Dig Dis Sci (2015) 60:465–470 DOI 10.1007/s10620-014-3375-0
ORIGINAL ARTICLE
Treatment with Immunosuppressive Therapy May Improve Depressive Symptoms in Patients with Inflammatory Bowel Disease Sara Horst • Andrew Chao • Michael Rosen • Anne Nohl • Caroline Duley • Julianne H. Wagnon • Dawn B. Beaulieu • Warren Taylor • Lawrence Gaines David A. Schwartz
•
Received: 18 October 2013 / Accepted: 24 September 2014 / Published online: 2 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Introduction Recent research suggests a relationship of inflammatory bowel disease (IBD) and depression. Our objective was to evaluate for improvement of depressive symptoms with treatment of IBD using immunosuppressive medications. Methods A retrospective study of consecutive patients with IBD started on immunosuppressive agents [anti-tumor necrosis factor (anti-TNF) or immunomodulator therapy] was conducted. Patients were evaluated if disease activity indices using Harvey Bradshaw Index for Crohn’s disease (CD) and Simple Clinical Colitis Disease Activity Index for ulcerative colitis (UC) and depressive indices using Patient Health Questionnaire-9 (PHQ-9) scores were obtained before and at least 30 days after initiation of therapy. Results Sixteen patients with UC and 53 patients with CD (all with active disease symptoms) were evaluated over a 60 day median follow-up evaluation (range 30, 140 days). Twenty-two patients started on immunomodulator therapy, and 47 patients started on anti-TNF therapy. Crohn’s
S. Horst (&) A. Chao A. Nohl C. Duley J. H. Wagnon D. B. Beaulieu L. Gaines D. A. Schwartz Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 1211 21st Ave South, Medical Arts Building Suite 220, Nashville, TN 37232, USA e-mail: [email protected] M. Rosen Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA W. Taylor L. Gaines Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
disease patients had significantly decreased PHQ-9 scores at follow-up [median 9 (range 3, 14) to 4 (1, 8)], with significant decreases only in those started on anti-TNF therapy. Changes in PHQ-9 and CRP were correlated (q = 0.38, p \ 0.05). In patients with UC, PHQ-9 scores [5 (3, 9) to 2 (0, 5)] were significantly decreased. Percentage at risk of moderate to severe depression (PHQ-9 scores C10) was lower after treatment [Crohn’s disease 51–18 % (p \ 0.05), ulcerative colitis 18–0 %]. Conclusion Depressive scores decreased significantly in patients with IBD treated with immunosuppressive therapy and the number at risk for moderate to severe depression improved significantly. Keywords Inflammatory bowel disease Depression Ulcerative colitis Crohn’s disease Anti-tumor necrosis factor antibody Azathioprine
Introduction Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing and potentially debilitating diseases. Recent studies have consistently shown higher rates of depression and anxiety in patients diagnosed with IBD compared to the general population [1–6]. Also, higher rates of anxiety and depression have been reported in those with active disease compared to those in remission [7–10]. These findings may be linked as these comorbidities could worsen the course of IBD and its related symptoms [11–13]. In this context, it is crucial to better understand the relationship between IBD and psychologic comorbidities and acknowledge the importance of addressing the psychologic needs of patients with IBD [14].
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One consideration often arises in the discussion of depression and IBD: Will simply treating the underlying disease effectively improve the symptoms of depression? Studies have shown the severity of depressive and anxiety symptoms decrease with improvement in inflammatory bowel disease activity [7, 15]. Several studies suggest that treatment with anti-tumor necrosis factor alpha (anti-TNF) therapy may improve depressive symptoms and healthrelated quality of life [16–18]. A recent prospective study of fifteen patients with Crohn’s disease also suggested improvement in depressive symptoms within 8 weeks after treatment with one infusion of anti-TNF therapy, infliximab [19]. Importantly, there are only limited data on longer term effects of anti-TNF therapy on depressive symptoms. Also, there are little data about whether other types of immunosuppression commonly used in IBD treatment, such as immunomodulator therapy including azathioprine and methotrexate, can benefit depressive symptoms. Within IBD, patients with Crohn’s disease and ulcerative colitis likely have different disease immunology and pathogenesis, and these diseases can have very different clinical manifestations and outcomes. These differences could be important for their effects on mental health. For example, depressive symptoms may have less or no impact on disease activity and subsequent flares in patients with ulcerative colitis [20]. However, some studies have shown that IBD activity is a greater driver of depression and healthrelated quality of life than IBD type [21–23]. Our study aimed to evaluate the impact of new initiation of immunosuppressive therapy (anti-TNF therapy or immunomodulator therapy) on depressive symptoms in patients with active inflammatory bowel disease. We sought to evaluate if disease activity improvement correlated with depressive symptom improvement and to evaluate if outcomes differed between patients with Crohn’s disease compared to ulcerative colitis.
