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Coeliac disease, diet adherence and depressive symptoms
Journal of Psychosomatic Research 74 (2013) 155–160
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Journal of Psychosomatic Research
Coeliac disease, diet adherence and depressive symptoms Nathalie J.M. van Hees a,⁎, Willem Van der Does a, b, Erik J. Giltay b a b
Institute of Psychology, Leiden University, Leiden, The Netherlands Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 20 April 2012 Received in revised form 9 November 2012 Accepted 13 November 2012 Keywords: Coeliac disease Depression Diet adherence Gluten-free diet Psychopathology
a b s t r a c t Objectives: We aimed to investigate whether long-term adherence to a gluten-free diet is related to depressive symptoms in coeliac disease (CD) patients. Methods: A cross-sectional survey was performed in 2265 adult CD patients recruited through the Dutch Coeliac Association. Self-reported diet adherence was compared among groups based on self-reported depressive symptoms (categorized into current [1-month], remitted, and never). Results: The life-time prevalence rate of self-reported depressive symptoms was 39.0% (n = 883), of whom 270 (11.9%) suffered from current depressive symptoms. Adherence to gluten-free diet was strict in 50.2% of patients, sufficient in 46.3%, and insufficient in 3.6%. Insufficient adherence was not associated with current depressive symptoms (odds ratio [OR] 0.95; 95% confidence interval [CI]: 0.48–1.92). Keeping a gluten-free diet for longer than five years was associated with lower OR of current depressive symptoms compared to being on a diet for less than two years (OR 0.69; 95% CI: 0.50–0.95). Conclusions: Lifetime depressive symptoms may be present in one third of the CD patients who adhere to gluten-free diet. Long-term adherence to the gluten-free diet may reduce the risk of current depressive symptoms. © 2012 Elsevier Inc. All rights reserved.
Introduction Coeliac disease (CD) is an immune-mediated intolerance for gluten in genetically predisposed individuals and is characterized by an inappropriate immune response of the T-lymphocytes of the small intestines to gluten peptides. This results in intestinal malabsorption, atrophy of the intestinal villi and chronic inflammation of the jejunal mucosa of the small intestine. The clinical presentation varies widely, as CD is now considered a multisystem disorder affecting multiple organs, such as the skin, thyroid, heart, nervous system, pancreas, spleen, liver [1], as well as the brain. CD has a prevalence rate in Europe and the USA of about 1:100 [2] and is associated with an increased prevalence of psychopathology [3,4]. The only available treatment is a strict gluten-free diet (GFD), which leads to restoration of the atrophied intestinal villi. It may, however, take years to achieve complete recovery of the intestinal villi [5], and the effects of the diet on mood and psychiatric symptoms are largely unknown. Common psychiatric symptoms in untreated CD are depressive symptoms, apathy, anxiety, and irritability [6–9]. A cross-sectional, case–control study in 36 CD patients and 144 controls used the Composite International Diagnostic Interview (CIDI) to assess lifetime psychopathology [7]. They found that the risks of major depression (MD; 41.7%), dysthymic disorder (8.3%), adjustment disorders ⁎ Corresponding author at: Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands. Tel.: +31 71 527 6751; fax: +31 71 527 3932. E-mail address: [email protected] (N.J.M. van Hees). 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2012.11.007
(30.5%), and panic disorder (13.9%) were increased in CD. Increased rates of depressive and anxiety symptoms were also found in CD patients on a GFD [4,10,11]. The reported prevalence of depressive symptoms in CD patients varies widely across studies, ranging from 6 to 69% [8,12–17]. Differences in patient characteristics, cultural background, and study design may account for the large variability [3,18,19]. In a large longitudinal population-based cohort study, CD patients were at an 80% increased risk of depression compared to controls [19]. Only one case–control study found equal prevalence rates of depression (17.2% versus 16%) [20]. However, diagnoses for depression in this study were solely based on notes from primary care providers or gastroenterologists and reliability may be questioned. The increased risk of depressive symptoms in CD patients could be explained by several mechanisms. Firstly, dietary non-compliance and sustained malabsorption