Rate of Corticosteroid-Induced Mood Changes in Patients with Inflammatory Bowel Disease: A Prospective Study

Rate of Corticosteroid-Induced Mood Changes in Patients with Inflammatory Bowel Disease: A... Journal of the Canadian Association of Gastroenterology, 2018, XX(X), 1–8 doi: 10.1093/jcag/gwy023 Original Article Original Article Rate of Corticosteroid-Induced Mood Changes in Patients with Inflammatory Bowel Disease: A Prospective Study George Ou, MD, Brian Bressler, MD, Cherry Galorport, MD, Eric Lam, MD, Hin Hin Ko, MD, Robert Enns, MD, Jennifer Telford, MD, Nathan Schaffer , MD, Terry Lee, PhD, Greg Rosenfeld MD University of British Columbia, Faculty of Medicine, Department of Medicine. St. Paul’s Hospital, Vancouver, B.C. Canada Correspondence: Greg Rosenfeld, 770-1190 Hornby Street, Vancouver, British Columbia, Canada V6Z 2K5. Telephone 604-688- 6332, fax 604-689-2004, e-mail: greg.rosenfeld@me.com. ABSTRACT Background: Corticosteroid is an effective therapeutic option for inflammatory bowel disease flares, but its adverse effects may compromise treatment adherence and reduce patients’ quality of life. There is lack of data on the incidence of corticosteroid-induced mood changes in this patient population, which may be underappreciated by healthcare providers in clinical practice and interfere with optimal care. This study aimed to determine the rate of mood changes in this patient population. Methods: In this prospective observational study, adult outpatients treated with prednisone for inflammatory bowel disease flares were considered for inclusion. Participants completed validated questionnaires (Beck Depression Inventory-II and Activation Subscale of Internal State Scale version two) before starting prednisone, ae ft r two weeks of prednisone, and at the end of prednisone taper to assess for mood changes. Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index were used to monitor clinical disease activity. Results: Fifty-three subjects were included in the analyses. The rate of mood change ae ft r two weeks of prednisone was 49.1%, primarily driven by increase in mood towards (hypo)mania. Younger age was an independent risk factor. Mood state returned to pretreatment level at the end of treatment. There was no correlation between clinical disease activity change and mood change. Conclusions: Oral prednisone for inflammatory bowel disease a fl re is associated with high rate of mood change. As prednisone is a critical part of induction therapy, ways to minimize this adverse event must be studied. For now, healthcare providers should inform patients and monitor closely for this adverse event. Keywords: Corticosteroid, Crohn’s disease, Inflammatory bowel disease, Mood, Prednisone, Ulcerative colitis. Since its introduction in 1948, corticosteroids (CS) have While much ae tt ntion has been paid to the systemic effects, played a significant role in the treatment of allergic and relatively little is known about the neuropsychiatric effects immunological disorders such as asthma, giant cell arteri- that encompass a wide range of manifestations, most com- tis, systemic lupus erythematosus, rheumatoid arthritis and mon of which include hypomania, depression and psychosis inflammatory bowel disease (IBD). However, its use is pri- (8). Although previous studies have ae tt mpted to define the marily limited by the potential serious adverse effects, which incidence of CS-induced mood changes (CIMC), most of the can be systemic or neuropsychiatric (1–5). Current guide- studies assessed either non-IBD conditions, which may have lines, therefore, recommend only short courses of CS in the different baseline susceptibilities (9–18), or pediatric IBD treatment of acute IBD flares, with emphasis on CS-sparing patients (19, 20). Having a clear understanding of the neuro- maintenance therapy (6, 7). psychiatric adverse events will facilitate communication with © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com by Ed 'DeepDyve' Gillespie user on 07 June 2018 2 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX patients and identification of such events more promptly, fatigue within the past two weeks (25). The total BDI-II possible which is particularly important given that up to one-third of score was 63. Hypomanic and manic symptoms were assessed IBD patients may be nonadherent because of adverse medica- using the Activation subscale of the Internal State Scale version tion effects (21). Education and early recognition may encour - 2 (AS-ISSv2), which consists of five questions that ask partici - age dialogue between care providers and patients and prevent pants to rate the degree of manic symptoms such as impulsivity, patients from simply discontinuing therapy. In the current rapid thought process, over-activity and restlessness over the study, we aimed to determine the rate of CIMC in patients with past 24 hours (26). The total AS-ISSv2 score was 500, and a IBD undergoing outpatient oral CS therapy. score of ≥155 was suggestive of mood elevation in the range of hypomania or mania and mixed state as seen in bipolar disorder. Of note is that hypomania and mania cannot be distinguished by this scoring system. METHODS Mood changes were defined, a priori, as BDI-II increase by Study Design and Patient Population ≥10 and/or AS-ISSv2 increase by ≥50 between the first and This is a prospective observational study at an outpatient second visit (i.e., ae ft r two weeks of prednisone). A  change in clinic affiliated with an academic tertiary care centre (St. Paul’s BDI-II of 10 was chosen, as this increment also defines the vari - Hospital, University of British Columbia, Vancouver, Canada). ous levels of depression severity. An AS-ISSv2 change of 50 was Adult patients (age ≥19 as per provincial definition) with chosen because this is the minimum change required to appre- inflammatory bowel disease, diagnosed on endoscopy and/ ciate symptom escalation in all five questions of this subscale or imaging, who were undergoing outpatient oral prednisone and is also the amount previously observed in other studies therapy for acute flares of IBD between October 2013 and April with non-IBD conditions (13, 27). 2016 were considered for inclusion. Exclusion criteria included hospitalization for management of IBD within 2 weeks prior to Statistical Analysis study entry (due to possible use of intravenous CS), liver cir- rhosis (due to potential effect on CS metabolism), use of medi - Our primary objective was to determine the rate of CIMC. cations that interfere with CS metabolism (e.g., clarithromycin, A sample size calculation was performed based on an antici- cyclosporine, ritonavir and ketoconazole), change in psychiat- pated 40% rate of CS -induced mood change in IBD patients, ric medication within one month of study entry, and active rec- based on previously published studies primarily focused on reational drug use or alcohol abuse. other immunological conditions (13, 28, 29) using a 95% Proposed CS course consisted of prednisone 40 mg daily for confidence interval with precision of 0.15 and an antici- two weeks (6, 22–24), followed by a tapering course of 5 mg/ pated drop out rate of 20%. The original target sample size day reduction every week. The treatment course could be was 50. However, given that a higher than expected drop