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Depression symptoms increase the risk for initiation or switching to biologic therapy in pediatric inflammatory bowel disease patients in remission

BMC Gastroenterology volume 23, Article number: 355 (2023) Cite this article

Abstract

Background and aims

Anxiety and depression symptoms are common in IBD population, both adult and pediatric patients. Increased psychological distress might contribute to initiation and switching to biologic therapy in adult patients with IBD or other chronic inflammatory diseases. Aim of the present study are to evaluate anxiety and depression symptoms in IBD pediatric patients with disease remission and investigate their role in initiation or switching to biologic therapy.

Methods

We performed a retrospective analysis on IBD pediatric patients, assessing for anxiety (GAD-7) and depression (PHQ-9) symptoms. Demographic and disease characteristics were obtained from medical records.

Results

Eighty-six patients [31 (36%) females - mean age = 15.6 (SD = 2.8) years] were included. Patients scored above cut-off (> 10) on PHQ-9 and GAD-7 were 17 (19.7%) and 18 (20.9%), respectively. No differences were found between UC and CD patients. Baseline clinically relevant depression symptoms were significantly associated with the odds of initiating or switching to biologic therapy within 2 years [OR = 4.5 (1.4–14.3)], even after confounders adjustment [4.2 (1.2–14.9)]. Relationship was not significant with anxiety symptoms.

Conclusion

Anxiety and depression symptoms is relatively common in pediatric IBD population, even with disease remission. Pediatric IBD patients with high depression symptoms are at increased risk of initiating or switching to biologic therapy. Mental health screening programs should be incorporated in routine clinical practice, especially for depression, regardless of disease activity and disease type. Early diagnosis and proper intervention for mental illness should be part of routine IBD management.

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Introduction

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD), ulcerative colitis (UC), and inflammatory bowel disease-undefined (IBD-U), is characterized by chronic intestinal inflammation with a relapsing-remitting course. Main symptoms include diarrhea, abdominal pain, rectal bleeding/bloody stools, weight loss and fatigue [1]. The incidence and prevalence of pediatric IBD is increasing globally [2]. Pediatric age raises several age-specific considerations related to growth, pubertal development and the acquirement towards adulthood of autonomy, body image, and self-confidence [3]. Anxiety and depression symptoms are common in IBD patients, and disease activity has been described as an important risk factor for mental health both in adult and pediatric IBD population [4,5,6,7]. Conversely, psychological disorders such as anxiety or depression might be a risk factor for disease relapse, as demonstrated in adult IBD population [8].

Treatment options for pediatric IBD include non-biological therapies (such as aminosalicylates, thiopurines, and steroids) and biological therapies (monoclonal antibody targeting inflammatory cytokines) [9]. In a recent research on adult IBD population, elevated depressive symptoms were associated with two-fold increased odds of using biologic therapy [10]. Several studies on other chronic inflammatory conditions (such as Rheumatoid Arthritis) suggest that increased psychological distress symptoms may contribute to initiation and switching to biologic therapy [11, 12]. To date, no studies have investigated the association between anxiety and depression symptoms and step-up biologic therapy in IBD pediatric population. The aims of the present study are to evaluate anxiety and depression symptoms in IBD pediatric patients with disease remission and investigate their role in initiation or switching to biologic therapy.

Methods

Study design

We performed a retrospective analysis on data from consecutive IBD pediatric patients from Bambino Gesù Children’s Hospital of Rome, a tertiary care referral hospital with a dedicated pediatric IBD care program, caring for approximately 400 patients. Ethics approval from Bambino Gesù Ethics Committee was obtained for a comprehensive study about mental health assessment and therapeutic intervention in all IBD patients (protocol n. 2588). For the present study, retrospective data were collected from medical records of outpatient visits from January 1, 2019, to August 31, 2022. Demographic and disease variables were collected at baseline and after 12 months. A licensed psychologist examined psychological assessment through brief self-report instruments. Inclusion criteria were: (1) confirmed IBD diagnosis, (2) disease remission at baseline evaluation, (3) age > 11 years, (4) a sufficient knowledge of the Italian language to complete written questionnaires or clinical interview, and (5) minimum follow-up period of 12 months after psychological assessment. Exclusion criteria included active disease, neurological or neurodevelopmental impairment and/or other health conditions that could explain biologic initiation or switching therapy.

