Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.
Depression and anxiety are common comorbidities in inflammatory bowel disease (IBD), but the prevalence varies across studies owing to heterogeneity in study populations and assessment tools for depression and anxiety.
The relationship between IBD and depression and anxiety seems to be bidirectional.
The mechanisms behind the relationship between IBD and depression and anxiety include increased pro-inflammatory cytokines, vagal nerve signalling, gut dysbiosis and changes in brain signalling and morphology.
Antidepressants and behavioural therapies show not only effectiveness in the treatment of depression and anxiety but might also alleviate IBD symptoms or decrease the risk of relapse, although evidence is still limited.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
A qualitative analysis of stress experiences and coping strategies in adolescents with Crohn's disease
BMC Psychiatry Open Access 20 October 2023
BMC Gastroenterology Open Access 06 October 2023
Nature Communications Open Access 06 June 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Podolsky, D. Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429 (2002).
Baumgart, D. C. & Sandborn, W. J. Crohn’s disease. Lancet 380, 1590–1605 (2013).
Danese, S. & Fiocchi, C. Ulcerative colitis. N. Engl. J. Med. 365, 1713–1725 (2011).
Wehkamp, J., Götz, M., Herrlinger, K., Steurer, W. & Stange, E. F. Inflammatory bowel disease. Dtsch. Arztebl Int. 113, 72–82 (2016).
Walker, J. R. et al. The Manitoba IBD cohort study: a population-based study of the prevalence of lifetime and 12-month anxiety and mood disorders. Am. J. Gastroenterol. 103, 1989–1997 (2008).
Panara, A. J. et al. The incidence and risk factors for developing depression after being diagnosed with inflammatory bowel disease: a cohort study. Aliment. Pharmacol. Ther. 39, 802–810 (2014).
Persoons, P. et al. The impact of major depressive disorder on the short- and long-term outcome of Crohn’s disease treatment with infliximab. Aliment. Pharmacol. Ther. 22, 101–110 (2005).
Nowakowski, J., Chrobak, A. & Dudek, D. Psychiatric illnesses in inflammatory bowel diseases–psychiatric comorbidity and biological underpinnings. Psychiatr. Pol. 50, 1157–1166 (2016).
Marrie, R. A., Graff, L. A., Fisk, J. D. & Patten, S. B. The relationship between symptoms of depression and anxiety and disease activity in IBD over time. Inflamm. Bowel Dis. 27, 1285–1293 (2021).
Morais, L. H., Schreiber, H. L. & Mazmanian, S. K. The gut microbiota–brain axis in behaviour and brain disorders. Nat. Rev. Microbiol. 19, 241–255 (2021).
Mikocka-Walus, A., Knowles, S. R., Keefer, L. & Graff, L. Controversies revisited: a systematic review of the comorbidity of depression and anxiety with inflammatory bowel diseases. Inflamm. Bowel Dis. 22, 752–762 (2016).
Neuendorf, R., Harding, A., Stello, N., Hanes, D. & Wahbeh, H. Depression and anxiety in patients with inflammatory bowel disease: a systematic review. J. Psychosom. Res. 87, 70–80 (2016).
Barberio, B., Zamani, M., Black, C. J., Savarino, E. V. & Ford, A. C. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 6, 359–370 (2021).
Stapersma, L., van den Brink, G., Szigethy, E. M., Escher, J. C. & Utens, E. M. W. J. Systematic review with meta-analysis: anxiety and depression in children and adolescents with inflammatory bowel disease. Aliment. Pharmacol. Ther. 48, 496–506 (2018).
Frolkis, A. D. et al. Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression. Gut 68, 1606–1612 (2019).
Ananthakrishnan, A. N. et al. Association between depressive symptoms and incidence of Crohn’s disease and ulcerative colitis: results from the Nurses’ Health Study. Clin. Gastroenterol. Hepatol. 11, 57–62 (2013).
Blackwell, J. et al. Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case-control study. Gut 70, 1642–1648 (2020).
Bernstein, C. N. et al. Increased burden of psychiatric disorders in inflammatory bowel disease. Inflamm. Bowel Dis. 25, 360–368 (2019).
Choi, K. et al. Risk of anxiety and depression in patients with inflammatory bowel disease: a nationwide, population-based study. J. Clin. Med. 8, 654 (2019).
Ludvigsson, J. F. et al. Association between inflammatory bowel disease and psychiatric morbidity and suicide: a Swedish nationwide population-based cohort study with sibling comparison. J. Crohn’s Colitis 15, 1824–1836 (2021).