Methods Study Design This is a retrospective cohort of consecutive patients seen in a single tertiary care IBD clinic for either active Crohn’s disease or active ulcerative colitis from October 2009 to February 2010. Patients were C18 years of age and had prior confirmation of the diagnosis of Crohn’s disease or ulcerative colitis based on endoscopy or radiology findings. Subjects included in the study had both the clinical evidence of active disease based on endoscopic, radiologic, or biomarker documentation of active disease and were being newly initiated on anti-TNF therapy (including
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infliximab, adalimumab, or certolizumab) or immunomodulator (IMM) therapy (methotrexate or azathioprine). The subjects were included if they had indices of depression, quality of life, and disease activity completed prior to and at least 30 days after initiation of the medication. Subjects were included if they were already on an anti-TNF therapy or IMM therapy but were changing to a different medical therapy because of lack of efficacy or intolerance of their baseline therapy. Exclusion criteria included subjects who were pregnant, subjects with ostomies (disease activity could not be measured using patient report questionnaires), and those who did not have complete follow-up measures recorded in the medical record. Measures After obtaining approval from the Vanderbilt University Institutional Review Board, measures were obtained via chart review of the patient electronic medical record which includes clinical care notes, radiology, endoscopy, and laboratory data. Baseline characteristics of the patients were obtained, including age, sex, site of disease, prior surgical history, medications at the start of anti-TNF therapy or IMM including steroid and psychiatric medication use, prior or current smoking status, and the history of psychiatric disease. Also, the addition of psychiatric medications such as antidepressants during the study period was documented. Measures including disease activity, depression symptom assessment, and health-related quality of life were obtained at each clinic visit as part of routine clinic practice. Disease activity was evaluated using the Harvey Bradshaw Index (HBI) [24] for CD or the Simple Clinical Colitis Disease Activity Index (SCCAI) for UC [25]. Depressive symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9) [26, 27]. The PHQ-9 is a well-validated questionnaire used in clinical practice to evaluate for risk of depression. It evaluates 9 items on which the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) depressive disorders diagnosis are based. The developers have reported the following interpretive guidelines (scores 1–4 = no depression, 5–9 = mild depression, 10–14 = moderate depression, 15–19 = moderately severe depression, and 20–27 = severe depression) [26]. A PHQ-9 score of C10 had a sensitivity of 88 % and a specificity of 88 % of diagnosing major depression [26]. Quality of life symptoms were evaluated using the well-validated Short Inflammatory Bowel Disease Questionnaire (SIBDQ) [28]. These measures were evaluated prior to the initiation of anti-TNF and/or IMM and again at least 30 days after the initiation of the medication at the patient’s next clinic visit to allow for adequate medication effect.
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Table 1 Demographics of subjects Type of inflammatory bowel disease (IBD) Ulcerative colitis
16 (23 %)
Crohn’s disease
53 (77 %)
Ileocolonic disease
25
Colitis only
12
Small bowel and colonic disease
13
Perianal disease only
3
Sex (number, % female)
40 (58 %)
Median age in years (range)
33 years (18, 73)
Current smoker
18 (26 %)
Median BMI (range)
24.5 (17.2, 43.6)
History of IBD-related operation Ileocecal resection
12 (17 %)
Partial colectomy
3 (4 %)
Ileal pouch anal anastomosis Other concominant baseline medications
2 (3 %)
5-ASA (oral)
23 (33 %)
Prednisone
21 (30 %)
Budesonide
13 (18 %)
Immunomodulator
13 (19 %)
Table 2 New immunosuppressive medication initiation in patients with inflammatory bowel disease and active symptoms Ulcerative colitis (n = 16) Immunomodulator
Crohn’s disease (n = 53) 8 (50 %)
Immunomodulator
Azathioprine
7
Azathioprine
Methotrexate
1
Methotrexate
Anti-TNF therapy
Fig. 1 Significant improvement in depressive symptoms after therapy with anti-TNF and/or immunomodulator therapy in patients with Crohn’s disease (n = 53) and ulcerative colitis (n = 16)
8 (50 %)
Anti-TNF therapy
14 (26 %) 10 4 39 (74 %)
Infliximab
7
Infliximab
8
Adalimumab
1
Adalimumab
18
Certolizumab
0
Certolizumab
13
Statistical Analysis Continuous variables were compared using Wilcoxon matched paired signed-rank test, and categorical variables compared using chi-squared analysis. Changes in C-reactive protein (CRP) and depressive symptoms were compared using Spearman correlation coefficient.
