for their target gastrointestinal symptoms, mechanisms, usual dosing and titration, common side effects and other key prescribing issues. Respectively, we review tricyclics, serotonin and norepinephrine reuptake inhibitors (SNRIs) (eg, duloxetine), mirtazapine, selective serotonin reuptake inhibitors (SSRIs) and antipsychotics (eg, olanzapine and haloperidol). We also provide practical guidance on combining different central neuromodulators. We suggest that mirtazapine can be combined safely and effectively with SSRIs or SNRIs. While amitriptyline should be combined cautiously with other serotonergic antidepressants, nortriptyline combines more rationally and effectively with SSRIs. Overall, by applying positive psychoeducation about DGBI and using even a modest repertoire of central gut–brain acting neuromodulators, gastroenterology clinicians can support recovery from DGBI symptoms and enable patients to apply non-pharmacological techniques, such as graded food re-exposure. Further clinical trials of central neuromodulator medications across the range of DGBI are now needed.

Zahra Mohamedali, Gehanjali Amarasinghe, Christopher W P Hopkins, and Calum D Moulton. J Neurogastroenterol Motil 2025;31:18-27. https://doi.org/10.5056/jnm24115

The interleukin-23/Th17 axis is a promising modifiable target for depression. However, its association with depression has not been systematically evaluated. We systematically searched four databases (EMBASE, Web of Science, Pubmed and PsycINFO) for studies comparing patients with major depression and healthy controls for plasma/serum levels of Th17 cells and their canonical cytokines (interleukin-17A [IL-17A], IL-22, granulocyte macrophage colony stimulating factor [GM-CSF]). We also compared counts of Th1, Th2 and Th9 cells between depressed/non-depressed patients and their respective canonical cytokines. We performed random-effects meta-analysis of the standardised mean difference (SMD) in immune measures between groups. Risk of bias was assessed using the Newcastle–Ottawa scale. Of 3154 studies screened, 36 studies were included in meta-analysis. Patients with depression had elevated IL-17A compared to controls (SMD = 0.80 [95% CI 0.03 to 1.58], p = 0.042), an association moderated by antidepressant use (Z = 2.12, p = 0.034). Patients with depression had elevated GM-CSF (SMD = 0.54 [95% CI 0.16 to 0.91], p = 0.0047), and a trend towards higher Th17 counts (SMD = 0.44 [− 0.01 to 0.88], p = 0.052). Whilst the Th2-associated cytokine IL-5 was elevated in depression (SMD = 0.36 [95% CI 0.05 to 0.66], p = 0.02), Th2 cell counts (p = 0.97), Th1 cell counts (p = 0.17) and interferon-γ (p = 0.22) were not. Data for Th9 cells, IL-9 and IL-22 were insufficient for meta-analysis. Respectively, 22, 25 and 5 studies were good, fair and poor in quality. Patients with major depression show peripheral over-activation of the IL-23/Th17 axis. Future interventional studies should test whether this is a modifiable target for depression.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle–Ottawa scale (cohort studies). We included 11 studies (n = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = −0.71 (95% confidence interval (CI) −1.32 to −0.10), P = 0.02, I ² = 51%] and QoL [SMD = 0.88 (95% CI 0.30–1.45), P = 0.003, I ² = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = −0.95 (95% CI −1.45 to −0.45, P < 0.001, I ² = 11%], anxiety [SMD = −0.92 (95% CI 1.72 to −0.13), P = 0.023, I ² = 65%] and QoL [SMD = 1.14 (95% CI 0.66–1.62), P < 0.001, I ² = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Lay Summary: Patients with inflammatory bowel disease (IBD) often report fatigue. However, the reasons for this are poorly understood. In this study of people with IBD, we demonstrate that all-or-nothing behavior (being very active then needing to resting a while) and catastrophic thinking (making very negative assumptions about outcomes) both predict worsening in fatigue over time.