adjusted at the physician’s discretion based on the subject’s clin- out rate of ~33% after the initial 15 subjects, an updated ical condition. sample size of 66 was calculated based on an estimated 40% Participants completed two validated questionnaires for drop out rate. mood assessment at the time of CS initiation (first visit), at two- Baseline characteristics that are continuous variables were week follow-up ae ft r initiation of CS therapy (second visit), and summarized as mean and standard deviation or median at the end of the CS taper (third visit). Disease activity was also and quartiles, while categorical variables were reported as monitored at each visit using Harvey-Bradshaw Index (HBI) frequency and percentage. Comparisons between subjects and Simple Clinical Colitis Activity Index (SCCAI) for Crohn’s were conducted using Chi-square test, Fisher exact test, disease and ulcerative colitis, respectively, by a physician, nurse t-test and Wilcoxon rank sum test, as appropriate, to identif y or trained research assistant. potential risk factors. Univariate analysis was performed for This study was approved by the institutional research ethics participants who developed mood changes by the second board and registered on clinicaltrials.gov (NCT01981889). visit. Multivariate logistic regression was performed for vari- ables with P<0.20 in the univariate analysis. Correlations Questionnaire between mood score changes and IBD activity score changes Participants’ mood states were assessed at each visit using were assessed using Spearman rank correlation coefficient. self-administered questionnaires that were validated in patients Pretreatment mood scores (baseline) and IBD activities with various psychiatric disorders in the outpatient setting. were compared to those at follow-up visits using Wilcoxon Depressive symptoms were assessed using the Beck Depression signed-rank test. Inventory II (BDI-II), a 21-item multiple choice questionnaire Statistical analyses were performed using SAS 9.3 (SAS that asks participants to rate their symptoms such as sadness, Institute Inc., Cary, NC, USA). Statistical significance was loss of interest, guilt, agitation, suicidality, concentration and defined as P value less than 0.05. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 3 level following the completion of tapering course at the third RESULTS visit (mean 79.6 ± 86.4 versus 60.4 ± 72.5, P=0.250). However, During the study period, 66 patients were considered for inclu- no significant change in the BDI-II was seen between initial and sion. Thirteen subjects were excluded ( Figure  1). There was subsequent visits. (Figure 2) no significant difference in baseline characteristics ( Table  1) between IBD patients who were excluded (n=13) compared Clinical Disease Activities with those who were included (n=53). Participants’ IBD symptoms improved with CS therapy both Of the 53 subjects included in analyses, two subjects required during and aeft r completion of prednisone therapy. SCCAI hospitalization during the study period for escalation of ther- improved from mean of 9.2  ±  2.7 to 2.7  ±  2.0 (P<0.001), and apy, including intravenous CS and surgery. Five subjects did not HBI improved from mean of 9.9 ± 6.2 to 6.4 ± 4.5 (P=0.024) at complete the third-visit questionnaire. Median follow-up time third visit ae ft r completion of CS treatment. of those included in analyses was 64 (range 7–125, interquartile range [IQR] 57–72) days since start of prednisone therapy. Risk Factors and Disease Activity Association Thirty-three (62%) subjects completed the prednisone In the univariate analysis, younger age (32.8 versus 46.9 years) course per protocol. Seven subjects had prolonged taper due and female gender (65.4% versus 33.3%) were found to be to persistent clinical symptoms, while 15 had rapid taper (one associated with significant AS-ISSv2 or BDI-II changes, while by physician during therapy due to insomnia; one by physician IBD diagnosis, presence of psychiatric condition, type of during therapy due to hypomania, which was also captured by maintenance therapy, initial disease activity score, duration of AS-ISSv2; one by physician during therapy due to surgical cure prednisone before mood reassessment, and positive response obviating need for CS; one by physician during therapy due to treatment (defined as HBI/SCCAI reduction from ≥5 in to poor response prompting therapy switch; four by physician first visit to <5 in second visit) were not. ( Table 2) In the mul- during therapy due to exceptional response making longer ther- tivariate analysis, only younger age remained an independent apy unnecessary; one by physician at initiation of therapy due risk factor (every five-year decrease, odds ration [OR] 1.41) to history of mood change; four by physician at initiation of (Table 3). therapy; two without specified reason). Both initial assessment of SCCAI and HBI were found to have weak to moderate correlation with BDI-II (Spearman cor- Rate of Corticosteroid-Induced Mood Changes relation of 0.37 [P=0.022] and 0.59 [P=0.020], respectively) Overall, the rate of mood changes with oral prednisone therapy but not with AS-ISSv2 at the initial visit prior to prednisone was 49.1% (26 of 53) ae ft r a median of 15 (range 7–32, IQR 7–32) therapy. However, the correlation between IBD disease activ- days on prednisone; the majority of the cases (25 of 26) were sec- ity and BDI-II disappears during and ae ft r prednisone therapy ondary to increases in manic symptoms as measured by AS-ISSv2, (i.e., at second and third visits). There was also no significant of which four also had concomitant depressive symptoms. correlation between the changes in the IBD disease activities There was a significant increase in the AS-ISSv2 score with and the changes in the mood symptoms between first and sec - prednisone therapy at the second visit (mean 79.6 ± 86.4 versus ond visits. 135.5 ± 120.2, P=0.004), which later returned to pretreatment Figure 1. Enrollment flow chart. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Table 1. Baseline characteristics Variable Included (n=53) Excluded (n=13) P Age 0.285 Mean (SD) 40.0 (15.0) 45.1 (16.7) Median (IQR) 36.0 (26.0, 56.0) 48.0 (29.0, 57.0) Range (21.0, 68.0) (22.0, 70.0) Gender, n (%) 0.420 Female 26 (49.1) 8 (61.5) Male 27 (50.9) 5 (38.5) Diagnosis, n (%)* 0.729 Ulcerative colitis 38 (71.7) 8 (66.7) Crohn’s disease 15 (28.3) 4 (33.3) Presence of psychiatric condition, n (%)† 1.000 None 48 (90.6) 9 (90.0) Depression 4 (7.5) 1 (10.0) Anxiety 1 (1.9) 0 (0.0) Prior steroid exposure, n (%)† 0.393 No 24 (45.3) 6 (60.0) Yes 29 (54.7) 4 (40.0) IBD maintenance therapy, n (%)† None 7 (13.2) 2 (10.0) 0.573 5ASA 33 (62.3) 5 (50.0) 0.467 Immunomodulator 7 (13.2) 0 (0.0) 0.223 Biologic 12 (22.6) 2 (20.0) 0.854 Topical steroid 4 (7.5) 1 (10.0) 1.000 First visit SCCAI 0.321 Median (IQR) 9.0 (8.0, 11.8) 9.0 (6.3, 10.0) Mean (SD) 9.2 (2.7) 7.6 (3.1) Range (3.0, 14.0) (2.0, 10.0) First visit HBI‡ 0.203 Median (IQR) 8.0 (5.5, 14.0) 5.0 (4.5, 5.5) Mean (SD) 9.9 (6.2) 5.0 (1.4) Range (2.0, 22.0) (4.0, 6.0) First visit BDI-II§ 0.881 Median (IQR) 9.0 (5.0, 13.0) 11.0 (7.0, 12.0) Mean (SD) 10.2 (7.3) 12.1 (11.5) Range (0.0, 25.0) (2.0, 41.0) First visit AS-ISSv2¶ 0.541 Median (IQR) 50.0 (0.0, 140.0) 40.0 (0.0, 102.5) Mean (SD) 79.6 (86.4) 64.0 (78.3) Range (0.0, 300.0) (0.0, 200.0) 5ASA, 5-aminosalicylic acid *1 excluded patient with non-IBD diagnosis †Data not available for three excluded patients ‡Data not available for two excluded patients §Data not available for four excluded patients ¶Data not available for three excluded patients self-administered scoring systems that have been validated in DISCUSSION general population with various psychiatric condition (25, This is the first prospective study to formally assess 30). To the best of our knowledge, there is no evidence directly CS-induced mood changes in adult patients with IBD using Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 5 st Figure 2. Mood scores and disease activities before, during, and ae ft r steroid therapy. * P < 0.05 compared to 1 visit X mean linking CIMC to treatment nonadherence or poor outcomes in and mixed state of bipolar disorder (i.e., AS-ISSv2 ≥155) at the IBD patients, but medication adverse events and psychological second visit (26), of whom eight had complete resolution at distress are associated with compromised adherence to therapy the third visit. It was not possible to pinpoint the onset of the in IBD patients (21, 30). In addition, mood disturbances (e.g., changes given the study design, but previous studies demon- depression, mania and hypomania) are associated with reduced strated CIMC in as early as three days of therapy when at least quality of life in patients with bipolar disorder (31) and so is a 40 mg equivalent of prednisone was used (13, 14). The clini - CIMC in pediatric oncology patients and their families (32). cal implication is less clear for the 13 patients who experienced A  bee tt r understanding of CIMC is therefore needed to allow increases in AS-ISSv2 by at least 50 points but did not meet healthcare providers and patients to bee tt r prepare for such an cutoff for hypomania, mania or mixed state. Nonetheless, this adverse event and minimize its impact. detectable change likely remains clinically relevant and is an The rate of 49.1% is consistent with the results from previ - outcome of interest in this observational study. ous studies. For example, psychological and behavioural distur- It is worth noting in this study that mood changes simply bances among IBD patients were observed at a rate of 65 events reversed with tapering course of CS and did not require addi- per 100 patient-years in a meta-analysis by Hoes et  al., which tional intervention such as psychotropic medications, which included studies employing various types of CS and dichoto- have been reported in the past (35). None of the subjects mous adverse event outcomes (9). In a randomized controlled required hospitalization for the management of psychological trial comparing different prednisolone formulations, Rhodes symptoms. et al. reported 42% incidence of mood changes ae ft r two weeks Over one-third of the participants’ CS course deviated from of prednisolone (33). However, the incidence was defined the protocol, but the majority was guided by clinical response based on patients’ perception of presence or absence of mood to therapy. Three subjects’ courses were shortened due to intol - change instead of more formal assessment tools. erance (hypomania, insomnia and history of mood change), Previous reports demonstrated that hypomania and frank while no clinical rationale was provided in six (including four mania tend to occur more frequently than depressive symp- whose shorter courses were determined at initiation). The per - toms in acute CS therapy for non-IBD conditions (12–14, 34). son with a history of CIMC did develop symptoms consistent Similarly, symptoms of (hypo)mania (i.e., impulsivity, rapid with hypomania or mania (i.e., AS-ISSv2  ≥155) during treat- thought process, overactivity, feeling “sped up” inside or restless- ment but returned to pretreatment state at the end of the study. ness) were the primary psychological or behavioural changes in Given that the protocol deviations were primarily guided by this study population. Twelve participants (22.6%) developed clinical symptoms, they were understandably not associated new onset mood features in the range of hypomania or mania with detectable psychological changes on the questionnaires. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 6 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Table 2. Univariate analysis of factors associated with mood score changes Variable BDI-II increase by ≥10 and/or AS-ISSv2 increase by ≥50 No (n=27) Yes (n=26) P Age <0.001 Mean (SD) 46.9 (15.2) 32.8 (11.1) Median (IQR) 52.0 (33.0, 61.0) 30.5 (24.0, 38.0) Range (21.0, 68.0) (21.0, 65.0) Female, n (%) 9 (33.3) 17 (65.4) 0.020 Diagnosis, n (%) 0.317 Ulcerative colitis 21 (77.8) 17 (65.4) Crohn’s 6 (22.2) 9 (34.6) Presence of psychiatric condition, n (%) 0.610 None 24 (88.9) 24 (92.3) Depression 3 (11.1) 1 (3.8) Anxiety 0 (0.0) 1 (3.8) Prior Steroid exposure, n (%) 13 (48.1) 16 (61.5) 0.328 IBD maintenance therapy, n (%) None 2 (7.4) 5 (19.2) 0.250 5ASA 20 (74.1) 13 (50.0) 0.071 Immunomodulator 3 (11.1) 4 (15.4) 0.704 Biologic 6 (22.2) 6 (23.1) 0.941 Topical steroid 2 (7.4) 2 (7.7) 1.000 First visit SCCAI 0.280 Median (IQR) 9.0 (7.0, 11.0) 9.0 (8.0, 12.0) Mean (SD) 8.7 (3.0) 9.8 (2.3) Range (3.0, 14.0) (6.0, 13.0) First visit HBI 0.636 Median (IQR) 10.5 (5.0, 15.0) 7.0 (6.0, 10.0) Mean (SD) 10.8 (6.2) 9.2 (6.4) Range (4.0, 20.0) (2.0, 22.0) Positive response to treatment, n (%) 0.771 No 13 (54.2) 14 (58.3) Yes 11 (45.8) 10 (41.7) No. of days between 1st and 2nd visit 0.551 Median (IQR) 14.0 (14.0, 17.0) 15.0 (14.0, 16.0) Mean (SD) 15.3 (4.4) 16.0 (3.5) Range (7.0, 32.0) (12.0, 27.0) Therapy protocol deviation, n (%) 0.306 Shorter 10 (37.0) 5 (19.2) Longer 13 (48.1) 18 (69.2) Per protocol 4 (14.8) 3 (11.5) 5ASA, 5-aminosalicylic acid The mood changes observed in this study appeared largely supports prednisone’s role in the mood score changes. It is also independent of the IBD activity, as was observed in obstructive worth noting that neither clinical disease activity indices incor- airway diseases (13, 18). This is demonstrated by the return of porated objective measures such as endoscopic assessment or the mood state to pretreatment level while clinical IBD activity biomarkers, but SCCAI was previously demonstrated to corre- remained stable or improved following completion of therapy. late well with endoscopic inflammation, as well as serum and In addition, there was no correlation between the changes in fecal inflammatory markers (36). The Harvey-Bradshaw Index clinical IBD activities and the changes in mood scores, which was chosen for its straightforward administration and good Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 7 Table  3. Multivariate analysis of factors associated with mood lymphoblastic leukemia compared with school-aged children score changes. (41). It was postulated that the developing brain may be more susceptible to CS adverse effect (20), but this hypothesis is not BDI-II increase by ≥10 and/or applicable to adult patients. It is possible that the observed asso- AS-ISSv2 increase by ≥50 ciation was related to the greater proportion of younger patients Variable Odds ratio (95% CI) P with IBD in this study, compared with other autoimmune conditions included in previous reports. Alternatively, it may Age (per 