Butwicka, A. et al. Association of childhood-onset inflammatory bowel disease with risk of psychiatric disorders and suicide attempt. JAMA Pediatr. 173, 969–978 (2019).
Marrie, R. A. et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol. Psychiatr. Sci. 28, 333–342 (2019).
Marrie, R. A. et al. Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. J. Psychosom. Res. 101, 17–23 (2017).
Fairbrass, K. M. et al. Bidirectional brain–gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut https://doi.org/10.1136/gutjnl-2021-325985 (2021).
Alexakis, C., Kumar, S., Saxena, S. & Pollok, R. Systematic review with meta-analysis: the impact of a depressive state on disease course in adult inflammatory bowel disease. Aliment. Pharmacol. Ther. 46, 225–235 (2017).
Duffy, L. C. et al. Relevance of major stress events as an indicator of disease activity prevalence in inflammatory bowel disease. Behav. Med. 17, 101–110 (1991).
Levenstein, S. et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am. J. Gastroenterol. 95, 1213–1220 (2000).
Melinder, C., Hiyoshi, A., Fall, K., Halfvarson, J. & Montgomery, S. Stress resilience and the risk of inflammatory bowel disease: a cohort study of men living in Sweden. BMJ Open 7, e014315 (2017).
Levenstein, S. et al. Psychological stress and disease activity in ulcerative colitis: a multidimensional cross-sectional study. Am. J. Gastroenterol. 89, 1219–1225 (1994).
Miyazawa, T. et al. Long-term course of inflammatory bowel disease after the great east Japan earthquake. J. Gastroenterol. Hepatol. 33, 1956–1960 (2018).
Li, J., Nørgard, B., Precht, D. H. & Olsen, J. Psychological stress and inflammatory bowel disease: a follow-up study in parents who lost a child in Denmark. Am. J. Gastroenterol. 99, 1129–1133 (2004).
Lerebours, E. et al. Stressful life events as a risk factor for inflammatory bowel disease onset: a population-based case–control study. Am. J. Gastroenterol. 102, 122–131 (2007).
Targownik, L. E. et al. The relationship among perceived stress, symptoms, and inflammation in persons with inflammatory bowel disease. Am. J. Gastroenterol. 110, 1001–1012 (2015).
Bitton, A. et al. Psychosocial determinants of relapse in ulcerative colitis: a longitudinal study. Am. J. Gastroenterol. 98, 2203–2208 (2003).
Jaghult, S. et al. Stress as a trigger for relapses in IBD: a case-crossover study. Gastroenterol. Res. 6, 10–16 (2013).
Cruz-Pereira, J. S. et al. Depression’s unholy trinity: dysregulated stress, immunity, and the microbiome. Annu. Rev. Physiol. 71, 49–78 (2020).
Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).
Thomson, C. A., McColl, A., Cavanagh, J. & Graham, G. J. Peripheral inflammation is associated with remote global gene expression changes in the brain. J. Neuroinflammation 11, 73 (2014).
Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).
D’Mello, C. & Swain, M. G. Immune-to-brain communication pathways in inflammation-associated sickness and depression. Curr. Top. Behav. Neurosci. https://doi.org/10.1007/7854_2016_37 (2016).
Carloni, S. et al. Identification of a choroid plexus vascular barrier closing during intestinal inflammation. Science 22, 439–448 (2021).
Haj-Mirzaian, A. et al. Anxiety- and depressive-like behaviors are associated with altered hippocampal energy and inflammatory status in a mouse model of Crohn’s disease. Neuroscience 366, 124–137 (2017).
Heydarpour, P. et al. Behavioral despair associated with a mouse model of Crohn’s disease: role of nitric oxide pathway. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 131–141 (2016).
Zonis, S. et al. Chronic intestinal inflammation alters hippocampal neurogenesis. J. Neuroinflammation 12, 65 (2015).
Kraus, M. R., Schäfer, A., Faller, H., Csef, H. & Scheurlen, M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J. Clin. Psychiatry 64, 708–714 (2003).
Ghia, J.-E., Blennerhassett, P. & Collins, S. M. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J. Clin. Invest. 118, 2209–2218 (2008).
Zhang, L., Hu, L., Chen, M. & Yu, B. Exogenous interleukin-6 facilitated the contraction of the colon in a depression rat model. Dig. Dis. Sci. 58, 2187–2196 (2013).
Ghia, J.-E. et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology 136, 2280–2288 (2009).
Ghia, J.-E., Park, A. J., Blennerhassett, P., Khan, W. I. & Collins, S. M. Adoptive transfer of macrophage from mice with depression-like behavior enhances susceptibility to colitis. Inflamm. Bowel Dis. 17, 1474–1489 (2011).
