MIT-COP (College of Pharmacy), Moradabad, Uttar Pradesh, India. Pin – 244001
The study of depression has always been an important topic because of its widespread nature in people above 20 years of age. The comorbidity of depression with various diseases has always been an important topic of interest from the 1990s till now. As some of the mediators of both IBD and depression share a universal nature to some extent, I can say that they are dependent on each other. In this review article, I have discussed the various developments of comorbid depression and its relation to IBD or colitis. I have also discussed the pathophysiological concepts related to both depression and IBD in this review article. Finding a target that is common in inflammation compared to both IBD and depression can be a great help in finding treatments for people suffering from IBD as well as comorbid depression.
The prevalence of depression and anxiety in IBD occurs due to the relation between intestinal inflammation and brain with immune dysregulation (1). Ulcerative colitis is a disease of the large intestine or colon that includes ulcers or other harmful effects (2).
IBD can lead to colon cancer affecting colon and there are many types of cancer like lung cancer, prostate cancer, breast cancer and colorectal cancer (3). Both depression and IBD involves common inflammatory markers like IL-1, IL-1 RA, sIL-2R, IL-6, sIL-6R, IL-17, IL-22, IL-23, TNF-α, and IFN-γ (4). Many inflammatory cytokines found in the patients suffering from both IBD and depression, of which TNF-α is one of the major ones confirmed by the anti-inflammatory effects of anti-TNF-α medications (5). In a study, the blunted HPA axis in Lewis rats as compared to Fisher rats becomes a reason for the more susceptibility for autoimmune/inflammatory diseases like IBD (6).
This review article provides useful insight into the complexity between depression and IBD. I have also tried to evaluate the various cytokines levels in the serum of patients affected with both UC and CD.
All of the relevant databases (Google Scholar, Science Direct) searched for the terms “comorbid depression in IBD,” “comorbid depression in UC,” “comorbid depression,” “pathophysiology of IBD” from 1996 to 2018. Clinical studies checked from different research and review articles.
A Short Introduction to Inflammatory Bowel Disease and Colitis:
IBD is a combination of three diseases, i.e., Crohn’s disease, ulcerative colitis, and IBD unclassified (7). The etiology of IBD is still a mystery, but environmental factors genetic factors and immunological factors may play an important role (8). Ulcerative colitis affects only the innermost lining or mucosa of the colon or rectum, continuous with no patches of healthy tissue but with a risk of colon cancer (9). The symptoms of ulcerative colitis includes bloody diarrhea, diagnosed by endoscopy and histological findings (10). IBD, if not treated well, then it can lead to colon cancer (9). Risks by which IBD leads to colon cancer depends on the duration of the disease and extent (11). There is a distinction between the UC and CD patients based on tests like ASCA and pANCA, but these tests did not have 100% accuracy (12). The risk of IBD-associated colorectal cancer generally increases after 8-10 years of diagnosis of IBD (13). More specifically, we can say that UC leads to colitis-associated cancer by about 33.2%, while CD, about 8.3% as compared to the general population (14). Some cytokines like IL-22 via a signal transducer and activation of transcription 3 (Stat3)-mediated mechanism had been proposed to protect the intestines besides having inflammatory functions through the induction of IL-6 and IL-8 (15). Essential features of IBD include severe diarrhea, bleeding, abdominal pain, fluid, and electrolyte loss (16).