5-year decrease) 1.41 (1.09, 1.82) 0.010 be related to a different phenotype of the disease in younger Male 0.44 (0.12, 1.69) 0.233 patients. Larger prospective data is required to draw more defin- Use of 5ASA 0.32 (0.08, 1.21) 0.093 itive conclusions regarding female gender and younger age as 5ASA, 5-aminosalicylic acid risk factors for CIMC among IBD patients. This study has several limitations, including the single-centre design and the lack of a control group. However, as CS use is correlation with Crohn’s Disease Activity index, which has the standard of care in patients with IBD flares, ethical consid - been utilized extensively in previous Crohn’s disease trials (37). erations preclude the institution of a placebo-controlled group. Although HBI does not correlate well with endoscopic inflam- Comparison with an alternate induction agent such as anti-tu- mation or fecal inflammatory marker (36, 38), use of such clini- mor necrosis factor alpha was also not feasible, as many patients cal disease activity index is warranted in absence of an objective were on concomitant CS or immunomodulator at the time modality that can accurately assess all phenotypes of Crohn’s of anti-tumor necrosis factor alpha initiation. To address this disease. deficit, we incorporated a follow-up visit at the end of the CS Patients with psychiatric comorbidities only accounted for treatment as internal control and demonstrated that the mood 9% (five of 53)  of the study population, and all were taking state returned to pretreatment level ae ft r completion of therapy. stable doses of psychiatric medications. Only two of five devel - A potential confounder is patient adherence to prednisone ther- oped detectable mood changes, which is comparable to the rest apy. As the first step to demonstrate the rate of CIMC in a real- of the study population, but the numbers are too small to draw life experience, patient adherence was not monitored; however, any meaningful conclusion. We did not include patients who this information could be vital in future studies as an endpoint had recent change in psychiatric medications to minimize the since nonadherence may be a result of CIMC. impact of their underlying mental illness. The relatively small sample size limited the precision in assess - Female gender and younger age were associated with mood ing the rate of CIMC but did so without sacrificing accuracy. changes in the univariate analysis, but only age remained sta- A larger sample size would have required a substantial, prohibitive tistically significant in the multivariate analysis. Naber et  al. amount of resources for recruitment. Therefore, we calculated the reported that gender is not a risk factor for “neuropsychological sample size based on a precision of 0.15. This study’s results are and psychopathological changes” in patients receiving high- not generalizable to inpatients with IBD flares, which represent dose CS for ocular conditions (14). In contrast, higher inci- a significant portion of patients requiring systemic CS therapy dence of CIMC in females was observed in earlier studies, but at our centre. Inpatients were excluded to avoid potentially con- the interpretation was confounded by female predominance in founding effects of their severe disease activity and comorbidi - certain autoimmune conditions such as rheumatoid arthritis ties, such as malnutrition and infection, on psychological state and systemic lupus erythematosus (28, 39, 40). (42–44). Similarly, recent psychiatric medication changes and Similar finding of emotional function impairment was active alcohol or recreational drug use were excluded to minimize observed in pediatric IBD patients treated with CS, compared confounding. Further prospective study with larger sample size with controls (IBD in remission) not taking CS (20). However, is needed to clarify the effect of CS on mood in these subgroups. there is paucity of data on the relationship between age and In conclusion, CS treatment was associated with frequent risk of CIMC in the literature. Younger age has emerged as an mood changes, affecting nearly half of the subjects in this study. independent risk factor for CIMC in our study, contrary to a The most common manifestation was mood elevation during previous report by Lewis and Smith examining psychiatric dis- therapy, but subsequently the affective state returned to pre- turbances in a variety of conditions requiring CS for immuno- treatment level upon completion of therapy without relapse suppression (28) and contrary to a prospective study by Brown of clinical disease activity. Healthcare providers should inform et  al. assessing mood changes during prednisone treatment patients of such a risk and monitor for need of intervention. of asthma (13). To our knowledge, there is no data directly Future studies may help to clarify the role for concomitant comparing pediatric to adult population in terms of suscep- therapy to ameliorate the mood-related side effects for patients tibility to CIMC, but an earlier study found greater impact of requiring CS for management of their IBD. CS on behaviour and mood in preschool children with acute Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 8 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 18. Swinburn CR, Wakefield JM, Newman SP, et  al. Evidence of prednisolone induced Acknowledgements mood change (‘steroid euphoria’) in patients with chronic obstructive airways disease. Br J Clin Pharmacol. 1988;26:709–13. The authors would like to thank Amy Wong and Oliver Takach for 19. Castaneda AE, Tuulio-Henriksson A, Aronen ET, et  al. Cognitive functioning and their assistance in subject recruitment and data collection. This work depressive symptoms in adolescents with inflammatory bowel disease. World J was supported by the 2014 Procter & Gamble-Canadian Association Gastroenterol. 2013;19:1611–7. 20. Mrakotsky C, Forbes PW, Bernstein JH, et al. Acute cognitive and behavioral effects of Gastroenterology Resident Research Award. GO contributed to the of systemic corticosteroids in children treated for inflammatory bowel disease. J Int conception and design of study, the acquisition, analysis and interpre- Neuropsychol Soc. 2013;19:96–109. tation of data, and the drafting and final approval of the article. BB, NS, 21. Cerveny P, Bortlik M, Kubena A, et al. Nonadherence in inflammatory bowel disease: Results of factor analysis. Inflamm Bowel Dis. 2007;13:1244–9. contributed to conception and design of study and the critical revision 22. Bar-Meir S, Chowers Y, Lavy A, et al. 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Gen Hosp Psychiatry. the association between psychological distress and disease activity. Dig Dis Sci. 1988;10:56–60. 2004;49:492–7. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of the Canadian Association of Gastroenterology Oxford University Press

Rate of Corticosteroid-Induced Mood Changes in Patients with Inflammatory Bowel Disease: A Prospective Study