Measures

Demographic and disease variables included the following: age, gender, body mass index (BMI), IBD duration, IBD type (UC or CD), surgical history, medications (including psychotropic drug, corticosteroid, mesalamine, immunomodulators and biologic therapy). Clinical indexes for disease activity, namely Pediatric Crohn’s Disease Activity Index (PCDAI) [13] and Pediatric Ulcerative Colitis Activity Index (PUCAI) [14], identified remission state (PUCAI or PCDAI score < 10 points). Biologic initiation or switching therapy was defined as any occurrence of infliximab, adalimumab, vedolizumab, or ustekinumab initiation or switching from one to other. Follow-up period was minimum 12 months and maximum 24 months after baseline assessment.

Generalized anxiety disorder (GAD-7)

The GAD-7 is a seven-item instrument that is used to measure or assess the severity of anxiety symptoms [15]. Items were scored on a four-point scale (0 = not at all, 1 = several days, 2 = more than half the days, and 3 = nearly every day), with total scores ranging from zero to twenty-one. The recommended screening cutoff was > 10, corresponding to at least a moderate level of anxiety [16].

Patient health questionnaire (PHQ-9)

The PHQ-9 is a depression symptoms scale consisting of nine questions and it can be used as a tool for monitoring the depressive symptoms. Items were scored on a four-point scale (0 = not at all, 1 = several days, 2 = more than half the days, and 3 = nearly every day), with total scores ranging from zero to twenty-seven. A score > 10 had a sensitivity of 89.5% and a specificity of 77.5% for detecting clinically meaningful depression symptoms in adolescents [17].

Statistical analyses

Continuous variables were presented as mean ± standard deviation (SD) and categorical variables were presented as counts and percentage (%). Chi-squared test or Fisher exact test (as appropriate) was used to evaluate anxiety/depression symptoms differences between CD and UC. A binary logistic regression was used to investigate the effects of anxiety and depression on biologic initiation or switching therapy within the follow-up period (Unadjusted). A multiple logistic regression model was then performed, incorporating variables that have been previously associated with anxiety or depression as potential confounders (sex, age and disease type) [18], to examine the odds of biologic initiation or switching therapy with higher baseline anxiety and depression score (Adjusted). P values less than 0.05 were considered to be statistically significant. Data were analyzed using SPSS - Version 25 (Armonk, NY).

Results

Out of 140 IBD patients aged 12–21 years who underwent psychological assessment during study period, 86 patients fulfilled the inclusion criteria for the study. Among them, 31 were female (36%, mean age = 15.6 ± 2.8 years). Forty-six (53%) had a diagnosis of UC and 40 (47%) were affected by CD. Sample characteristics are shown in Table 1.

Table 1 Sample characteristics
Full size table

Average score for depression symptoms (PHQ-9) was 6.3 (SD = 4.8) and score for anxiety symptoms was 5.8 (SD = 3.8) (GAD-7). Patients with score above 10 on PHQ-9 and GAD-7 were 17 (19.7%) and 18 (20.9%), respectively. Concerning symptoms severity, approximately 50% of patients reported mild to severe symptoms, with no differences between UC and CD (Table 2). Binary logistic regression showed that baseline clinically meaningful depression symptoms (score > 10) were significantly associated with the odds of initiation or switching to biologic therapy within 2 years [OR = 4.5 (1.4–14.3)]. Anxiety did not show any influence on the risk to initiation or switching to biologic therapy [OR = 2.7 (0.9–7.8)]. In multiple logistic regression analysis, baseline depression increased the risk of biologic initiation or switching therapy [4.2 (1.2–14.9)], whereas baseline anxiety did not [2.3 (0.7–7.3)], after controlling for confounders. None of the confounders reached the statistical significance both for anxiety and depression model. Results of logistic regression are shown in Table 3.

Table 2 Severity of depression and anxiety symptoms according to disease type
Full size table
Table 3 Logistic regression on the effect of baseline depression/anxiety and biologic initiation or switching therapy within 2 years
Full size table

Discussion

Anxiety and depression symptoms are relatively common in IBD patients, compared to healthy subjects. Adult population seems to be more at risk than pediatric population, with a prevalence of 35–38% for anxiety and 20–24% for depression, compared to 16 and 15% in children, respectively [4, 5, 19]. Our study, including adolescents and youths, showed intermediate results, with a prevalence of 20.9% for anxiety and 19.7% for depression. No difference was noticed between UC and CD. These results are noteworthy, as they refer to patients with disease remission. This underlines the importance of mental health assessment in all pediatric IBD patients as a routine work up, regardless of disease activity and disease phenotype. Indeed, this approach could lead to early diagnosis of mental health symptoms and proper intervention.