Inflammation in Inflammatory Bowel Disease and Colitis:
As TNF-α increased in mucosa of IBD patients, it will lead to activation of NFKB and MAPK, which will ultimately lead to CRC while overexpression of TNF-α in adipose tissues of obese patients leads to T2DM (17). NFKB plays a middleman role in the relation between IBD, CRC, and T2DM (17). IL-10 plays an essential role in the formation of IBD, like conditions such as discontinuous transmural lesions affected small and large intestines lead to the production of proinflammatory cytokines (18). Inflammation in IBD found to be associated with COX-2 which increased in the large intestine (19). Inflammation in IBD is also proved by genetic studies where a COX-2 deficient mouse found to be more sensitive towards chemically induced colitis (19). Inflammatory bowel disease is closely associated with oxidative stress, i.e., elevated levels of oxidants within the cell (20). The various cytokines IL-1, IL-6, IL-8, IL-10, TNF-α, and leukotrienes, together with LPS, commonly found in the mucosal injury related to IBD (21). Inflammation in IBD involves the oxidation of cell membranes and damage by ROS (22). CRP is found in the acute phase of IBD and is a well-known indicator or marker of IBD (23). Although TNF – α is a well-known marker of IBD it is not consistent in its values, it increases in the beginning but fails to do so in the whole period (23). Proinflammatory cytokines like IL-6, IL-10, TNF-α, IFN-γ, and metabolites of arachidonic acid leads to an inflammatory background which leads to activation of NF-κВ ultimately leads to cancer development (24). IL-6 is dependent on in vitro human colon cancer proliferation mediated by hyperphosphorylation of the transcription factor STAT3 (24). IL-1 and TNF-α enhance the production of COX2, an enzyme that interferes with cell proliferation, angiogenesis, apoptosis, and its mRNA levels increased in the inflamed mucosa and IBD-associated cancer (24). Oxidative stress also plays an essential role in the CAC by the mediators like ROS and RNI (24). Oxidative stress damages DNA, lipids, and proteins (24). Based on the oxazolone-induced colitis model, anti-IL-9 antibodies are supposed to be new targets for ulcerative colitis therapy (25). The use of COX-2 inhibitors and soluble epoxide hydrolase are the new emerging approach for the treatment of inflammation related with IBD (26).
Inflammation in Depression:
Dowlati et al. reported that IL-6 concentrations were higher in depressed subjects as compared with control subjects (27). Holtzman et al. reported IL-10 to be increased in depressed patients (28). Mesquita et al., through the forced swim test, stated that IL-10 deficient female mice displayed more depressive-like behavior, but when IL-10 injected, this phenotype was reversed (29). Kreisel et al. demonstrated that IL-1 levels in the brain lead to depressive conditions (30). Antidepressants of several classes reduce the level of pro-inflammatory cytokines like TNF-α, IF-γ while increases IL-10 (31). sIL-6R levels in serum increased in bipolar disorder and unipolar depression, suggesting the role of IL trans-signaling in depression (32). Some cytokines like IFN-γ, TNF-α, IL-2, IL-18, and IL-1β lead to induction of IDO, which ultimately makes L-tryptophan catabolize into TRYCATs, i.e., quinolinic acid, kynurenine by which the depression-like symptoms occur (33). Experiments have shown that depressive-like signs are seen in individuals undergoing viral and bacterial infections due to the involvement of TNF-α and IL-1β (34).
Comorbid Depression in Inflammatory Bowel Disease:
Comorbid depression associated with IBD is more related to adolescent patients as compared to other age group patients (35). Depression is common among many diseases like cancer, diabetes and IBD (36). Depression may be caused due to high intake of antibiotics or mental stress (37). Depression is also related with ageing (38). Depression will be the second-leading cause of disability globally by 2020 (39). There are many three common types of depression like major depressive disorder, minor depression, bipolar disorder (40). Major depressive disorder is characterized by low mood, low self-esteem, loss of pleasure in normal activities (41). Filipović BR et al. found that the patients freshly diagnosed with IBD have higher levels of depression and anxiety (42). Walker et al. reported higher rates of both anxiety and depression in patients suffering from IBD compared to controls (43). Besharat et al. reported a high percentage, i.e., 32 patients with depression characteristics in 50 patients diagnosed recently in their study with IBD (44). Panara et al. reported a high incidence of depression in groups like female gender, aggressive diseases, and increased endoscopic/radiological activity (45). In a study done by Sweeney et al., it is found out that IBD patients also suffer from emotional disturbances as well as cognitive-behavioral factors (46). Due to the prevalence of depressive symptoms in young IBD patients, they were psychological screened (47). Irregular sleep or high rates of poor sleep quality had been associated with patients of ulcerative colitis, showing a strong correlation with depression (48). In a study, 25.9% of patients with IBD show symptoms of a probable psychological disorder on any of the two datas i.e either the depression or anxiety subscales of the Hospital Anxiety and Depression Scale (49).