Results Of the 357 charts evaluated, 69 patients met criteria for evaluation during the study period. Sixteen patients were diagnosed with UC, and 53 patients were diagnosed with Crohn’s disease. Baseline characteristics are summarized in Table 1. Twenty-two patients were started only on IMM
(8 with ulcerative colitis, 14 patients with Crohn’s disease), and 47 patients were started on anti-TNF therapy (8 patients with ulcerative colitis and 39 patients with Crohn’s disease). Details of medication initiation are summarized in Table 2. Of patients starting on anti-TNF therapy, 13 were already on IMM and 11 patients also had IMM added when anti-TNF therapy was started. Median follow-up after starting anti-TNF therapy was 50 days (30, 140 days), and median follow-up after starting immunomodulator therapy was 80 days (53, 120 days). Seven patients had a history of psychiatric disease, three with a history of major depressive disorder, two with a history of bipolar disorder, and two with a history of anxiety disorder. Six patients with Crohn’s disease were on antidepressant therapy consisting of selective serotonin reuptake inhibitors (SSRIs), and one patient was on an atypical anti-psychotic. None of the patients with UC were on antidepressants at medication initiation. During the treatment time period, two patients with Crohn’s disease were started on an SSRI and one patient with UC was started on an SSRI. In Crohn’s disease patients, 51 % (n = 28) were at risk for moderate to severe depression (PHQ-9 C10) prior to the therapy, and 18 % (n = 10) met criteria for moderate to severe depression after therapy, (p \ 0.05) (Fig. 1). In a subset of patients with biomarker measurements (n = 50), CRP improved in patients with Crohn’s disease (19.0 ± 37.9–9.4 ± 20.4, p = 0.05). Crohn’s disease patients initiated on therapy had significantly decreased PHQ-9 scores at follow-up and significantly decreased HBI scores and increased SIBDQ scores (Table 3). In a subset analysis, only subjects with Crohn’s disease initiated on an anti-TNF medication had this significant decrease in PHQ9 scores [10 (2, 17) to 4 (1, 9), p \ 0.05]. The patients with Crohn’s disease initiated on immunomodulator therapy only (n = 14) had no statistically significant decrease in PHQ-9 scores [5 (2, 12) to 5 (0, 8), p = 0.9). PHQ-9 scores decreased significantly whether subjects with Crohn’s
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Table 3 PHQ-9, HBI or SSCAI, and SIBDQ scores before and after initiation of biologic (±IMM) or IMM only in CD (A) and UC (B) Before therapy median (25 %, 75 % IQR)
After therapy median (25 %, 75 % IQR)
p value
Table 4 Patients with Crohn’s disease had improvement in depressive symptoms after therapy regardless of disease activity improvement Disease activity response or remissiona
(A) Crohn’s disease (n = 53) PHQ-9 HBI SIBDQ
4 (1, 8)
\0.01
4.5 (2, 8)
2 (0, 6)
\0.01
44.5 (35, 60)
54.5 (41, 63)
\0.01
9 (3, 14)
PHQ-9
5 (3, 9)
SCCAI
8.5 (5, 11)
SIBDQ
43 (41, 53)
2 (0, 5)
\0.01
4 (3, 6)
\0.01
57.5 (51, 60)
\0.01
Wilcoxon matched pairs signed-rank test used for statistical comparison and significant decreases were noted in all scores PHQ-9 Personal Health Questionnaire-9, HBI Harvey Bradshaw Index, SSCAI Simple Clinical Colitis Activity Index, SIBDQ Short Inflammatory Bowel Disease Questionnaire
disease achieved remission or response based on HBI (Table 4). Changes in PHQ-9 were correlated with changes in CRP (q = 0.38, p \ 0.05). In UC patients, 18 % (n = 3) were at risk for moderate to severe depression (PHQ-9 C10) prior to the therapy, and no subjects met criteria after treatment (Fig. 1). In patients with UC, PHQ-9, and SCCAI scores at follow-up were significantly decreased and SIBDQ scores were significantly increased (Table 3). CRP improved but not statistically significantly in a subset of patients with UC (n = 14) with biomarker measurements (21.9 ± 55.2–6.8 ± 10.0, p = 0.2).
