Introduction
Inflammatory bowel disease (IBD) involves a group of chronic diseases of the gastrointestinal tract which is recurrent and remitting; the term includes mainly Crohn's disease (CD) and ulcerative colitis (UC). The prevalence of UC and CD has expanded within the past decades, up to 120–200 per 100000 and 50–200 per 100000, respectively [1]. IBD exists in both active and remission (inactive) forms. Clinical and environmental factors contribute to the prognosis of recurrence in patients with IBD, including younger age at the time of diagnosis, female gender, intestinal involvement, history of smoking, and medication [2, 3]. 
Due to the disease chronicity that needs long-term coping and self-management, it is expected that patients with IBD are at higher risk for mental health problems such as depression [4]. Psychiatric dysfunction in patients with active IBD was reported to be significantly higher than in patients with inactive IBD, and the relationship between IBD and depression seems to be bidirectional [5, 6]. 
The suggested associated mechanisms between IBD and depression included increased pro-inflammatory cytokines, vagal nerve signaling, gut dysbiosis, and changes in neuronal, in which antidepressants and behavioral therapies have been reported ineffective on depression but alleviate IBD symptoms or its relapse [7]. One prior study showed that IBD patients experience depression three times that of the general population [8]. 
In IBD patients, depression is associated with a lower quality of life, sexual dysfunction, worsened disease activity, and increased frequency of flares [9, 10]. However, even IBD patients in clinical remission can have depression [11]. Therefore, we aimed to investigate whether depression is associated with active or inactive IBD and the related risk factors among patients with IBD.
Materials and Methods
Study design and patients
This cross-sectional study was conducted on 156 patients with IBD referred to Razi Hospital, Rasht City, Iran, during 2015-2016. They were divided into two active and inactive IBD groups diagnosed by a gastroenterologist and liver specialist in Gastroenterology and Hepatology ward based on the clinical, laboratory, endoscopic, and pathologic findings. The enrolled patients were informed about the study procedure, and their written consent was obtained. 
Demographic data and clinical characteristics of participants included gender, familial history of IBD, marital status, income, education level, history of smoking, alcohol consumption, oral and dental hygiene, history of autoimmune disease, IBD-related surgeries, and medication. Also, the Beck Depression Inventory (BDI) was administered by a psychologist, and the obtained scores were classified as no (score 1-15), mild (score 16-31), moderate (score 32-47), and severe (score 48-63) depression. According to the study by Dadfar et al., BDI had good validity and reliability for research in Iran [12].
Activity status of IBD 
Two valid tools of modified Truelove and Witts severity index (MTWSI) for UC [13] and Harvey Bradshaw severity index (HBSI) for CD [14] were used to quantitate IBD activity. Based on these scores, UC patients who scored ≥10 on the MTWSI and CD patients who scored ≥7 on the HBSI were classified as patients with active diseases. Activity indices were evaluated while filling out the questionnaire. 
Statistical analysis
SPSS software, version 16 was used for descriptive and inferential statistical evaluation. The Chi-square test was used to evaluate the associations of demographic parameters with IBD status and depression. P<0.05 was considered a significant difference. 
Results
Data from 78 patients in the active IBD group and 86 patients in the inactive IBD group were analyzed. Based on the results, the Mean±SD age of patients in active and inactive IBD groups were 38.50±14.73 and 39.11±14.29 years, respectively (P=0.791). Their Mean±SD BMI values were 25.95±18.94 and 24.79±4.13 kg/m2, respectively (P=0.598). Females had more active IBD and depression than males, but the differences were not significant (P>0.05). No statistically significant association was reported between the familial history of IBD, marital status, alcohol consumption, oral and dental hygiene, and history of drug consumption and IBD and depression among patients (P>0.05). The prevalence rates of no, mild, and moderate depression among patients were significantly different in terms of autoimmune disease, educational level, history of smoking, and IBD-related surgeries, while only income was reported to be different among active and inactive IBD groups (P<0.05) (Table 1).


According to Table 2, the logistic regression showed that among patients with depression, the prevalence of active IBD (60.7%) was higher than that of inactive IBD (39.3%) (odds ration [OR]: 2.01; 95% CI: 1.03-3.89).


Discussion
It has been reported that depression is prevalent in IBD patients, and baseline depression is related to a higher risk for aggressive IBD at follow-up [15]. In this study, we investigated the role of depression in IBD flare among patients with both depression and IBD.
The reported frequency of depression in IBD patients was nearly 36%, which was higher than reported in a systematic review, illustrating that depression was as high as 21.2% in patients with IBD vs 13.4% in healthy controls. It has been reported that in patients with active IBD, the rate of depression is 34.7%, with no significant differences between CD and UC [16]. 
A study by Al-Aamri et al. reported that among patients with IBD, female gender and younger age had significant associations with higher depression. The prevalence of reported depressive symptoms was 23.4% in females [17]. In this study, while females were more frequent in the active IBD group, gender showed no statistically significant association between active and inactive IBD and depression status in patients. Also, various studies reported the association between gender and age with the risk of depression among patients with IBD [18, 19, 20].
Our results revealed that among patients with IBD, the comorbidity of depression predisposes patients to a higher prevalence of active IBD than patients without depression. Similar to our results, depression was reported to be more frequent among patients with active IBD [19]. One of the possible mechanisms for this positive association between depression level and IBD activity can be the lower medication adherence in depressed patients, which affects the IBD status. Although, IBD patients are at the same risk for psychological disorders as the general population [21]
Based on our results, a higher frequency of depression among patients with an autoimmune disease that received immunosuppressive drugs was obtained. Corticosteroids, as one of the main used drug groups in IBD patients, can affect mood status. On the other hand, depression, through a decrease in medication adherence, can affect chronic disease activity [22]. Despite drug-related effects, it has been confirmed that psychological problems such as stress have some associations with IBD status through changes in the hypothalamic-pituitary-adrenal axis, bacterial-mucosal interactions, and cellular and molecular pathways [23, 24]. 
Gao et al. reported no association between smoking status and the prevalence of IBD among patients with depression [25]. Our results illustrated that the majority of patients did not smoke and also had a higher prevalence of mild depression. Due to the higher severity of depression in patients with active IBD, diagnosis, and treatment of depression in IBD patients are highly suggested, which can improve the patient’s quality of life.
Conclusion
According to our results, depression increases the patient’s susceptibility to recurrent active IBD. In this regard, by controlling depression in patients with IBD, the cycle of active IBD can be reduced.

Ethical Considerations
Compliance with ethical guidelines
All study procedures followed the ethical guidelines of the Declaration of Helsinki 2013. The study was approved by the Ethics Committee of Guilan University of Medical Sciences, Rasht, Iran (Ethical Code: IR.GUMS.REC. 1394.196).

Funding
This research received no grant from funding agencies in the public, commercial, or not-for-profit sectors..

Authors contributions
Conceptualization: Farahnaz Joukar, Mehrnaz Asgharnezhad, and Amineh Hojati; Methodology: Sara Maveddati and Masood Sepehrimanesh; Investigation: Adeleh Isanazar and Alireza Mansour-Ghanaei; Writing the original draft: All authors; Writing, review, and editing: Niloofar Faraji and Tahereh Zeinali; Resources: Alireza Samadi and Fariborz Mansour-Ghanaei; Supervision: Farahnaz Joukar and Fariborz Mansour-Ghanaei.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgements
All authors express their gratitude and appreciation to all involved in this project.


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