Animal models confirming comorbid depression in Inflammatory Bowel Disease:
DSS-treated rats, after 10-20 days of inflammation, show fewer entries in the open arm in the EPM test, reinforcing higher anxiety-like behavior (50). DSS rats consumed less sucrose in the sucrose preference test, and they were immobile for a more extended period in FST than the control rats (50). DSS-treated male Wistar rats show an increase in levels of TNF-α, IL-6 in the substantia nigra (51). DSS-treated rats show alteration in BBB with the loss of dopaminergic neurons in the substantia nigra (51). TNBS-treated adult male Sprague-Dawley rats showed increased levels of TNF-α and microglial activity than control animals within the hippocampal area after the 4th day of inflammation induction (52). In TNBS-treated rats, the level of mRNA expression of cytokine IL-6 by real-time reverse transcription-polymerase chain reaction found to be higher in the brain and colon tissues as compared with controls (53).
From the various research and review articles published so far, we have concluded that IBD leads to comorbid depression. However, the path from IBD to comorbid depression is not an easy task. Inflammation is a standard feature found in IBD and depression. This review will provide an insight into using anti-inflammatory drugs and other drugs related to depression for both IBD and comorbid depression. We have also concluded that oxidation of the cells in IBD, leading to the generation of free radicals, which ultimately leads to the damaging of the fundamental properties of the cells. The reason for using antioxidants in comorbid depression may be due to the oxidation of cells leading to inflammation in IBD and comorbid depression in IBD. Overall comorbid depression involves the same pathophysiological conditions as found in inflammation related to IBD to some extent in terms of common inflammatory markers.
This review article comes out by the excellent guidance of Dr. Prasanta Kumar Nayak (Assistant Professor, IIT-BHU, Varanasi), Dr. Sairam Krishnamurthy (Professor, IIT-BHU, Varanasi), Aarzoo Setia, Akanksha Suchita Arun, Ankit Puri Goswami, Neha Goel, Rohit Chauhan, Rohan Aggarwal, Shivanki Rajput, Atul Kumar, Pallavi Singh, Vivek Kumar, Rajni Sabat, Juhi Singhal, Poornima Sharma, Poornima Manocha, Roshani Bhavsar, Shubham Roy, Himanshi Gupta who helped in writing this review article by providing essential informations from time to time.
IBD – Inflammatory Bowel Disease, CD – Crohn’s Disease, UC – Ulcerative Colitis, TNF-α – Tumor Necrosis Factor-alpha, IL – Interleukin, IFN-γ – Interferon-gamma, sIL – Soluble Interleukin, ASCA - Anti-Saccharomyces cerevisiae antibodies, pANCAs - Perinuclear antineutrophil cytoplasmic antibodies, NFκB - Nuclear factor kappa-light-chain-enhancer of activated B cells, MAPK - Mitogen-activated protein kinases, IDO - Indoleamine-2,3-dioxygenase, TRYCAT – Tryptophan catabolites, mRNA – Messenger Ribonucleic acid, COX – Cyclooxygenase, CAC – Colitis associated cancer, DSS – Dextran Sodium Sulphate, TNBS – Trinitrobenzenesulphonic acid.
1. Nowakowski J, Chrobak AA, Dudek D. Psychiatric illnesses in inflammatory bowel diseases—psychiatric comorbidity and biological underpinnings. Psychiatria Polska. 2016;50(6):1157-66.
2. Sudarshan S, Sangeeta S, Sheth N, Roshan P, Ushir Y, Gendle R. Colon specific drug delivery system of mesalamine for eradication of ulcerative colitis. Research Journal of Pharmacy and Technology. 2009;2(4):819-23.
3. Chanda C. Role of Inflammatory Cytokines during Lung Cancer Progression: A Review. Research Journal of Pharmacy and Technology. 2018;11(11):5163-5.
4. Martin-Subero M, Anderson G, Kanchanatawan B, Berk M, Maes M. Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways. CNS spectrums. 2016;21(2):184-98.
5. Horst S, Chao A, Rosen M, Nohl A, Duley C, Wagnon JH, et al. Treatment with immunosuppressive therapy may improve depressive symptoms in patients with inflammatory bowel disease. Digestive Diseases and Sciences. 2015;60(2):465-70.
6. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144(1):36-49.
7. Uhlig HH, Powrie F. Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease. Annual Review of Immunology. 2018;36:755-81.
8. Wirtz S, Neurath MF. Mouse models of inflammatory bowel disease. Advanced Drug Delivery Reviews. 2007;59(11):1073-83.
9. Head KA, Jurenka JS. Inflammatory bowel disease part I: ulcerative colitis--pathophysiology and conventional and alternative treatment options. Alternative Medicine Review. 2003;8(3):247-84.