may play a role [18], which could lead to sustained nutritional deficiencies (e.g. of vitamin B6, vitamin B12, and folic acid) which in turn may have increased the risk of depression [21]. Secondly, nutritional deficiencies may be a consequence of the strict restrictive GFD. Many of the gluten-free grains do not inherently contain thiamin, riboflavin, niacin, folate, and iron, nor are gluten-free food products in general required to be enriched with these micronutrients by food authorities [22–24]. Whether nutritional deficiencies caused by the daily diet in general contribute to the risk of depression is unknown at this time. There might also be reductions in brain monoamine availability and metabolism [27] and regional cerebral hypoperfusion [28] in patients with CD that may subsequently have induced depression. Thirdly, psychosocial
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mechanisms may be involved. Due to the strict dietary regimen CD patients may avoid social situations which involve eating and also may experience more psychological distress due to daily hassles, negative responses to the diet by their social surroundings, and continued worrying about dietary mistakes and negative health outcomes [25–28]. Distress, social isolation and loneliness may subsequently lead to depression [29]. Fourthly, depression in CD may be secondary to an association between CD and other auto-immune diseases that carry a high risk of depression, such as thyroid disease and diabetes mellitus [7,20]. It is often assumed that dietary non-compliance increases the risk of depressive symptoms. It is common practice to refer CD patients to a dietician for a diet review. The literature on the relationship between adherence to gluten-free diet and depression however is inconclusive and long term dietary compliance in relation to depression has not been studied in depth. Two case series found that psychiatric disturbances and depressive symptoms improved rapidly after the introduction of a gluten-free diet [30,31], but several other studies found no improvement [7,25,32]. One study even reported more depressive symptoms for GFD-treated versus untreated CD patients [33]. In addition, one study found a small significant correlation between non-compliance and depressive symptoms [34], one study found diet adherence not to be a predictor of depressive symptoms [35], and one study found that strict diet adherence was related to an increase in depressive symptoms independent from duration of diet [12]. Most studies included recently diagnosed CD patients and did not study patients who were on a diet for more than one year, while the restoration of the absorption function may take two [36] to five years [5]. In the present study, we investigated the association of duration and stringency of the GFD with the prevalence of depressive symptoms. We performed a cross-sectional survey on a representative sample, comparing groups of adult CD patients who report never having had depressive symptoms, who are remitted from depressive symptoms or who currently experience depressive symptoms. We hypothesized that CD patients who adhere badly to the GFD have an increased risk of currently having depressive symptoms compared to CD patients who strictly adhere to the GFD. We also expected that increased length of the GFD is associated with a lower risk of depressive symptoms. Methods Patients Participants were recruited from the 7119 adult members of the Dutch Coeliac Association (NCV). The NCV comprises CD patients with varying treatment history and severity of illness. According to self-report, 87% of this population had the diagnosis of coeliac disease confirmed by a biopsy of the intestinal lining. In 7% the diagnosis was made by other means and 5% was on GFD for other medical reasons [37]. Instruments Adherence to gluten-free diet Diet adherence of the GFD was assessed by one self-report reply to the question: “I keep my diet: very stringent/simply right/moderately well/not well”. Similar questions and methodology have been used in other studies [8,28,35,38–41]. Self-reported depressive symptoms Self-reported current and past depressive symptoms were assessed with the Major Depression Questionnaire (MDQ) [42], an 18 item self-reported questionnaire which assesses the diagnostic criteria for MD according to the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV-TR) [43] criteria for MD. A previous validation study in a small sample (n = 39) showed excellent sensitivity (100%) and negative predictive value (100%), good positive predictive value (79%), specificity (75%) and overall kappa (0.75), compared with interview-based diagnoses [44]. The MDQ consists of a series of questions that cover all DSM-IV diagnostic criteria for current and past major depression [43], including impact on functioning and exclusion criteria (e.g., mourning). The scoring criteria and the cut-off for caseness versus noncaseness also follow DSM-IV, in other words no case of depression is assumed when both core symptoms of depression are absent or self-reported impact on functioning is low. This leads to self-reported depressive symptoms which can be categorized as MDQ cases and MDQ noncases. MDQ caseness can be further subdivided in never, remitted and current cases. The items that make up a positive caseness score in the MDQ include an item on changes in quality of sleep and an item on changes in body weight. As these symptoms may overlap with those of CD, we made an attempt to exclude the most profound physical consequences of CD through additional instructions and item-wording. Although participants were instructed to disregard the cause of physical symptoms and just report whether the symptom was present or not, they were asked to only report weight change achieved without intent and caused by increased or decreased appetite and only to report sleep disturbance leading to at least a 2 hour change from usual for most of the time during a 2 week period. Symptoms of anxiety and depression The Hospital Anxiety and Depression Scale (HADS) [45] is a 14 item self-reported questionnaire for the assessment of symptoms of anxiety and depression with good case-finding ability. Cronbach's alpha is .83 for the HADS anxiety scale (HADS-A) and .82 for the HADS depression scale (HADS-D). The optimal cut-off score is 8 and the concurrent validity of the HADS was found to be good to very high [46]. The Dutch version has good internal consistency in medical outpatients (HADS total score, α = .90). The sensitivity and specificity to detect MD with a cut-off point of 8 on the depression subscale are 56% and 82%, respectively [47]. The HADS is designed to screen non-psychiatric hospital outpatients for possible anxiety or depressive disorder and items referring to eating and sleep disturbances are not included in the scale making it a fitting tool for populations with somatic illness such as CD. It has been suggested in a recent review that the results of the HADS should be interpreted as a unidimensional measure of “emotional distress” [48] and therefore we reported both the HADS subscale scores as well as total scores. Vulnerability to depression Cognitive vulnerability to depression was measured with the short (6-item) version of the self-report Leiden Index of Depression Sensitivity (Leids-R-SF), derived from the 34 item Leids-R [49]. The Leids-R consists of questions like “When I am feeling down, I more often think about how I am unable to make anyone happy” and “I can only think positive when I feel well” followed by a five point Likert scale. The Leids-R-SF in our sample had good internal consistency (α = 0.87). Procedure The questionnaires were bundled in a questionnaire-booklet, which was sent out as unsolicited mail accompanying a 2007 issue of the NCV quarterly magazine. The questionnaires were also handed out during five NCV events, were made available online, and were announced on various Dutch CD websites, forums and mailing lists. Articles about the questionnaire and the study were published in four issues of the quarterly magazine and these articles were also made available through the online questionnaire website. This study was approved by the ethics committee of the institute of psychology of
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Leiden University. All patients gave written informed consent to participate in the study when returning the completed questionnaire. Statistical analysis Records were excluded on the basis of one or more missing values on the main variables of interest. Data imputation was not performed in any of the measures except the HADS. Data imputation with case means per subscale was performed for records with 3 or less missing values per subscale (n = 74, 3.1%). Records with more than 3 missing values per subscale were excluded (n = 14, 0.6%). Patients were categorized into the three groups (i.e., absent, remitted or current depressive symptoms) based on MDQ scores. Differences between these study groups were analyzed for socio-demographic characteristics, comorbid disorders, other depression assessment variables, characteristics of depressive symptom episodes and dietary habits by