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Journal of the Canadian Association of Gastroenterology, 2018, XX(X), 1–8 doi: 10.1093/jcag/gwy023 Original Article Original Article Rate of Corticosteroid-Induced Mood Changes in Patients with Inflammatory Bowel Disease: A Prospective Study George Ou, MD, Brian Bressler, MD, Cherry Galorport, MD, Eric Lam, MD, Hin Hin Ko, MD, Robert Enns, MD, Jennifer Telford, MD, Nathan Schaffer , MD, Terry Lee, PhD, Greg Rosenfeld MD University of British Columbia, Faculty of Medicine, Department of Medicine. St. Paul’s Hospital, Vancouver, B.C. Canada Correspondence: Greg Rosenfeld, 770-1190 Hornby Street, Vancouver, British Columbia, Canada V6Z 2K5. Telephone 604-688- 6332, fax 604-689-2004, e-mail: greg.rosenfeld@me.com. ABSTRACT Background: Corticosteroid is an effective therapeutic option for inflammatory bowel disease flares, but its adverse effects may compromise treatment adherence and reduce patients’ quality of life. There is lack of data on the incidence of corticosteroid-induced mood changes in this patient population, which may be underappreciated by healthcare providers in clinical practice and interfere with optimal care. This study aimed to determine the rate of mood changes in this patient population. Methods: In this prospective observational study, adult outpatients treated with prednisone for inflammatory bowel disease flares were considered for inclusion. Participants completed validated questionnaires (Beck Depression Inventory-II and Activation Subscale of Internal State Scale version two) before starting prednisone, ae ft r two weeks of prednisone, and at the end of prednisone taper to assess for mood changes. Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index were used to monitor clinical disease activity. Results: Fifty-three subjects were included in the analyses. The rate of mood change ae ft r two weeks of prednisone was 49.1%, primarily driven by increase in mood towards (hypo)mania. Younger age was an independent risk factor. Mood state returned to pretreatment level at the end of treatment. There was no correlation between clinical disease activity change and mood change. Conclusions: Oral prednisone for inflammatory bowel disease a fl re is associated with high rate of mood change. As prednisone is a critical part of induction therapy, ways to minimize this adverse event must be studied. For now, healthcare providers should inform patients and monitor closely for this adverse event. Keywords: Corticosteroid, Crohn’s disease, Inflammatory bowel disease, Mood, Prednisone, Ulcerative colitis. Since its introduction in 1948, corticosteroids (CS) have While much ae tt ntion has been paid to the systemic effects, played a significant role in the treatment of allergic and relatively little is known about the neuropsychiatric effects immunological disorders such as asthma, giant cell arteri- that encompass a wide range of manifestations, most com- tis, systemic lupus erythematosus, rheumatoid arthritis and mon of which include hypomania, depression and psychosis inflammatory bowel disease (IBD). However, its use is pri- (8). Although previous studies have ae tt mpted to define the marily limited by the potential serious adverse effects, which incidence of CS-induced mood changes (CIMC), most of the can be systemic or neuropsychiatric (1–5). Current guide- studies assessed either non-IBD conditions, which may have lines, therefore, recommend only short courses of CS in the different baseline susceptibilities (9–18), or pediatric IBD treatment of acute IBD flares, with emphasis on CS-sparing patients (19, 20). Having a clear understanding of the neuro- maintenance therapy (6, 7). psychiatric adverse events will facilitate communication with © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com by Ed 'DeepDyve' Gillespie user on 07 June 2018 2 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX patients and identification of such events more promptly, fatigue within the past two weeks (25). The total BDI-II possible which is particularly important given that up to one-third of score was 63. Hypomanic and manic symptoms were assessed IBD patients may be nonadherent because of adverse medica- using the Activation subscale of the Internal State Scale version tion effects (21). Education and early recognition may encour - 2 (AS-ISSv2), which consists of five questions that ask partici - age dialogue between care providers and patients and prevent pants to rate the degree of manic symptoms such as impulsivity, patients from simply discontinuing therapy. In the current rapid thought process, over-activity and restlessness over the study, we aimed to determine the rate of CIMC in patients with past 24 hours (26). The total AS-ISSv2 score was 500, and a IBD undergoing outpatient oral CS therapy. score of ≥155 was suggestive of mood elevation in the range of hypomania or mania and mixed state as seen in bipolar disorder. Of note is that hypomania and mania cannot be distinguished by this scoring system. METHODS Mood changes were defined, a priori, as BDI-II increase by Study Design and Patient Population ≥10 and/or AS-ISSv2 increase by ≥50 between the first and This is a prospective observational study at an outpatient second visit (i.e., ae ft r two weeks of prednisone). A  change in clinic affiliated with an academic tertiary care centre (St. Paul’s BDI-II of 10 was chosen, as this increment also defines the vari - Hospital, University of British Columbia, Vancouver, Canada). ous levels of depression severity. An AS-ISSv2 change of 50 was Adult patients (age ≥19 as per provincial definition) with chosen because this is the minimum change required to appre- inflammatory bowel disease, diagnosed on endoscopy and/ ciate symptom escalation in all five questions of this subscale or imaging, who were undergoing outpatient oral prednisone and is also the amount previously observed in other studies therapy for acute flares of IBD between October 2013 and April with non-IBD conditions (13, 27). 2016 were considered for inclusion. Exclusion criteria included hospitalization for management of IBD within 2 weeks prior to Statistical Analysis study entry (due to possible use of intravenous CS), liver cir- rhosis (due to potential effect on CS metabolism), use of medi - Our primary objective was to determine the rate of CIMC. cations that interfere with CS metabolism (e.g., clarithromycin, A sample size calculation was performed based on an antici- cyclosporine, ritonavir and ketoconazole), change in psychiat- pated 40% rate of CS -induced mood change in IBD patients, ric medication within one month of study entry, and active rec- based on previously published studies primarily focused on reational drug use or alcohol abuse. other immunological conditions (13, 28, 29) using a 95% Proposed CS course consisted of prednisone 40 mg daily for confidence interval with precision of 0.15 and an antici- two weeks (6, 22–24), followed by a tapering course of 5 mg/ pated drop out rate of 20%. The original target sample size day reduction every week. The treatment course could be was 50. However, given that a higher than expected drop adjusted at the physician’s discretion based on the subject’s clin- out rate of ~33% after the initial 15 subjects, an updated ical condition. sample size of 66 was calculated based on an estimated 40% Participants completed two validated questionnaires for drop out rate. mood assessment at the time of CS initiation (first visit), at two- Baseline characteristics that are continuous variables were week follow-up ae ft r initiation of CS therapy (second visit), and summarized as mean and standard deviation