10. Akshaya K, Chitra V. A Review on Pathological State and Herbal Remedies on Ulcerative Colitis. Research Journal of Pharmacy and Technology. 2019;12(3):1409-17.
11. Kim ER, Chang DK. Colorectal cancer in inflammatory bowel disease: the risk, pathogenesis, prevention and diagnosis. World Journal of Gastroenterology: WJG. 2014;20(29):9872.
12. Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. Gastroenterology. 2011;140(6):1817-26. e2.
13. Romano M, De Francesco F, Zarantonello L, Ruffolo C, Ferraro GA, Zanus G, et al. From inflammation to cancer in inflammatory bowel disease: molecular perspectives. Anticancer Research. 2016; 36(4): 1447-60.
14. Francescone R, Hou V, Grivennikov SI. Cytokines, IBD, and colitis-associated cancer. Inflammatory Bowel Diseases. 2015;21(2):409-18.
15. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947-57.
16. Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. The Korean Journal of Physiology & Pharmacology. 2014;18(4):279-88.
17. Jurjus A, Eid A, Al Kattar S, Zeenny MN, Gerges-Geagea A, Haydar H, et al. Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links. BBA Clinical. 2016;5:16-24.
18. Sato Y, Takahashi S, Kinouchi Y, Shiraki M, Endo K, Matsumura Y, et al. IL-10 deficiency leads to somatic mutations in a model of IBD. Carcinogenesis. 2006;27(5):1068-73.
19. Wang D, DuBois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29(6):781.
20. Rudyk O, Eaton P. Biochemical methods for monitoring protein thiol redox states in biological systems. Redox Biology. 2014;2:803-13.
21. McKenzie S, Baker M, Buffinton G, Doe W. Evidence of oxidant-induced injury to epithelial cells during inflammatory bowel disease. The Journal of Clinical Investigation. 1996;98(1):136-41.
22. Yan H, Wang H, Zhang X, Li X, Yu J. Ascorbic acid ameliorates oxidative stress and inflammation in dextran sulfate sodium-induced ulcerative colitis in mice. International Journal of Clinical and Experimental Medicine. 2015;8(11):20245.
23. Desai D, Faubion W, Sandborn W. biological activity markers in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2007;25(3):247-55.
24. Saraggi D, Fassan M, Mescoli C, Scarpa M, Valeri N, Michielan A, et al. The molecular landscape of colitis-associated carcinogenesis. Digestive and Liver Disease. 2017;49(4):326-30.
25. Atreya R, Neurath MF. IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD. Nature Reviews Gastroenterology & Hepatology. 2015;12(2):67.
26. Anitha K, Geetha K. Soluble Epoxide Hydrolase: A Pharmaceutical Target for Inflammation. Research Journal of Pharmacy and Technology. 2019;12(10):5113-8.
27. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biological Psychiatry. 2010;67(5):446-57.
28. Holtzman S, Abbey SE, Chan C, Bargman JM, Stewart DE. A genetic predisposition to produce low levels of IL-10 is related to depressive symptoms: a pilot study of patients with end stage renal disease. Psychosomatics. 2012;53(2):155-61.
29. Mesquita AR, Correia-Neves M, Roque S, Castro AG, Vieira P, Pedrosa J, et al. IL-10 modulates depressive-like behavior. Journal of Psychiatric Research. 2008;43(2):89-97.
30. Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Molecular Psychiatry. 2008;13(7):717.
31. Kenis G, Maes M. Effects of antidepressants on the production of cytokines. International Journal of Neuropsychopharmacology. 2002;5(4):401-12.
32. Maes M, Anderson G, Kubera M, Berk M. Targeting classical IL-6 signalling or IL-6 trans-signalling in depression? Expert opinion on Therapeutic Targets. 2014;18(5):495-512.
33. Oxenkrug GF. Genetic and hormonal regulation of tryptophan–kynurenine metabolism. Annals of the New York Academy of Sciences. 2007;1122(1):35-49.
34. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience. 2008;9(1):46.