analysis of variance (ANOVA) or Pearson chi-squared (χ2) tests for categorical variables. Hochberg's GT2 and Games–Howell post-hoc tests were used, when appropriate. Kruskal–Wallis test (H) was used to assess length of depressive symptom episode and length of diet per depression category. Jonckheere–Terpstra and Mann–Whitney post-hoc tests were used, when appropriate. Associations between GFD characteristics and current depressive symptoms were analyzed using multivariate logistic regression analysis, which yielded odds ratios (OR) with 95% confidence intervals (CI). Multivariate analyses were adjusted for potential confounding by age, gender, and level of education (in Model 1) and additionally for number of other chronic diseases (in Model 2). Statistical significance was inferred at p b .05. All analyses were done with SPSS software (SPSS Inc., Chicago, IL) [50]. Results Participant flow In total we received 2407 valid responses (response rate of 33.8%). 1793 participants returned the paper questionnaire and 614 completed it online. During a brief interview on the reasons for dropout among 30 subjects, a lack of time was most frequently reported. A small minority indicated never having had depressive symptoms and therefore thought themselves unsuitable, and others anticipated that participation
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would be too depressing. Records with missing data on the variables age (n = 8), level of education (n=8), gender (n=14), status of GFD (n=2), length of GFD (n=50), total MDQ (n=50), total HADS (n=14), and dietary adherence (n=51) were excluded from analysis. Records of CD patients who were not on a GFD and had not been on a GFD in the past (patient is in the process of receiving a diagnosis), were also excluded (n=32). The total number of excluded records was 142 (5.9%). The total sample therefore consisted of 2265 (94.1%) CD patients. However, some of these participants had missing data on the variables describing psychiatric characteristics. The sample size was therefore smaller for analyses involving description of: vulnerability to depression (n = 2081); age at first depressive symptom onset (n = 2173); number of lifetime depressive symptom episodes (n = 2135); and length of the most severe episode (n = 1980). Patient characteristics Patients were on average 52 years old (range 18–93 years), 75.5% was female, and they had above average educational attainment (Table 1). Comorbid disorders were reported by 882 patients (38.9%), most often mentioned were chronic pulmonary disease (n = 168), osteoporosis (n = 123), hypothyroidism (n = 116) and cardiovascular disease (n = 110). Table 1 shows the results for 11 comorbid disorders in relation to depression categories (never, remitted and current). Comorbid chronic pulmonary disease and hypothyroidism were significantly associated with depressive symptom categories (p b .001 and p = .008, respectively). The results for inflammatory bowel disease (Chron's disease, colitis ulcerosa, collagenous-, lymphocytic-, microcytic colitis) should be interpreted with some caution since the expected cell count was below five for the currently depressed category (n = 30, p = .66). Table 1 also shows that there was an overall effect of number of comorbid diseases on depressive symptoms (χ2 (4) = 30.4; p b .001). Having one comorbid disorder raised the OR of having current depressive symptoms compared to having no comorbid disorder (1.43, 95% CI: 1.06–1.93). Having more than one comorbid disorder in addition to CD doubled the OR of having current depressive symptoms (2.15; 95% CI: 1.54–3.01). Characteristics of depressive symptoms The life-time prevalence rate of depressive symptoms (i.e., current plus remitted) was 39.0% (n = 883), of whom 270 (11.9%) suffered from current depressive symptoms. Table 1 shows demographic and medical characteristics of CD patients according to the three depressive symptom categories. The mean age differed among the three groups (F (2, 2265)=56.7; pb .001). Post-hoc tests revealed that the group who never experienced depressive symptoms was significantly older than the groups with current and remitted depressive symptoms. The gender distribution also differed among groups (χ2 (2) = 63.8; p b .001), driven by the higher OR of female versus male CD patients in the remitted or current groups (2.37; 95% CI: 1.91–2.94). The level of education also significantly differed among the groups (χ2 (4) = 42.6; p b .001), driven by the higher OR for high versus low-educated CD patients in the remitted or current groups (3.26; 95% CI: 2.64–4.04).