or median at the end of the CS taper (third visit). Disease activity was also and quartiles, while categorical variables were reported as monitored at each visit using Harvey-Bradshaw Index (HBI) frequency and percentage. Comparisons between subjects and Simple Clinical Colitis Activity Index (SCCAI) for Crohn’s were conducted using Chi-square test, Fisher exact test, disease and ulcerative colitis, respectively, by a physician, nurse t-test and Wilcoxon rank sum test, as appropriate, to identif y or trained research assistant. potential risk factors. Univariate analysis was performed for This study was approved by the institutional research ethics participants who developed mood changes by the second board and registered on clinicaltrials.gov (NCT01981889). visit. Multivariate logistic regression was performed for vari- ables with P<0.20 in the univariate analysis. Correlations Questionnaire between mood score changes and IBD activity score changes Participants’ mood states were assessed at each visit using were assessed using Spearman rank correlation coefficient. self-administered questionnaires that were validated in patients Pretreatment mood scores (baseline) and IBD activities with various psychiatric disorders in the outpatient setting. were compared to those at follow-up visits using Wilcoxon Depressive symptoms were assessed using the Beck Depression signed-rank test. Inventory II (BDI-II), a 21-item multiple choice questionnaire Statistical analyses were performed using SAS 9.3 (SAS that asks participants to rate their symptoms such as sadness, Institute Inc., Cary, NC, USA). Statistical significance was loss of interest, guilt, agitation, suicidality, concentration and defined as P value less than 0.05. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 3 level following the completion of tapering course at the third RESULTS visit (mean 79.6 ± 86.4 versus 60.4 ± 72.5, P=0.250). However, During the study period, 66 patients were considered for inclu- no significant change in the BDI-II was seen between initial and sion. Thirteen subjects were excluded ( Figure  1). There was subsequent visits. (Figure 2) no significant difference in baseline characteristics ( Table  1) between IBD patients who were excluded (n=13) compared Clinical Disease Activities with those who were included (n=53). Participants’ IBD symptoms improved with CS therapy both Of the 53 subjects included in analyses, two subjects required during and aeft r completion of prednisone therapy. SCCAI hospitalization during the study period for escalation of ther- improved from mean of 9.2  ±  2.7 to 2.7  ±  2.0 (P<0.001), and apy, including intravenous CS and surgery. Five subjects did not HBI improved from mean of 9.9 ± 6.2 to 6.4 ± 4.5 (P=0.024) at complete the third-visit questionnaire. Median follow-up time third visit ae ft r completion of CS treatment. of those included in analyses was 64 (range 7–125, interquartile range [IQR] 57–72) days since start of prednisone therapy. Risk Factors and Disease Activity Association Thirty-three (62%) subjects completed the prednisone In the univariate analysis, younger age (32.8 versus 46.9 years) course per protocol. Seven subjects had prolonged taper due and female gender (65.4% versus 33.3%) were found to be to persistent clinical symptoms, while 15 had rapid taper (one associated with significant AS-ISSv2 or BDI-II changes, while by physician during therapy due to insomnia; one by physician IBD diagnosis, presence of psychiatric condition, type of during therapy due to hypomania, which was also captured by maintenance therapy, initial disease activity score, duration of AS-ISSv2; one by physician during therapy due to surgical cure prednisone before mood reassessment, and positive response obviating need for CS; one by physician during therapy due to treatment (defined as HBI/SCCAI reduction from ≥5 in to poor response prompting therapy switch; four by physician first visit to <5 in second visit) were not. ( Table 2) In the mul- during therapy due to exceptional response making longer ther- tivariate analysis, only younger age remained an independent apy unnecessary; one by physician at initiation of therapy due risk factor (every five-year decrease, odds ration [OR] 1.41) to history of mood change; four by physician at initiation of (Table 3). therapy; two without specified reason). Both initial assessment of SCCAI and HBI were found to have weak to moderate correlation with BDI-II (Spearman cor- Rate of Corticosteroid-Induced Mood Changes relation of 0.37 [P=0.022] and 0.59 [P=0.020], respectively) Overall, the rate of mood changes with oral prednisone therapy but not with AS-ISSv2 at the initial visit prior to prednisone was 49.1% (26 of 53) ae ft r a median of 15 (range 7–32, IQR 7–32) therapy. However, the correlation between IBD disease activ- days on prednisone; the majority of the cases (25 of 26) were sec- ity and BDI-II disappears during and ae ft r prednisone therapy ondary to increases in manic symptoms as measured by AS-ISSv2, (i.e., at second and third visits). There was also no significant of which four also had concomitant depressive symptoms. correlation between the changes in the IBD disease activities There was a significant increase in the AS-ISSv2 score with and the changes in the mood symptoms between first and sec - prednisone therapy at the second visit (mean 79.6 ± 86.4 versus ond visits. 135.5 ± 120.2, P=0.004), which later returned to pretreatment Figure 1. Enrollment flow chart. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Table 1. Baseline characteristics Variable Included (n=53) Excluded (n=13) P Age 0.285 Mean (SD) 40.0 (15.0) 45.1 (16.7) Median (IQR) 36.0 (26.0, 56.0) 48.0 (29.0, 57.0) Range (21.0, 68.0) (22.0, 70.0) Gender, n (%) 0.420 Female 26 (49.1) 8 (61.5) Male 27 (50.9) 5 (38.5) Diagnosis, n (%)* 0.729 Ulcerative colitis 38 (71.7) 8 (66.7) Crohn’s disease 15 (28.3) 4 (33.3) Presence of psychiatric condition, n (%)† 1.000 None 48 (90.6) 9 (90.0) Depression 4 (7.5) 1 (10.0) Anxiety 1 (1.9) 0 (0.0) Prior steroid exposure, n (%)† 0.393 No 24 (45.3) 6 (60.0) Yes 29 (54.7) 4 (40.0) IBD maintenance therapy, n (%)† None 7 (13.2) 2 (10.0) 0.573 5ASA 33 (62.3) 5 (50.0) 0.467 Immunomodulator 7 (13.2) 0 (0.0) 0.223 Biologic 12 (22.6) 2 (20.0) 0.854 Topical steroid 4 (7.5) 1 (10.0) 1.000 First visit SCCAI 0.321 Median (IQR) 9.0 (8.0, 11.8) 9.0 (6.3, 10.0) Mean (SD) 9.2 (2.7) 7.6 (3.1) Range (3.0, 14.0) (2.0, 10.0) First visit HBI‡ 0.203 Median (IQR) 8.0 (5.5, 14.0) 5.0 (4.5, 5.5) Mean (SD) 9.9 (6.2) 5.0 (1.4) Range (2.0, 22.0) (4.0, 6.0) First visit BDI-II§ 0.881 Median (IQR) 9.0 (5.0, 13.0) 11.0 (7.0, 12.0) Mean (SD) 10.2 (7.3) 12.1 (11.5) Range (0.0, 25.0) (2.0, 41.0) First visit AS-ISSv2¶ 0.541 Median (IQR) 50.0 (0.0, 140.0) 40.0 (0.0, 102.5) Mean (SD) 79.6 (86.4) 64.0 (78.3) Range (0.0, 300.0) (0.0, 200.0) 5ASA, 5-aminosalicylic acid *1 excluded patient with non-IBD diagnosis †Data not available for three excluded patients ‡Data not available for two excluded patients §Data not available for four excluded patients ¶Data not available for three excluded patients self-administered scoring systems that have been validated in DISCUSSION general population with various psychiatric condition (25, This is the first prospective study to formally assess 30). To the best of our