Another intriguing result of the present study is that pediatric IBD patients with depression symptoms were four times more likely to start or switch to biologic therapy within two years, compared with non-depressed patients. These data are consistent with findings in adult population. For instance, a recent study demonstrated that IBD patients with elevated depression symptoms had two-fold times the odds of using biologic therapy [10]. In another IBD cohort, biologic medications were more frequently prescribed to patients with anxiety or depression symptoms [20]. The same trend has been observed in other chronic inflammatory diseases. Indeed, patients with Rheumatoid Arthritis and early depression were less likely to achieve a good response to biologic therapy [11, 21, 22]. Other Authors suggested that depression and anxiety might contribute to initiation and switching to biologics, either by aggravating disease severity and/or by distorting the perception of patient-reported outcome measures [12]. Depression symptoms were demonstrated to influence the course and severity of various chronic inflammatory diseases [23, 24]. Depressive symptoms might worsen the subjective experience of illness, decrease adherence to medications or limiting healthy behaviors, and have been associated with elevated levels of inflammation and inflammatory markers [25,26,27]. Based on our result and previous studies, we speculate that depression may contribute to worsening disease activity, reducing response to medication and leading to a step-up biologic therapy.

Limitations should also be noted. We did not capture the effect of several clinical factors [such as steroid dependence, disease duration, disease phenotype (stricturing/fistulizing) and BMI] can influence the risk of biologic usage and needs to be evaluated in multivariate analysis. We did not capture the use of psychological intervention or psychotropic therapies for depression and anxiety during the follow-up period; however, these therapies may influence the course of anxiety and depression symptoms and should be evaluated in the regression model.

Conclusions

Clinically significant increase in anxiety and depression symptoms is relatively common in pediatric IBD population, even with disease remission. Prevalence seems to be equivalent in the two major disease phenotypes, namely UC and CD. Pediatric IBD patients with depression symptoms are more at risk of initiating or switching to biologic therapy, compared with patients without elevated depression symptoms. Mental health screening programs should be incorporated in routine clinical practice, especially for depression, regardless of disease activity and disease phenotype. Early diagnosis and proper intervention for mental illness should be part of routine IBD management.

Data Availability

The datasets of this study are availability from the corresponding author on reasonable request.

Abbreviations

IBD:

Inflammatory Bowel Disease

CD:

Crohn’s Disease

UC:

Ulcerative Colitis

SD:

Standard Deviation

BMI:

Body mass index

References

  1. Guan Q. A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res. 2019;2019:7247238.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kuenzig ME, Fung SG, Marderfeld L, et al. Twenty-first Century trends in the Global Epidemiology of Pediatric-Onset Inflammatory Bowel Disease: systematic review. Gastroenterology. 2022;162(4):1147–1159e4.

    Article  PubMed  Google Scholar 

  3. Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative Colitis–lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative Colitis. J Crohns Colitis. 2014;8(1):1–4.

    Article  PubMed  Google Scholar 

  4. Stapersma L, van den Brink G, Szigethy EM, et al. Systematic review with meta-analysis: anxiety and depression in children and adolescents with inflammatory bowel Disease. Aliment Pharmacol Ther. 2018;48(5):496–506.

    Article  CAS  PubMed  Google Scholar 

  5. Barberio B, Zamani M, Black CJ, et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel Disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(5):359–70.

    Article  PubMed  Google Scholar 

  6. van den Brink G, Stapersma L, Vlug LE, et al. Clinical Disease activity is associated with anxiety and depressive symptoms in adolescents and young adults with inflammatory bowel Disease. Aliment Pharmacol Ther. 2018;48(3):358–69.

    Article  PubMed  Google Scholar 

  7. Mules TC, Swaminathan A, Hirschfeld E, et al. The impact of Disease activity on psychological symptoms and quality of life in patients with inflammatory bowel disease-results from the stress, anxiety and depression with Disease Activity (SADD) Study. Aliment Pharmacol Ther. 2022;55(2):201–11.

    Article  PubMed  Google Scholar 

  8. Gracie DJ, Hamlin PJ, Ford AC. The influence of the brain-gut axis in inflammatory bowel Disease and possible implications for treatment. Lancet Gastroenterol Hepatol. 2019;4(8):632–42.

    Article  PubMed  Google Scholar 

  9. Na SY, Moon W. Perspectives on current and novel treatments for inflammatory bowel Disease. Gut Liver. 2019;13(6):604–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marrie RA, Graff LA, Fisk JD, et al. The relationship between symptoms of depression and anxiety and Disease Activity in IBD over Time. Inflamm Bowel Dis. 2021;27(8):1285–93.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rathbun AM, Harrold LR, Reed GW. A prospective evaluation of the effects of prevalent depressive symptoms on Disease activity in rheumatoid arthritis patients treated with Biologic Response modifiers. Clin Ther. 2016;38(7):1759–1772e3. PMC4947560.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bournia VK, Tektonidou MG, Vassilopoulos D, et al. Introduction and switching of biologic agents are associated with antidepressant and anxiolytic medication use: data on 42 815 real-world patients with inflammatory rheumatic Disease. RMD Open. 2020;6(3):e001303.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn’s Disease activity index. J Pediatr Gastroenterol Nutr. 1991;12(4):439–47.