Table 1 Socio-demographic and medical characteristics of the study patients with coeliac disease according to categories of depressive symptoms
Number of patients—n (%) Age (years)—mean (SD) Gender: n (%) • Male • Female Level of education: n (%) • Low • Intermediate • High Comorbidity (% total n):b n (%) • Cardiovascular disease • Diabetes mellitus • Chronic pulmonary disease • Rheumatoid disease • Arthrosis • Hypothyroidism • Other thyroid diseases • Osteoporosis • Cancer • IBD Number of comorbid disorders:b n (%) • No comorbidity • 1 comorbid disorder • ≥2 comorbid disorders
Total
Never
Remitted
Current
p-Value
2265 51.8 ± 16.1
1382 54.6 ± 16.1
613 47.7 ± 15.0
270 46.6 ± 15.3
b.001
556 (24.5%) 1709 (75.5%)
419 (30.3%) 963 (69.7%)
94 (15.3%) 519 (84.7%)
43 (15.9%) 227 (84.1%)
b.001
627 (27.7%) 691 (30.5%) 947 (41.8%)
432 (31.3%) 386 (27.9%) 564 (40.8%)
116 (18.9%) 204 (33.3%) 293 (47.8%)
79 (29.3%) 101 (37.4%) 90 (33.3%)
b.001
110 (4.9%) 81 (3.6%) 168 (7.4%) 59 (2.6%) 44 (1.9%) 116 (5.1%) 46 (2%) 123 (5.4%) 42 (1.9%) 30 (1.3%)
66 (4.8%) 51 (3.7%) 91 (6.6%) 34 (2.5%) 19 (1.4%) 55 (4%) 34 (2.5%) 72 (5.2%) 23 (1.7%) 19 (1.4%)
24 (3.9%) 18 (2.9%) 41 (6.7%) 17 (2.8%) 17 (2.8%) 43 (7%) 6 (1%) 35 (5.7%) 14 (2.3%) 9 (1.5%)
20 (7.4%) 12 (4.4%) 36 (13.3%) 8 (3%) 8 (3%) 18 (6.7%) 6 (2.2%) 16 (5.9%) 5 (1.9%) 2 (0.7%)
.08 .50 b.001 .85 .49 .008 .09 .84 .64 .66
1383 (61.1%) 575 (25.4%) 307 (13.6%)
888 (64.3%) 341 (24.7%) 153 (11.1%)
360 (58.7%) 157 (25.6%) 96 (15.7%)
135 (50%) 77 (28.5%) 58 (21.5%)
b.001
Data are presented as n (%) or mean (± SD), when appropriate. IBD denotes Inflammatory Bowel Disease. a p-Values by chi-squared test for categorical variables and by ANOVA for continuous variables. b Comorbidity is self-reported and defined as being diagnosed by a physician.
a
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Table 2 Psychiatric characteristics of the study patients with coeliac disease according to categories of depressive symptoms
Number of patients HADS—mean ± SD • HADS Depression • HADS Anxiety • HADS Total Cognitive vulnerability—mean ± SD First onset of depressive symptomsb—n • Before introduction of GFD • During the first 2 years on GFD • During the 2nd to 5th year on GFD • After more than 5 years on GFD Number of lifetime episodes—Mdn (Q1–Q3) Length of most severe episode (years)—Mdn (Q1–Q3)
Total
Never
Remitted
Current
2265
1382
613
270
4.5 ± 3.9 6.1 ± 4.0 10.6 ± 7.3 8.4 ± 5.6 791 590 (74.6%) 10 (1.3%) 39 (4.9%) 152 (19.2%) 3.0 (1.0–10.0) 1.0 (0.5–3.0)
3.3 ± 3.2 4.7 ± 3.4 8.0 ± 6.0 6.3 ± 5.0
5.2 ± 3.9 7.3 ± 3.7 12.5 ± 6.9 10.2 ± 4.7 527 424 (74.1%) 7 (1.2%) 30 (5.2%) 111 (19.4%) 2.0 (1.0–5.8) 1.0 (0.4–2.5)
9.2 ± 3.4 10.6 ± 3.3 19.8 ± 5.8 14.2 ± 4.6 219 166 (75.8%) 3 (1.4%) 9 (4.1%) 41 (18.7%) 8.0 (3.5–20.0) 2.0 (0.5–5.4)
– – – –
p-Value
a
b0.001 b0.001 b0.001 b0.001 0.89
b0.001 b.03
Data are presented as n (%), mean (± SD) and median (Q1–Q3) when appropriate. HADS denotes the Hospital Anxiety and Depression Questionnaire; GFD, gluten-free diet. a p-Values based on chi-square test for categorical variables, F-test for continuous variables and Kruskall–Wallis H for non-parametric continuous variables. b First onset of depressive symptoms was calculated in a smaller sample (n = 2173) due to missing data.