Discussion We found that treatment with medications for inflammatory bowel disease including anti-TNF therapy and immunomodulator therapy significantly improved depressive symptoms and significantly decreased the number of patients who met criteria for moderate to severe depression after treatment for 1–6 months [for Crohn’s disease 51–18 % (p \ 0.05)], for ulcerative colitis 18–0 %). Only a small number of patients (10 %) had reported a formal diagnosis of a psychiatric disorder, and only 10 % were on antidepressant medications before or during the follow-up period. However, in our patients with inflammatory bowel disease and active symptoms, a significant number met criteria for moderate to severe depression prior to a change in medical therapy. Recent research has highlighted increased rates of depression and anxiety in patients with IBD [2–4, 6, 29]. Crucially, depressive symptoms may affect disease activity
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PHQ-9 after therapy Median (25 %, 75 % IQR)
p value
Yes
6 (3, 14)
3 (0, 8)
\0.05
No
12 (5, 14)
7 (3, 9)
\0.05
a
(B) Ulcerative colitis (n = 16)
PHQ-9 before therapy Median (25 %, 75 % IQR)
Based on Harvey Bradshaw Index
over time. Recently a large multi-institution cohort study of patients with IBD found an increased risk of surgery in patients with Crohn’s disease with a diagnosis of major depressive disorder or generalized anxiety based on ICD-9 codes compared to those without these diagnoses [12]. Similarly, a prospective study reported that individuals with IBD with higher levels of depressive symptoms at baseline are more likely to relapse, relapse more quickly, and have a greater number of relapses than individuals without depression [13]. Other studies suggest that therapy for IBD may actually influence depressive symptoms. Minderhoud et al. [18] found significantly improved depressive symptoms after one to two infusions of infliximab in 14 patients with CD. Persoons et al. [16] found that following a single infusion of infliximab, a significantly lower proportion of patients with CD (n = 100) met criteria for major depressive disorder (24–16 %, p \ 0.05). However, patients meeting criteria for major depressive disorder were less likely to exhibit clinical improvement in IBD symptoms with infliximab treatment. A similar result of improvement in depressive symptoms, possibly independent of disease activity, was found in a small study of 15 patients given one infusion of infliximab and followed for 8 weeks [19]. In our study, the decrease in PHQ-9 scores in patients with Crohn’s disease correlated with decrease in C-reactive protein (CRP). However, depressive symptoms improved significantly in Crohn’s disease patients regardless of whether the patients achieved remission or response based on the HBI when a new therapy was started (Table 4). Several other small studies mentioned above also found that depressive symptom improvement did not correlate with disease activity improvement after anti-TNF therapy in inflammatory conditions including Crohn’s disease and ankylosing spondylitis [19, 30]. Measuring disease activity using the Harvey Bradshaw Index (HBI) has limitations including capturing functional gastrointestinal symptoms that can be associated with depression, and there is literature regarding lack of precision of this tool as a measure for active inflammatory bowel disease [31]. Also, depressive symptoms in Crohn’s disease could be mediated along a
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pathway of cytokine dysregulation that may improve with alterations in these pathways (including decrease in CRP) even before mucosal healing and hence disease activity improvement. Indeed, there is the substantial literature linking depression with proinflammatory processes. A recent review found that, regardless of chronic disease state, depression was associated with elevated levels of CRP, IL-1, and IL-6 [32]. Supporting this relationship, a recent placebo-controlled randomized trial evaluated the role of infliximab in the treatment of patients without inflammatory disease but with treatment-resistant depression. The authors did not find a significant overall improvement in depressive symptoms with infliximab treatment; however, they did find an improvement in depressive symptoms in patients with increased baseline CRP levels (high sensitivity CRP C5 mg/L) [33]. Our study is limited in the retrospective study design with its inherent weaknesses such as interpretation bias and inability to control for confounders such as length on medication before a follow-up PHQ-9 score was obtained as we were limited to when the patient had a follow-up clinic visit. Also, the PHQ-9 is a well-validated questionnaire for evaluation of depressive symptoms, but it is not a formal evaluation for depressive disorders. Depressive symptom improvement may not have been due to medication initiation, but secondary to improvement in disease activity itself, simply due to time, or other factors such as specific antidepressant medications. However, less than 10 % of the patients were on antidepressant therapy, and it was only added in the follow-up period in three patients. We have no data regarding other possible treatment for depression such as psychotherapy. Also, given the small number of patients, it was difficult to control for confounders such as corticosteroid use, smoking status, and the presence of psychiatric disorder at baseline. In our study, improvement in depressive symptoms seems most pronounced with anti-TNF therapy, at least in patients with Crohn’s disease. However, it is possible that our small sample size of those patients with Crohn’s disease or ulcerative colitis started only on immunomodulator therapy limited adequate evaluation. Small number of patients with ulcerative colitis included in the study precluded subgroup evaluation of PHQ-9 improvement by medication. Immunomodulator therapy could have same effect on depressive symptoms, but this medication has a longer time to therapeutic response (up to 3 months) so a longer time to evaluate for effects may have been necessary. Also, some of our patients who started anti-TNF therapy were also started on IMM therapy, and therefore, the contribution of immunomodulator therapy is unclear. However, our work highlights a growing area of interest in patients with inflammatory bowel disease as we learn the
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importance of treating all aspects of a patient’s life, including psychologic comorbidities such as depression. It is possible that comorbid depressive symptoms may be a marker or even contribute to disease outcomes. This study demonstrates that medications aimed at treating disease activity may also improve psychologic parameters in inflammatory bowel disease. Further research into this area is needed as it is important both in furthering the understanding the pathophysiology of inflammatory bowel disease and the psychologic comorbidities so often associated with the disease. Conflict of interest
None.