knowledge, there is no evidence directly CS-induced mood changes in adult patients with IBD using Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 5 st Figure 2. Mood scores and disease activities before, during, and ae ft r steroid therapy. * P < 0.05 compared to 1 visit X mean linking CIMC to treatment nonadherence or poor outcomes in and mixed state of bipolar disorder (i.e., AS-ISSv2 ≥155) at the IBD patients, but medication adverse events and psychological second visit (26), of whom eight had complete resolution at distress are associated with compromised adherence to therapy the third visit. It was not possible to pinpoint the onset of the in IBD patients (21, 30). In addition, mood disturbances (e.g., changes given the study design, but previous studies demon- depression, mania and hypomania) are associated with reduced strated CIMC in as early as three days of therapy when at least quality of life in patients with bipolar disorder (31) and so is a 40 mg equivalent of prednisone was used (13, 14). The clini - CIMC in pediatric oncology patients and their families (32). cal implication is less clear for the 13 patients who experienced A  bee tt r understanding of CIMC is therefore needed to allow increases in AS-ISSv2 by at least 50 points but did not meet healthcare providers and patients to bee tt r prepare for such an cutoff for hypomania, mania or mixed state. Nonetheless, this adverse event and minimize its impact. detectable change likely remains clinically relevant and is an The rate of 49.1% is consistent with the results from previ - outcome of interest in this observational study. ous studies. For example, psychological and behavioural distur- It is worth noting in this study that mood changes simply bances among IBD patients were observed at a rate of 65 events reversed with tapering course of CS and did not require addi- per 100 patient-years in a meta-analysis by Hoes et  al., which tional intervention such as psychotropic medications, which included studies employing various types of CS and dichoto- have been reported in the past (35). None of the subjects mous adverse event outcomes (9). In a randomized controlled required hospitalization for the management of psychological trial comparing different prednisolone formulations, Rhodes symptoms. et al. reported 42% incidence of mood changes ae ft r two weeks Over one-third of the participants’ CS course deviated from of prednisolone (33). However, the incidence was defined the protocol, but the majority was guided by clinical response based on patients’ perception of presence or absence of mood to therapy. Three subjects’ courses were shortened due to intol - change instead of more formal assessment tools. erance (hypomania, insomnia and history of mood change), Previous reports demonstrated that hypomania and frank while no clinical rationale was provided in six (including four mania tend to occur more frequently than depressive symp- whose shorter courses were determined at initiation). The per - toms in acute CS therapy for non-IBD conditions (12–14, 34). son with a history of CIMC did develop symptoms consistent Similarly, symptoms of (hypo)mania (i.e., impulsivity, rapid with hypomania or mania (i.e., AS-ISSv2  ≥155) during treat- thought process, overactivity, feeling “sped up” inside or restless- ment but returned to pretreatment state at the end of the study. ness) were the primary psychological or behavioural changes in Given that the protocol deviations were primarily guided by this study population. Twelve participants (22.6%) developed clinical symptoms, they were understandably not associated new onset mood features in the range of hypomania or mania with detectable psychological changes on the questionnaires. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 6 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Table 2. Univariate analysis of factors associated with mood score changes Variable BDI-II increase by ≥10 and/or AS-ISSv2 increase by ≥50 No (n=27) Yes (n=26) P Age <0.001 Mean (SD) 46.9 (15.2) 32.8 (11.1) Median (IQR) 52.0 (33.0, 61.0) 30.5 (24.0, 38.0) Range (21.0, 68.0) (21.0, 65.0) Female, n (%) 9 (33.3) 17 (65.4) 0.020 Diagnosis, n (%) 0.317 Ulcerative colitis 21 (77.8) 17 (65.4) Crohn’s 6 (22.2) 9 (34.6) Presence of psychiatric condition, n (%) 0.610 None 24 (88.9) 24 (92.3) Depression 3 (11.1) 1 (3.8) Anxiety 0 (0.0) 1 (3.8) Prior Steroid exposure, n (%) 13 (48.1) 16 (61.5) 0.328 IBD maintenance therapy, n (%) None 2 (7.4) 5 (19.2) 0.250 5ASA 20 (74.1) 13 (50.0) 0.071 Immunomodulator 3 (11.1) 4 (15.4) 0.704 Biologic 6 (22.2) 6 (23.1) 0.941 Topical steroid 2 (7.4) 2 (7.7) 1.000 First visit SCCAI 0.280 Median (IQR) 9.0 (7.0, 11.0) 9.0 (8.0, 12.0) Mean (SD) 8.7 (3.0) 9.8 (2.3) Range (3.0, 14.0) (6.0, 13.0) First visit HBI 0.636 Median (IQR) 10.5 (5.0, 15.0) 7.0 (6.0, 10.0) Mean (SD) 10.8 (6.2) 9.2 (6.4) Range (4.0, 20.0) (2.0, 22.0) Positive response to treatment, n (%) 0.771 No 13 (54.2) 14 (58.3) Yes 11 (45.8) 10 (41.7) No. of days between 1st and 2nd visit 0.551 Median (IQR) 14.0 (14.0, 17.0) 15.0 (14.0, 16.0) Mean (SD) 15.3 (4.4) 16.0 (3.5) Range (7.0, 32.0) (12.0, 27.0) Therapy protocol deviation, n (%) 0.306 Shorter 10 (37.0) 5 (19.2) Longer 13 (48.1) 18 (69.2) Per protocol 4 (14.8) 3 (11.5) 5ASA, 5-aminosalicylic acid The mood changes observed in this study appeared largely supports prednisone’s role in the mood score changes. It is also independent of the IBD activity, as was observed in obstructive worth noting that neither clinical disease activity indices incor- airway diseases (13, 18). This is demonstrated by the return of porated objective measures such as endoscopic assessment or the mood state to pretreatment level while clinical IBD activity biomarkers, but SCCAI was previously demonstrated to corre- remained stable or improved following completion of therapy. late well with endoscopic inflammation, as well as serum and In addition, there was no correlation between the changes in fecal inflammatory markers (36). The Harvey-Bradshaw Index clinical IBD activities and the changes in mood scores, which was chosen for its straightforward administration and good Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 7 Table  3. Multivariate analysis of factors associated with mood lymphoblastic leukemia compared with school-aged children score changes. (41). It was postulated that the developing brain may be more susceptible to CS adverse effect (20), but this hypothesis is not BDI-II increase by ≥10 and/or applicable to adult patients. It is possible that the observed asso- AS-ISSv2 increase by ≥50 ciation was related to the greater proportion of younger patients Variable Odds ratio (95% CI) P with IBD in this study, compared with other autoimmune conditions included in previous reports. Alternatively, it may Age (per 5-year decrease) 1.41 (1.09, 1.82) 0.010 be related to a different phenotype of the disease in younger Male 0.44 (0.12, 1.69) 0.233 patients. Larger prospective data is required to draw more defin- Use of 5ASA 0.32 (0.08, 1.21) 0.093 itive conclusions regarding female gender and younger age as 5ASA, 5-aminosalicylic acid risk factors for CIMC among IBD patients. This study has several limitations, including the single-centre design and the lack of a control group. However, as CS use is correlation with