As expected, there was a significant overall difference in the mean HADS-Depression (F (2, 667)=366.2; pb .001), HADS-Anxiety (F (2, 687)=398.6, pb .001), and HADS-Total (F (2, 688)=496.2, pb .001) symptom scores among the three depressive symptom groups. Post-hoc tests showed that the mean HADS-D, HADS-A, and HADS-Total scores differed significantly in one-by-one comparisons (all psb .001). The biserial correlation coefficient between HADS-D scores and the category of current depressive symptoms defined by MDQ results showed a strong and significant correlation (rb =0.71, pb .001). There was a significant overall difference in the mean LEIDS-R-SF scores (H(2) = 357.0, p b .001), and all one-by-one comparisons were significant (all ps b .001). Of the 883 CD patients with lifetime depressive symptoms, 74.6% had the onset of their first depressive symptoms before introduction of the GFD (Table 2). Patients with current depressive symptoms reported more lifetime episodes of depressive symptoms than patients with remitted depressive symptoms (H(1) = 97.0; p b .001), and they also reported longer episodes (H(1) = 4.94; p b .03). Dietary adherence to the GFD On average, patients were maintaining a GFD for an uninterrupted period of 8.2 years, ranging between one week and sixty years (Table 3). Length of current GFD differed significantly among the three groups (H(2) = 31.80; p b .001). The Mann–Whitney test showed that duration of the GFD differed significantly between the never and remitted depressive symptom groups (p b .001), as well as between the remitted and current depressive symptom groups (p = .019), with the shortest duration of the GFD for the current depressive symptom group. The dietary adherence categories “moderately well” and “not well” were collapsed for the purpose of analyses, because of small numbers. There was no significant overall difference in categories of self-reported dietary adherence among the never, remitted and current groups (χ2 (4) = 1.185; p = .89). Associations between GFD characteristics and depressive symptoms The associations between GFD characteristics and depressive symptoms are presented in Table 4. The duration of the GFD related to the three depressive symptom categories. Although a duration of the GFD of 2 up to 5 years was not significantly associated with a reduced risk of current depressive symptoms, it was decreased in those CD patients being on a GFD longer than 5 years versus shorter than 2 years
(adjusted OR: 0.69, 95% CI: 0.50–0.95; Wald χ2(1) = 5.28, p = .02). The adherence to the GFD was not associated with current depressive symptoms in the fully adjusted model 2 (Wald χ2(1) = 0.01, p= .92).
Discussion In our group of 2265 adult CD patients, a lifetime prevalence of depressive symptom cases of 39% was found, based on MDQ questionnaire scores. This is in line with previous findings of high rates of MD [7] and depressive symptoms [8,25]. Long-term adherence to the gluten-free diet (over 5 years) was associated with a reduced risk of current depressive symptoms, which is in line with findings from an Italian study [27]. We found no association of self-reported diet stringency and depressive symptoms in our population, which is also in line with results found in Italy and Germany [8,35].
Why is the prevalence of depressive symptoms increased in CD? The one-month and lifetime prevalences of depressive symptom cases based on MDQ questionnaire scores observed in our study (i.e., 11.8% and 39.0%, respectively) appear to be higher than the rates of MD in the general Dutch population (2.7% and 15.4%, respectively) [51]. CD patients with current depressive symptoms also reported increased anxiety symptoms. This may be due to the well-established relationship between anxiety and mood disorders and the overlap between anxiety and depressive symptoms, or may signal an independent association between anxiety disorders and CD [4,7,10,25,35]. Cognitive vulnerability to depression scores were also increased in CD patients with remitted and current depressive symptoms [49].
Table 3 Dietary habits of the study patients according to categories of depressive symptoms
Number of patients Length of gluten-free diet—Mdn (Q1–Q3) Length of present diet • 0 to 2 years • 2 to 5 years • 5 years and longer Dietary adherence by self-report: “I keep my diet:” • Very stringent diet • Sufficient diet • Moderately well/not well
Total
Never
Remitted
Current
p-Value
2265 5.8 (2.3–12.0)
1382 6.4 (2.8–12.9)
613 5.0 (2.0–11.3)
270 4.0 (1.5–10.0)
b.001
466 (20.6%) 535 (23.6%) 1264 (55.8%)
248 (17.9%) 307 (22.2%) 827 (59.8%)
144 (23.5%) 154 (25.1%) 315 (51.4%)
74 (27.4%) 74 (27.4%) 122 (45.2%)
b.001
1136 (50.2%) 1048 (46.3%) 81 (3.6%)
687 (49.7%) 647 (46.8%) 48 (3.5%)
306 (49.9%) 284 (46.3%) 23 (3.8%)
143 (53.0%) 117 (43.3%) 10 (3.7%)
.89
Data are presented as n (%) or median (Q1–Q3), when appropriate. a p-Values based on chi-square test for categorical variables and Kruskall–Wallis H for non-parametric continuous variables.