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Dig Dis Sci (2015) 60:465–470 24. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514. 25. Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut. 1998;43:29–32. 26. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606–613. 27. Nease DE Jr, Maloin JM. Depression screening: a practical strategy. J Fam Pract. 2003;52:118–124. 28. Irvine EJ, Zhou Q, Thompson AK. The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT investigators. Canadian Crohn’s Relapse Prevention Trial. Am J Gastroenterol. 1996;91:1571–1578. 29. Lerebours E, Gower-Rousseau C, Merle V, et al. Stressful life events as a risk factor for inflammatory bowel disease onset: a population-based case–control study. Am J Gastroenterol. 2007;102:122–131. 30. Ertenli I, Ozer S, Kiraz S, et al. Infliximab, a TNF-alpha antagonist treatment in patients with ankylosing spondylitis: the impact on depression, anxiety and quality of life level. Rheumatol Int. 2012;32:323–330. 31. Williet N, Sandborn WJ, Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12:1246.e6–1256.e6. 32. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–186. 33. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41.
ORIGINAL ARTICLE
Treatment with Immunosuppressive Therapy May Improve Depressive Symptoms in Patients with Inflammatory Bowel Disease Sara Horst • Andrew Chao • Michael Rosen • Anne Nohl • Caroline Duley • Julianne H. Wagnon • Dawn B. Beaulieu • Warren Taylor • Lawrence Gaines David A. Schwartz
•
Received: 18 October 2013 / Accepted: 24 September 2014 / Published online: 2 October 2014 Ó Springer Science+Business Media New York 2014
Abstract Introduction Recent research suggests a relationship of inflammatory bowel disease (IBD) and depression. Our objective was to evaluate for improvement of depressive symptoms with treatment of IBD using immunosuppressive medications. Methods A retrospective study of consecutive patients with IBD started on immunosuppressive agents [anti-tumor necrosis factor (anti-TNF) or immunomodulator therapy] was conducted. Patients were evaluated if disease activity indices using Harvey Bradshaw Index for Crohn’s disease (CD) and Simple Clinical Colitis Disease Activity Index for ulcerative colitis (UC) and depressive indices using Patient Health Questionnaire-9 (PHQ-9) scores were obtained before and at least 30 days after initiation of therapy. Results Sixteen patients with UC and 53 patients with CD (all with active disease symptoms) were evaluated over a 60 day median follow-up evaluation (range 30, 140 days). Twenty-two patients started on immunomodulator therapy, and 47 patients started on anti-TNF therapy. Crohn’s
S. Horst (&) A. Chao A. Nohl C. Duley J. H. Wagnon D. B. Beaulieu L. Gaines D. A. Schwartz Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, 1211 21st Ave South, Medical Arts Building Suite 220, Nashville, TN 37232, USA e-mail: [email protected] M. Rosen Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA W. Taylor L. Gaines Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
disease patients had significantly decreased PHQ-9 scores at follow-up [median 9 (range 3, 14) to 4 (1, 8)], with significant decreases only in those started on anti-TNF therapy. Changes in PHQ-9 and CRP were correlated (q = 0.38, p \ 0.05). In patients with UC, PHQ-9 scores [5 (3, 9) to 2 (0, 5)] were significantly decreased. Percentage at risk of moderate to severe depression (PHQ-9 scores C10) was lower after treatment [Crohn’s disease 51–18 % (p \ 0.05), ulcerative colitis 18–0 %]. Conclusion Depressive scores decreased significantly in patients with IBD treated with immunosuppressive therapy and the number at risk for moderate to severe depression improved significantly. Keywords Inflammatory bowel disease Depression Ulcerative colitis Crohn’s disease Anti-tumor necrosis factor antibody Azathioprine
Introduction Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing and potentially debilitating diseases. Recent studies have consistently shown higher rates of depression and anxiety in patients diagnosed with IBD compared to the general population [1–6]. Also, higher rates of anxiety and depression have been reported in those with active disease compared to those in remission [7–10]. These findings may be linked as these comorbidities could worsen the course of IBD and its related symptoms [11–13]. In this context, it is crucial to better understand the relationship between IBD and psychologic comorbidities and acknowledge the importance of addressing the psychologic needs of patients with IBD [14].
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One consideration often arises in the discussion of depression and IBD: Will simply treating the underlying disease effectively improve the symptoms of depression? Studies have shown the severity of depressive and anxiety symptoms decrease with improvement in inflammatory bowel disease activity [7, 15]. Several studies suggest that treatment with anti-tumor necrosis factor alpha (anti-TNF) therapy may improve depressive symptoms and healthrelated quality of life [16–18]. A recent prospective study of fifteen patients with Crohn’s disease also suggested improvement in depressive symptoms within 8 weeks after treatment with one infusion of anti-TNF therapy, infliximab [19]. Importantly, there are only limited data on longer term effects of anti-TNF therapy on depressive symptoms. Also, there are little data about whether other types of immunosuppression commonly used in IBD treatment, such as immunomodulator therapy including azathioprine and methotrexate, can benefit depressive symptoms. Within IBD, patients with Crohn’s disease and ulcerative colitis likely have different disease immunology and pathogenesis, and these diseases can have very different clinical manifestations and outcomes. These differences could be important for their effects on mental health. For example, depressive symptoms may have less or no impact on disease activity and subsequent flares in patients with ulcerative colitis [20]. However, some studies have shown that IBD activity is a greater driver of depression and healthrelated quality of life than IBD type [21–23]. Our study aimed to evaluate the impact of new initiation of immunosuppressive therapy (anti-TNF therapy or immunomodulator therapy) on depressive symptoms in patients with active inflammatory bowel disease. We sought to evaluate if disease activity improvement correlated with depressive symptom improvement and to evaluate if outcomes differed between patients with Crohn’s disease compared to ulcerative colitis.