Crohn’s Disease Activity index, which has the standard of care in patients with IBD flares, ethical consid - been utilized extensively in previous Crohn’s disease trials (37). erations preclude the institution of a placebo-controlled group. Although HBI does not correlate well with endoscopic inflam- Comparison with an alternate induction agent such as anti-tu- mation or fecal inflammatory marker (36, 38), use of such clini- mor necrosis factor alpha was also not feasible, as many patients cal disease activity index is warranted in absence of an objective were on concomitant CS or immunomodulator at the time modality that can accurately assess all phenotypes of Crohn’s of anti-tumor necrosis factor alpha initiation. To address this disease. deficit, we incorporated a follow-up visit at the end of the CS Patients with psychiatric comorbidities only accounted for treatment as internal control and demonstrated that the mood 9% (five of 53)  of the study population, and all were taking state returned to pretreatment level ae ft r completion of therapy. stable doses of psychiatric medications. Only two of five devel - A potential confounder is patient adherence to prednisone ther- oped detectable mood changes, which is comparable to the rest apy. As the first step to demonstrate the rate of CIMC in a real- of the study population, but the numbers are too small to draw life experience, patient adherence was not monitored; however, any meaningful conclusion. We did not include patients who this information could be vital in future studies as an endpoint had recent change in psychiatric medications to minimize the since nonadherence may be a result of CIMC. impact of their underlying mental illness. The relatively small sample size limited the precision in assess - Female gender and younger age were associated with mood ing the rate of CIMC but did so without sacrificing accuracy. changes in the univariate analysis, but only age remained sta- A larger sample size would have required a substantial, prohibitive tistically significant in the multivariate analysis. Naber et  al. amount of resources for recruitment. Therefore, we calculated the reported that gender is not a risk factor for “neuropsychological sample size based on a precision of 0.15. This study’s results are and psychopathological changes” in patients receiving high- not generalizable to inpatients with IBD flares, which represent dose CS for ocular conditions (14). In contrast, higher inci- a significant portion of patients requiring systemic CS therapy dence of CIMC in females was observed in earlier studies, but at our centre. Inpatients were excluded to avoid potentially con- the interpretation was confounded by female predominance in founding effects of their severe disease activity and comorbidi - certain autoimmune conditions such as rheumatoid arthritis ties, such as malnutrition and infection, on psychological state and systemic lupus erythematosus (28, 39, 40). (42–44). Similarly, recent psychiatric medication changes and Similar finding of emotional function impairment was active alcohol or recreational drug use were excluded to minimize observed in pediatric IBD patients treated with CS, compared confounding. Further prospective study with larger sample size with controls (IBD in remission) not taking CS (20). However, is needed to clarify the effect of CS on mood in these subgroups. there is paucity of data on the relationship between age and In conclusion, CS treatment was associated with frequent risk of CIMC in the literature. Younger age has emerged as an mood changes, affecting nearly half of the subjects in this study. independent risk factor for CIMC in our study, contrary to a The most common manifestation was mood elevation during previous report by Lewis and Smith examining psychiatric dis- therapy, but subsequently the affective state returned to pre- turbances in a variety of conditions requiring CS for immuno- treatment level upon completion of therapy without relapse suppression (28) and contrary to a prospective study by Brown of clinical disease activity. Healthcare providers should inform et  al. assessing mood changes during prednisone treatment patients of such a risk and monitor for need of intervention. of asthma (13). To our knowledge, there is no data directly Future studies may help to clarify the role for concomitant comparing pediatric to adult population in terms of suscep- therapy to ameliorate the mood-related side effects for patients tibility to CIMC, but an earlier study found greater impact of requiring CS for management of their IBD. CS on behaviour and mood in preschool children with acute Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018 8 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 18. Swinburn CR, Wakefield JM, Newman SP, et  al. Evidence of prednisolone induced Acknowledgements mood change (‘steroid euphoria’) in patients with chronic obstructive airways disease. Br J Clin Pharmacol. 1988;26:709–13. The authors would like to thank Amy Wong and Oliver Takach for 19. Castaneda AE, Tuulio-Henriksson A, Aronen ET, et  al. Cognitive functioning and their assistance in subject recruitment and data collection. This work depressive symptoms in adolescents with inflammatory bowel disease. World J was supported by the 2014 Procter & Gamble-Canadian Association Gastroenterol. 2013;19:1611–7. 20. Mrakotsky C, Forbes PW, Bernstein JH, et al. Acute cognitive and behavioral effects of Gastroenterology Resident Research Award. GO contributed to the of systemic corticosteroids in children treated for inflammatory bowel disease. J Int conception and design of study, the acquisition, analysis and interpre- Neuropsychol Soc. 2013;19:96–109. tation of data, and the drafting and final approval of the article. BB, NS, 21. Cerveny P, Bortlik M, Kubena A, et al. Nonadherence in inflammatory bowel disease: Results of factor analysis. Inflamm Bowel Dis. 2007;13:1244–9. contributed to conception and design of study and the critical revision 22. Bar-Meir S, Chowers Y, Lavy A, et al. Budesonide versus prednisone in the treatment and final approval of the article. CG, EL, HHK , RE and JT contributed of active Crohn’s disease. The Israeli Budesonide Study Group. Gastroenterology. to acquisition of data and the critical revision and final approval of the 1998;115:835–40. 23. Rutgeerts P, Lofberg R , Malchow H, et al. A comparison of budesonide with prednis - article. TL contributed to the analysis and interpretation of data and olone for active Crohn’s disease. N Engl J Med. 1994;331:842–5. the critical revision and final approval of the article. GR contributed to 24. Campieri M, Ferguson A, Doe W, et  al. Oral budesonide is as effective as oral pred - the conception and design of study, interpretation of data and critical nisolone in active Crohn’s disease. The Global Budesonide Study Group. Gut. 1997;41:209–14. revision and final approval of the article. 25. Beck AT, Steer RA, Ball R , et al. 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Gen Hosp Psychiatry. the association between psychological distress and disease activity. Dig Dis Sci. 1988;10:56–60. 2004;49:492–7. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy023/5032837 by Ed 'DeepDyve' Gillespie user on 07 June 2018

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