a
N.J.M. van Hees et al. / Journal of Psychosomatic Research 74 (2013) 155–160 Table 4 Associations between the characteristics of the gluten-free diet and depressive symptoms Length of gluten-free diet
Total number of patients No. with current symptoms—n (%) - Crude association - Model 1a - Model 2b
b2 years
2–5 years
≥5 years
466 74 (15.9%)
535 74 (13.8%)
1264 122 (9.7%)
1.0 (ref) 1.0 (ref) 1.0 (ref)
0.85 (0.60–1.21) 0.93 (0.65–1.32) 0.94 (0.66–1.34)
0.56 (0.42–0.77)c 0.68 (0.49–0.93)c 0.69 (0.50–0.95)c
Dietary adherence by self-report
Total number of patients No. with current symptoms—n (%) - Crude association - Model 1a - Model 2b
Very stringent diet
Sufficient diet
Insufficient or no real diet
1136 143 (12.6%)
1048 117 (11.2%)
81 10 (12.3%)
1.0 (ref) 1.0 (ref) 1.0 (ref)
0.87 (0.67–1.13) 0.84 (0.65–1.10) 0.89 (0.68–1.16)
0.98 (0.49–1.94) 0.94 (0.47–1.89) 0.95 (0.48–1.92)
Odds ratios are presented (with 95% confidence intervals). a Adjusted for age, gender, and level of education. b Additionally adjusted for number of comorbid chronic diseases. c p b 0.05.
One of the hypotheses under study was that insufficient adherence to the GFD increases the risk of depressive symptoms in CD patients [8,19]. This was not supported by our data. However, only 3.8% of our patients kept an insufficient diet, which limited the power to detect any effects of insufficient dietary adherence. The high prevalence of depressive symptoms may also be explained by a general burden of suffering from a chronic disease [17,26,28,35,52]. Finally, depression and CD may share underlying biological causal factors, similar to the link between depression and cardiovascular diseases that may be explained by underlying atherosclerotic and inflammatory processes [53]. We also tested the hypothesis that a longer duration of the GFD is linked to a lower risk of depressive symptoms. This was supported by our findings, but only after more than five years of keeping a GFD. This may be a consequence of restoration of the intestinal lining [5] and a subsequent general improvement in health, which may take several years [54,55]. Continuing malabsorption problems, which take longer to dissipate than previously assumed, may induce depressive symptoms. Strengths and limitations of this study By using the survey methodology we were able to investigate a large sample of patients with CD representative of the NCV membership [37]. The response rate was a satisfactory 34% [37]. The sample was largely representative of the entire CD population, which in most studies was found to be skewed towards women and people with higher education [27,56]. Only 3.8% of our patients reported keeping an insufficient diet. Nevertheless, it is possible that poor adherence to the GFD was underreported as participants may tend to give socially desirable answers. Although assessment of GFD adherence by a specialized dietician is the most reliable instrument [40], self-report ratings of dietary adherence have been used in a range of studies in adults and children with CD. A French study found higher rates of non-compliance and dietary mistakes (28%) using an estimated intake of 18 g gluten in 2 months as a cut-off. Direct enquiries by experts uncovered more frequent occasional lapses of gluten intake [57]. In a study in which participants were interviewed by an expert, 7% transgressed at least once a week [27]. Another study using a four-point scale on a self-report survey showed that 8% of participants adhered to the GFD rarely to sometimes