Methods Study Design This is a retrospective cohort of consecutive patients seen in a single tertiary care IBD clinic for either active Crohn’s disease or active ulcerative colitis from October 2009 to February 2010. Patients were C18 years of age and had prior confirmation of the diagnosis of Crohn’s disease or ulcerative colitis based on endoscopy or radiology findings. Subjects included in the study had both the clinical evidence of active disease based on endoscopic, radiologic, or biomarker documentation of active disease and were being newly initiated on anti-TNF therapy (including
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infliximab, adalimumab, or certolizumab) or immunomodulator (IMM) therapy (methotrexate or azathioprine). The subjects were included if they had indices of depression, quality of life, and disease activity completed prior to and at least 30 days after initiation of the medication. Subjects were included if they were already on an anti-TNF therapy or IMM therapy but were changing to a different medical therapy because of lack of efficacy or intolerance of their baseline therapy. Exclusion criteria included subjects who were pregnant, subjects with ostomies (disease activity could not be measured using patient report questionnaires), and those who did not have complete follow-up measures recorded in the medical record. Measures After obtaining approval from the Vanderbilt University Institutional Review Board, measures were obtained via chart review of the patient electronic medical record which includes clinical care notes, radiology, endoscopy, and laboratory data. Baseline characteristics of the patients were obtained, including age, sex, site of disease, prior surgical history, medications at the start of anti-TNF therapy or IMM including steroid and psychiatric medication use, prior or current smoking status, and the history of psychiatric disease. Also, the addition of psychiatric medications such as antidepressants during the study period was documented. Measures including disease activity, depression symptom assessment, and health-related quality of life were obtained at each clinic visit as part of routine clinic practice. Disease activity was evaluated using the Harvey Bradshaw Index (HBI) [24] for CD or the Simple Clinical Colitis Disease Activity Index (SCCAI) for UC [25]. Depressive symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9) [26, 27]. The PHQ-9 is a well-validated questionnaire used in clinical practice to evaluate for risk of depression. It evaluates 9 items on which the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) depressive disorders diagnosis are based. The developers have reported the following interpretive guidelines (scores 1–4 = no depression, 5–9 = mild depression, 10–14 = moderate depression, 15–19 = moderately severe depression, and 20–27 = severe depression) [26]. A PHQ-9 score of C10 had a sensitivity of 88 % and a specificity of 88 % of diagnosing major depression [26]. Quality of life symptoms were evaluated using the well-validated Short Inflammatory Bowel Disease Questionnaire (SIBDQ) [28]. These measures were evaluated prior to the initiation of anti-TNF and/or IMM and again at least 30 days after the initiation of the medication at the patient’s next clinic visit to allow for adequate medication effect.
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Table 1 Demographics of subjects Type of inflammatory bowel disease (IBD) Ulcerative colitis
16 (23 %)
Crohn’s disease
53 (77 %)
Ileocolonic disease
25
Colitis only
12
Small bowel and colonic disease
13
Perianal disease only
3
Sex (number, % female)
40 (58 %)
Median age in years (range)
33 years (18, 73)
Current smoker
18 (26 %)
Median BMI (range)
24.5 (17.2, 43.6)
History of IBD-related operation Ileocecal resection
12 (17 %)
Partial colectomy
3 (4 %)
Ileal pouch anal anastomosis Other concominant baseline medications
2 (3 %)
5-ASA (oral)
23 (33 %)
Prednisone
21 (30 %)
Budesonide
13 (18 %)
Immunomodulator
13 (19 %)
Table 2 New immunosuppressive medication initiation in patients with inflammatory bowel disease and active symptoms Ulcerative colitis (n = 16) Immunomodulator
Crohn’s disease (n = 53) 8 (50 %)
Immunomodulator
Azathioprine
7
Azathioprine
Methotrexate
1
Methotrexate
Anti-TNF therapy
Fig. 1 Significant improvement in depressive symptoms after therapy with anti-TNF and/or immunomodulator therapy in patients with Crohn’s disease (n = 53) and ulcerative colitis (n = 16)
8 (50 %)
Anti-TNF therapy
14 (26 %) 10 4 39 (74 %)
Infliximab
7
Infliximab
8
Adalimumab
1
Adalimumab
18
Certolizumab
0
Certolizumab
13
Statistical Analysis Continuous variables were compared using Wilcoxon matched paired signed-rank test, and categorical variables compared using chi-squared analysis. Changes in C-reactive protein (CRP) and depressive symptoms were compared using Spearman correlation coefficient.