35. Szigethy E, Levy-Warren A, Whitton S, Bousvaros A, Gauvreau K, Leichtner AM, et al. Depressive symptoms and inflammatory bowel disease in children and adolescents: a cross-sectional study. Journal of Pediatric Gastroenterology and Nutrition. 2004;39(4):395-403.
36. Vijayalakshmi K. Assessment of Depression among Cancer Patients. Asian Journal of Nursing Education and Research. 2018;8(1):11-4.
37. Tripathi K. Herbs for Depression: A Review. Research Journal of Science and Technology. 2009;1(2):55-62.
38. Kaur M, Kaur S, Kaur R. Correlation of Depression and Quality of life among rural elderly. International Journal of Advances in Nursing Management. 2016;4(4):323-6.
39. Dave PH, Vishnupriya V, Gayathri R. Herbal Remedies for Anxiety and Depression-A Review. Research Journal of Pharmacy and Technology. 2016;9(8):1253-6.
40. Sharma I, Kaur M, Parashar B, Kainth A. Depression: An Overview. Asian Journal of Research in Pharmaceutical Science. 2014;4(1):28-31.
41. Patel MA, Patel CM, Patel DB, Anand I, Patel C. A Review on Novel Strategies for Pharmacotherapy of Depression. Research Journal of Pharmacology and Pharmacodynamics. 2010;2(2):153-9.
42. Filipović BR, Filipović BF, Kerkez M, Milinić N, Ranđelović T. Depression and anxiety levels in therapy-naive patients with inflammatory bowel disease and cancer of the colon. World Journal of Gastroenterology: WJG. 2007;13(3):438.
43. Walker JR, Graff LA, Dutz JP, Bernstein CN. Psychiatric disorders in patients with immune-mediated inflammatory diseases: prevalence, association with disease activity, and overall patient well-being. The Journal of Rheumatology Supplement. 2011;88:31-5.
44. Besharat S, Amiriani T, Roshandel G, Besharat M, Semnani S, Kamkar M. Depressive mood and disease activity in inflammatory bowel disease. Arab Journal of Gastroenterology. 2012;13(3):136-8.
45. Panara A, Yarur A, Rieders B, Proksell S, Deshpande A, Abreu M, et al. The incidence and risk factors for developing depression after being diagnosed with inflammatory bowel disease: a cohort study. Alimentary Pharmacology & Therapeutics. 2014;39(8):802-10.
46. Sweeney L, Moss Morris R, Czuber Dochan W, Meade L, Chumbley G, Norton C. Systematic review: psychosocial factors associated with pain in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2018;47(6):715-29.
47. Van Den Brink G, Stapersma L, Vlug L, Rizopolous D, Bodelier A, van Wering H, et al. Clinical disease activity is associated with anxiety and depressive symptoms in adolescents and young adults with inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2018.
48. Hood MM, Wilson R, Gorenz A, Jedel S, Raeisi S, Hobfoll S, et al. Sleep Quality in Ulcerative Colitis: Associations with Inflammation, Psychological Distress, and Quality of Life. International Journal of Behavioral Medicine. 2018;25(5):517-25.
49. Guthrie E, Jackson J, Shaffer J, Thompson D, Tomenson B, Creed F. Psychological disorder and severity of inflammatory bowel disease predict health-related quality of life in ulcerative colitis and Crohn's disease. The American journal of gastroenterology. 2002;97(8):1994.
50. Chen J, Winston JH, Fu Y, Guptarak J, Jensen KL, Shi X-Z, et al. Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2014;308(1):R18-R27.
51. Villarán RF, Espinosa‐Oliva AM, Sarmiento M, De Pablos RM, Argüelles S, Delgado‐Cortés MJ, et al. Ulcerative colitis exacerbates lipopolysaccharide‐induced damage to the nigral dopaminergic system: potential risk factor in Parkinsons disease. Journal of Neurochemistry. 2010;114(6):1687-700.
52. Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ. Microglial activation and TNFα production mediate altered CNS excitability following peripheral inflammation. Proceedings of the National Academy of Sciences. 2008.
53. Wang K, Yuan C-P, Wang W, Yang Z-Q, Cui W, Mu L-Z, et al. Expression of interleukin 6 in brain and colon of rats with TNBS-induced colitis. World Journal of Gastroenterology: WJG. 2010;16(18):2252.
Accepted on 25.02.2020 ©Asian Pharma Press All Right Reserved