    Article  CAS  PubMed  Google Scholar 

  14. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative Colitis activity index: a prospective multicenter study. Gastroenterology. 2007;133(2):423–32.

    Article  PubMed  Google Scholar 

  15. Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7.

    Article  PubMed  Google Scholar 

  16. Mossman SA, Luft MJ, Schroeder HK, et al. The generalized anxiety disorder 7-item scale in adolescents with generalized anxiety disorder: Signal detection and validation. Ann Clin Psychiatry. 2017;29(4):227–234A.

    PubMed  PubMed Central  Google Scholar 

  17. Richardson LP, McCauley E, Grossman DC, et al. Evaluation of the Patient Health Questionnaire-9 item for detecting major depression among adolescents. Pediatrics. 2010;126(6):1117–23. https://doi.org/10.1542/peds.2010-0852.

    Article  PubMed  Google Scholar 

  18. Nahon S, Lahmek P, Durance C, et al. Risk factors of anxiety and depression in inflammatory bowel Disease. Inflamm Bowel Dis. 2012;18(11):2086–91.

    Article  PubMed  Google Scholar 

  19. Neuendorf R, Harding A, Stello N, et al. Depression and anxiety in patients with inflammatory bowel Disease: a systematic review. J Psychosom Res. 2016;87:70–80.

    Article  PubMed  Google Scholar 

  20. Navabi S, Gorrepati VS, Yadav S, et al. Influences and impact of anxiety and depression in the setting of inflammatory bowel Disease. Inflamm Bowel Dis. 2018;24(11):2303–8.

    Article  PubMed  Google Scholar 

  21. Michelsen B, Kristianslund EK, Sexton J, et al. Do depression and anxiety reduce the likelihood of remission in rheumatoid arthritis and psoriatic arthritis? Data from the prospective multicentre NOR-DMARD study. Ann Rheum Dis. 2017;76(11):1906–10.

    Article  PubMed  Google Scholar 

  22. Matcham F, Davies R, Hotopf M, et al. The relationship between depression and biologic treatment response in rheumatoid arthritis: an analysis of the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2018;57(5):835–43.

    Article  PubMed  Google Scholar 

  23. Gao X, Tang Y, Lei N, et al. Symptoms of anxiety/depression is associated with more aggressive inflammatory bowel Disease. Sci Rep. 2021;11(1):1440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pezzato S, Bonetto C, Caimmi C, et al. Depression is associated with increased Disease activity and higher disability in a large Italian cohort of patients with rheumatoid arthritis. Adv Rheumatol. 2021;61(1):57.

    Article  PubMed  Google Scholar 

  25. Matcham F, Ali S, Irving K, et al. Are depression and anxiety associated with Disease activity in rheumatoid arthritis? A prospective study. BMC Musculoskelet Disord. 2016;17:155.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139(3):230–9.

    Article  CAS  PubMed  Google Scholar 

  27. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160(14):2101–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This work was supported also by the Italian Ministry of Health with Current Research funds.

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Authors and Affiliations

  1. Psychology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    F. Milo & P. Tabarini

  2. Gastroenterology and Nutrition Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    G. Angelino, E.F. Romeo & P. De Angelis

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  1. F. Milo
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  2. G. Angelino
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  3. E.F. Romeo
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  4. P. De Angelis
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  5. P. Tabarini
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Contributions

FM and PT designed this study. FM performed the data analysis and drafted the manuscript. GA, EFR and PDA collected the medical information. All authors read and approved the final manuscript.

Corresponding author

Correspondence to F. Milo.

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Ethic approval and consent to participate

This Ethic approval was obtained from the Ethics Committee of Bambino Gesù Children’s Hospital and all enrolled patients signed informed consent. All methods were carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from all the participants and/or their legal guardians.

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Not applicable.

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The authors declare no competing interests.

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Milo, F., Angelino, G., Romeo, E. et al. Depression symptoms increase the risk for initiation or switching to biologic therapy in pediatric inflammatory bowel disease patients in remission. BMC Gastroenterol 23, 355 (2023). https://doi.org/10.1186/s12876-023-02993-z

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Keywords

BMC Gastroenterology

ISSN: 1471-230X

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