Results Of the 357 charts evaluated, 69 patients met criteria for evaluation during the study period. Sixteen patients were diagnosed with UC, and 53 patients were diagnosed with Crohn’s disease. Baseline characteristics are summarized in Table 1. Twenty-two patients were started only on IMM
(8 with ulcerative colitis, 14 patients with Crohn’s disease), and 47 patients were started on anti-TNF therapy (8 patients with ulcerative colitis and 39 patients with Crohn’s disease). Details of medication initiation are summarized in Table 2. Of patients starting on anti-TNF therapy, 13 were already on IMM and 11 patients also had IMM added when anti-TNF therapy was started. Median follow-up after starting anti-TNF therapy was 50 days (30, 140 days), and median follow-up after starting immunomodulator therapy was 80 days (53, 120 days). Seven patients had a history of psychiatric disease, three with a history of major depressive disorder, two with a history of bipolar disorder, and two with a history of anxiety disorder. Six patients with Crohn’s disease were on antidepressant therapy consisting of selective serotonin reuptake inhibitors (SSRIs), and one patient was on an atypical anti-psychotic. None of the patients with UC were on antidepressants at medication initiation. During the treatment time period, two patients with Crohn’s disease were started on an SSRI and one patient with UC was started on an SSRI. In Crohn’s disease patients, 51 % (n = 28) were at risk for moderate to severe depression (PHQ-9 C10) prior to the therapy, and 18 % (n = 10) met criteria for moderate to severe depression after therapy, (p \ 0.05) (Fig. 1). In a subset of patients with biomarker measurements (n = 50), CRP improved in patients with Crohn’s disease (19.0 ± 37.9–9.4 ± 20.4, p = 0.05). Crohn’s disease patients initiated on therapy had significantly decreased PHQ-9 scores at follow-up and significantly decreased HBI scores and increased SIBDQ scores (Table 3). In a subset analysis, only subjects with Crohn’s disease initiated on an anti-TNF medication had this significant decrease in PHQ9 scores [10 (2, 17) to 4 (1, 9), p \ 0.05]. The patients with Crohn’s disease initiated on immunomodulator therapy only (n = 14) had no statistically significant decrease in PHQ-9 scores [5 (2, 12) to 5 (0, 8), p = 0.9). PHQ-9 scores decreased significantly whether subjects with Crohn’s
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Table 3 PHQ-9, HBI or SSCAI, and SIBDQ scores before and after initiation of biologic (±IMM) or IMM only in CD (A) and UC (B) Before therapy median (25 %, 75 % IQR)
After therapy median (25 %, 75 % IQR)
p value
Table 4 Patients with Crohn’s disease had improvement in depressive symptoms after therapy regardless of disease activity improvement Disease activity response or remissiona
(A) Crohn’s disease (n = 53) PHQ-9 HBI SIBDQ
4 (1, 8)
\0.01
4.5 (2, 8)
2 (0, 6)
\0.01
44.5 (35, 60)
54.5 (41, 63)
\0.01
9 (3, 14)
PHQ-9
5 (3, 9)
SCCAI
8.5 (5, 11)
SIBDQ
43 (41, 53)
2 (0, 5)
\0.01
4 (3, 6)
\0.01
57.5 (51, 60)
\0.01
Wilcoxon matched pairs signed-rank test used for statistical comparison and significant decreases were noted in all scores PHQ-9 Personal Health Questionnaire-9, HBI Harvey Bradshaw Index, SSCAI Simple Clinical Colitis Activity Index, SIBDQ Short Inflammatory Bowel Disease Questionnaire
disease achieved remission or response based on HBI (Table 4). Changes in PHQ-9 were correlated with changes in CRP (q = 0.38, p \ 0.05). In UC patients, 18 % (n = 3) were at risk for moderate to severe depression (PHQ-9 C10) prior to the therapy, and no subjects met criteria after treatment (Fig. 1). In patients with UC, PHQ-9, and SCCAI scores at follow-up were significantly decreased and SIBDQ scores were significantly increased (Table 3). CRP improved but not statistically significantly in a subset of patients with UC (n = 14) with biomarker measurements (21.9 ± 55.2–6.8 ± 10.0, p = 0.2).