Meregnani, J. et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton. Neurosci. Basic. Clin. 160, 82–89 (2011).
Bonaz, B. L. & Bernstein, C. N. Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144, 36–49 (2013).
Emge, J. R. et al. Modulation of the microbiota-gut-brain axis by probiotics in a murine model of inflammatory bowel disease. Am. J. Physiol. Liver Physiol. 310, G989–G998 (2016).
Gao, X. et al. Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. Proc. Natl Acad. Sci. USA 115, E2960–E2969 (2018).
Li, N. et al. Fecal microbiota transplantation from chronic unpredictable mild stress mice donors affects anxiety-like and depression-like behavior in recipient mice via the gut microbiota-inflammation-brain axis. Stress 22, 592–602 (2019).
Marcondes Ávila, P. R. et al. Effects of microbiota transplantation and the role of the vagus nerve in gut–brain axis in animals subjected to chronic mild stress. J. Affect. Disord. 277, 410–416 (2020).
Agostini, A. et al. Brain functional changes in patients with ulcerative colitis: a functional magnetic resonance imaging study on emotional processing. Inflamm. Bowel Dis. 17, 1769–1777 (2011).
Agostini, A. et al. New insights into the brain involvement in patients with Crohn’s disease: a voxel-based morphometry study. Neurogastroenterol. Motil. 25, 147–154 (2013).
Vogt, B. A. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544 (2009).
Nair, V. A. et al. Structural imaging changes and behavioral correlates in patients with Crohn’s disease in remission. Front. Hum. Neurosci. 10, 460 (2016).
Manichanh, C., Borruel, N., Casellas, F. & Guarner, F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599–608 (2012).
Schirmer, M., Garner, A., Vlamakis, H. & Xavier, R. J. Microbial genes and pathways in inflammatory bowel disease. Nat. Rev. Microbiol. 17, 497–511 (2019).
Limbana, T., Khan, F. & Eskander, N. Gut microbiome and depression: how microbes affect the way we think. Cureus 12, e9966 (2020).
Winter, G., Hart, R. A., Charlesworth, R. P. G. & Sharpley, C. F. Gut microbiome and depression: what we know and what we need to know. Rev. Neurosci. 29, 629–643 (2018).
Jiang, H. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav. Immun. 48, 186–194 (2015).
Kilinçarslan, S. & Evrensel, A. The effect of fecal microbiota transplantation on psychiatric symptoms among patients with inflammatory bowel disease: an experimental study. Actas Esp. Psiquiatr. 48, 1–7 (2020).
Sullivan, P. F., Daly, M. J. & O’Donovan, M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat. Rev. Genet. 13, 537–551 (2014).
Daly, J. et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013).
Kevans, D. et al. IBD genetic risk profile in healthy first-degree relatives of Crohn’s disease patients. J. Crohns. Colitis 10, 209–215 (2016).
International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. Nature 460, 748–752 (2009).
Luo, J. et al. Depression and inflammatory bowel disease: a bidirectional two-sample mendelian randomization study. J. Crohns Colitis 16, 633–642 (2022).
De Lange, K. M. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 49, 256–261 (2017).
Frenkel, S. et al. Copy number variation-based gene set analysis reveals cytokine signalling pathways associated with psychiatric comorbidity in patients with inflammatory bowel disease. Genomics 112, 683–693 (2020).
Janssen, D. G. A., Caniato, R. N., Verster, J. C. & Baune, B. T. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response. Hum. Psychopharmacol. 25, 201–215 (2010).
Minaiyan, M., Hajhashemi, V., Rabbani, M., Fattahian, E. & Mahzouni, P. Evaluation of anti-colitic effect of fluvoxamine against acetic acid-induced colitis in normal and reserpinized depressed rats. Eur. J. Pharmacol. 746, 293–300 (2015).
Minaiyan, M., Hajhashemi, V., Rabbani, M., Fattahian, E. & Mahzouni, P. Effect of venlafaxine on experimental colitis in normal and reserpinised depressed rats. Res. Pharm. Sci. 10, 295–306 (2015).
Fattahian, E., Hajhashemi, V., Rabbani, M., Minaiyan, M. & Mahzouni, P. Anti-inflammatory effect of amitriptyline on ulcerative colitis in normal and reserpine-induced depressed rats. Iran. J. Pharm. Res. 15, 125–137 (2016).
Zabihi, M., Hajhashemi, V., Minaiyan, M. & Talebi, A. Evaluation of the central and peripheral effects of doxepin on carrageenan-induced inflammatory paw edema in rat. Res. Pharm. Sci. 12, 337–345 (2017).