Discussion We found that treatment with medications for inflammatory bowel disease including anti-TNF therapy and immunomodulator therapy significantly improved depressive symptoms and significantly decreased the number of patients who met criteria for moderate to severe depression after treatment for 1–6 months [for Crohn’s disease 51–18 % (p \ 0.05)], for ulcerative colitis 18–0 %). Only a small number of patients (10 %) had reported a formal diagnosis of a psychiatric disorder, and only 10 % were on antidepressant medications before or during the follow-up period. However, in our patients with inflammatory bowel disease and active symptoms, a significant number met criteria for moderate to severe depression prior to a change in medical therapy. Recent research has highlighted increased rates of depression and anxiety in patients with IBD [2–4, 6, 29]. Crucially, depressive symptoms may affect disease activity
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PHQ-9 after therapy Median (25 %, 75 % IQR)
p value
Yes
6 (3, 14)
3 (0, 8)
\0.05
No
12 (5, 14)
7 (3, 9)
\0.05
a
(B) Ulcerative colitis (n = 16)
PHQ-9 before therapy Median (25 %, 75 % IQR)
Based on Harvey Bradshaw Index
over time. Recently a large multi-institution cohort study of patients with IBD found an increased risk of surgery in patients with Crohn’s disease with a diagnosis of major depressive disorder or generalized anxiety based on ICD-9 codes compared to those without these diagnoses [12]. Similarly, a prospective study reported that individuals with IBD with higher levels of depressive symptoms at baseline are more likely to relapse, relapse more quickly, and have a greater number of relapses than individuals without depression [13]. Other studies suggest that therapy for IBD may actually influence depressive symptoms. Minderhoud et al. [18] found significantly improved depressive symptoms after one to two infusions of infliximab in 14 patients with CD. Persoons et al. [16] found that following a single infusion of infliximab, a significantly lower proportion of patients with CD (n = 100) met criteria for major depressive disorder (24–16 %, p \ 0.05). However, patients meeting criteria for major depressive disorder were less likely to exhibit clinical improvement in IBD symptoms with infliximab treatment. A similar result of improvement in depressive symptoms, possibly independent of disease activity, was found in a small study of 15 patients given one infusion of infliximab and followed for 8 weeks [19]. In our study, the decrease in PHQ-9 scores in patients with Crohn’s disease correlated with decrease in C-reactive protein (CRP). However, depressive symptoms improved significantly in Crohn’s disease patients regardless of whether the patients achieved remission or response based on the HBI when a new therapy was started (Table 4). Several other small studies mentioned above also found that depressive symptom improvement did not correlate with disease activity improvement after anti-TNF therapy in inflammatory conditions including Crohn’s disease and ankylosing spondylitis [19, 30]. Measuring disease activity using the Harvey Bradshaw Index (HBI) has limitations including capturing functional gastrointestinal symptoms that can be associated with depression, and there is literature regarding lack of precision of this tool as a measure for active inflammatory bowel disease [31]. Also, depressive symptoms in Crohn’s disease could be mediated along a
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pathway of cytokine dysregulation that may improve with alterations in these pathways (including decrease in CRP) even before mucosal healing and hence disease activity improvement. Indeed, there is the substantial literature linking depression with proinflammatory processes. A recent review found that, regardless of chronic disease state, depression was associated with elevated levels of CRP, IL-1, and IL-6 [32]. Supporting this relationship, a recent placebo-controlled randomized trial evaluated the role of infliximab in the treatment of patients without inflammatory disease but with treatment-resistant depression. The authors did not find a significant overall improvement in depressive symptoms with infliximab treatment; however, they did find an improvement in depressive symptoms in patients with increased baseline CRP levels (high sensitivity CRP C5 mg/L) [33]. Our study is limited in the retrospective study design with its inherent weaknesses such as interpretation bias and inability to control for confounders such as length on medication before a follow-up PHQ-9 score was obtained as we were limited to when the patient had a follow-up clinic visit. Also, the PHQ-9 is a well-validated questionnaire for evaluation of depressive symptoms, but it is not a formal evaluation for depressive disorders. Depressive symptom improvement may not have been due to medication initiation, but secondary to improvement in disease activity itself, simply due to time, or other factors such as specific antidepressant medications. However, less than 10 % of the patients were on antidepressant therapy, and it was only added in the follow-up period in three patients. We have no data regarding other possible treatment for depression such as psychotherapy. Also, given the small number of patients, it was difficult to control for confounders such as corticosteroid use, smoking status, and the presence of psychiatric disorder at baseline. In our study, improvement in depressive symptoms seems most pronounced with anti-TNF therapy, at least in patients with Crohn’s disease. However, it is possible that our small sample size of those patients with Crohn’s disease or ulcerative colitis started only on immunomodulator therapy limited adequate evaluation. Small number of patients with ulcerative colitis included in the study precluded subgroup evaluation of PHQ-9 improvement by medication. Immunomodulator therapy could have same effect on depressive symptoms, but this medication has a longer time to therapeutic response (up to 3 months) so a longer time to evaluate for effects may have been necessary. Also, some of our patients who started anti-TNF therapy were also started on IMM therapy, and therefore, the contribution of immunomodulator therapy is unclear. However, our work highlights a growing area of interest in patients with inflammatory bowel disease as we learn the
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importance of treating all aspects of a patient’s life, including psychologic comorbidities such as depression. It is possible that comorbid depressive symptoms may be a marker or even contribute to disease outcomes. This study demonstrates that medications aimed at treating disease activity may also improve psychologic parameters in inflammatory bowel disease. Further research into this area is needed as it is important both in furthering the understanding the pathophysiology of inflammatory bowel disease and the psychologic comorbidities so often associated with the disease. Conflict of interest
None.
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