Mikocka-Walus, A. et al. Adjuvant therapy with antidepressants for the management of inflammatory bowel disease. Cochrane Database Syst. Rev. 4, CD012680 (2019).
Mikocka-Walus, A., Ford, A. C. & Drossman, D. A. Antidepressants in inflammatory bowel disease. Nat. Rev. Gastroenterol. Hepatol. 17, 184–192 (2020).
Goodhand, J. R. et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm. Bowel Dis. 18, 1232–1239 (2012).
Daghaghzadeh, H. et al. Efficacy of duloxetine add on in treatment of inflammatory bowel disease patients: a double-blind controlled study. J. Res. Med. Sci. 20, 595 (2015).
Iskandar, H. N. et al. Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. J. Clin. Gastroenterol. 48, 423–429 (2014).
Hall, B. J., Hamlin, P. J., Gracie, D. J. & Ford, A. C. The effect of antidepressants on the course of inflammatory bowel disease. Can. J. Gastroenterol. Hepatol. 2018, 2047242 (2018).
Mikocka-Walus, A. et al. Fluoxetine for maintenance of remission and to improve quality of life in patients with Crohn’s disease: a pilot randomized placebo-controlled trial. J. Crohns Colitis 11, 509–514 (2017).
Keefer, L. Behavioural medicine and gastrointestinal disorders: the promise of positive psychology. Nat. Rev. Gastroenterol. Hepatol. 15, 378–386 (2018).
Timmer, A. et al. Psychological interventions for treatment of inflammatory bowel disease. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.cd006913.pub2 (2011).
Gracie, D. J. et al. Effect of psychological therapy on disease activity, psychological comorbidity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2, 189–199 (2017).
Lores, T. et al. Integrated psychological care reduces health care costs at a hospital-based inflammatory bowel disease service. Clin. Gastroenterol. Hepatol. 19, 96–103 (2021).
Horst, S. et al. Treatment with immunosuppressive therapy may improve depressive symptoms in patients with inflammatory bowel disease. Dig. Dis. Sci. 60, 465–470 (2015).
Zhang, M. et al. Improvement of psychological status after infliximab treatment in patients with newly diagnosed Crohn’s disease. Patient Prefer. Adherence 12, 879–885 (2018).
Stevens, B. W. et al. Vedolizumab therapy is associated with an improvement in sleep quality and mood in inflammatory bowel diseases. Dig. Dis. Sci. 62, 197–206 (2017).
Raison, C. L. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. Arch. Gen. Psychiatry 70, 31–41 (2013).
Clark, J. G. et al. Predictors of depression in youth with Crohn disease. J. Pediatr. Gastroenterol. Nutr. 58, 569–573 (2014).
Thillard, E.-M. et al. Psychiatric adverse events associated with infliximab: a cohort study from the French nationwide discharge abstract database. Front. Pharmacol. 11, 513 (2020).
T.J. received funding from the Danish National Research Foundation (DNRF148) and the Lundbeck Foundation (R313-2019-857). The funding sources had no role in the development of this article.
A.N.A. served on scientific advisory boards for Gilead and Abbvie. L.K. is a consultant to Abbvie and Pfizer and has equity ownership in Trellus Health, Inc. The other authors declare no competing interests.
Peer review information
Nature Reviews Gastroenterology and Hepatology thanks David Gracie, Antonina Mikocka-Walus and Giovanni Monteleone for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The manuscript is based on a MEDLINE search using the terms: “inflammatory bowel disease” OR “Crohn’s diseases” OR “ulcerative colitis” AND “depression” OR “anxiety” combined with “epidemiology”, “incidence”, “prevalence”, “antidepressants”, “microbiome”, “microbiota”, “gut-brain axis”, “genetics”. The initial search yielded 529 results, and 132 articles were included for full article screening. Additional articles were identified through search of reference lists.
About this article
Cite this article
Bisgaard, T.H., Allin, K.H., Keefer, L. et al. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment. Nat Rev Gastroenterol Hepatol 19, 717–726 (2022). https://doi.org/10.1038/s41575-022-00634-6
This article is cited by
BMC Gastroenterology (2023)
A qualitative analysis of stress experiences and coping strategies in adolescents with Crohn's disease
BMC Psychiatry (2023)
Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation
Journal of Inflammation (2023)
Nature Communications (2023)
Lipocalin 2 in the Paraventricular Thalamic Nucleus Contributes to DSS-Induced Depressive-Like Behaviors
Neuroscience Bulletin (2023)