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[27,28]. Comparisons among studies are difficult, however, because of differences in cut-off points for compliance, and more agreement and guidelines on this matter are needed. Our study was limited by the cross-sectional design. A potential source of bias is the reliance on self-report questionnaires. We used self-report questionnaires for CD diagnoses and for psychiatric diagnoses, rather than medical file analysis or structured interviews. Although attempts have been made to exclude the most profound physical symptoms of CD that overlap with depressive symptoms, a self-report survey is not a suitable instrument for accurately differentiating between these symptoms. In addition, the MDQ should be validated more extensively. The HADS on the other hand has been extensively validated, although some debate has recently arisen on its subscales [58]. We focused in our survey on depressive symptoms as these were found to be prevalent in CD [8,25], the risk of other forms of psychopathology may also be increased [7]. Clinical implications and future research Depressive symptom rates were found to be high in CD patients. Depressed CD patients may benefit from available treatments for depression in addition to the GFD. In turn, improving depressive symptoms in CD patients may improve these patients' adherence to the GFD [59] as depression is a risk factor for non-adherence to medical advice and subsequent poor outcomes [60,61]. Future prospective studies and trials are needed to confirm the beneficial effects of long-term adherence to the gluten-free diet on depressive symptoms and MD. Prospective studies—with prolonged follow-up spanning at least five years—may help to unravel the time sequence between changes in the GFD habits and the onset and remission of depressive symptoms and MD. Acknowledgments This project was funded by a grant from the Netherlands Science Foundation (N.W.O-MaGW Vici) grant # 453-06-005 to WVdD, and grants from the Leiden University Fund (LUF) and Gratama Foundation. The research was conducted independently of the funding agencies. Appendix A. Supplementary data Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.jpsychores.2012.11.007. References [1] Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006;131(6):1981-2002. [2] Tommasini A, Not T, Kiren V, Baldas V, Santon D, Trevisiol C, et al. Mass screening for coeliac disease using antihuman transglutaminase antibody assay. Arch Dis Child 2004;89(6):512-5. [3] Addolorato G, Leggio L, D'Angelo C, Mirijello A, Ferrulli A, Cardone S, et al. Affective and psychiatric disorders in celiac disease. Dig Dis 2008;26(2):140-8. [4] Addolorato G, Mirijello A, D'Angelo C, Leggio L, Ferrulli A, Abenavoli L, et al. State and trait anxiety and depression in patients affected by gastrointestinal diseases: psychometric evaluation of 1641 patients referred to an internal medicine outpatient setting. Int J Clin Pract 2008;62(7):1063-9. [5] Rubio-Tapia A, Rahim M, See J, Lahr B, Wu T-T, Murray J. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol 2010;105(6):1412-20. [6] Addolorato G, Stefanini G F, Capristo E, Caputo F, Gasbarrini A, Gasbarrini G. Anxiety and depression in adult untreated celiac subjects and in patients affected by inflammatory bowel disease: a personality “trait” or a reactive illness? Hepatogastroenterology 1996,Nov–Dec;43(12):1513-7. [7] Carta MG, Hardoy MC, Boi MF, Mariotti S, Carpiniello B, Usai P. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res 2002 Sep;53(3):789-93. [8] Ciacci C, Iavarone A, Mazzacca G, De Rosa A. Depressive symptoms in adult coeliac disease. Scand J Gastroenterol 1998 Mar;33(3):247-50. [9] Hernanz A, Polanco I. Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. Gut 1991 Dec;32(12):1478-81.
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Journal of Psychosomatic Research
Coeliac disease, diet adherence and depressive symptoms Nathalie J.M. van Hees a,⁎, Willem Van der Does a, b, Erik J. Giltay b a b
Institute of Psychology, Leiden University, Leiden, The Netherlands Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
a r t i c l e
i n f o
Article history: Received 20 April 2012 Received in revised form 9 November 2012 Accepted 13 November 2012 Keywords: Coeliac disease Depression Diet adherence Gluten-free diet Psychopathology
a b s t r a c t Objectives: We aimed to investigate whether long-term adherence to a gluten-free diet is related to depressive symptoms in coeliac disease (CD) patients. Methods: A cross-sectional survey was performed in 2265 adult CD patients recruited through the Dutch Coeliac Association. Self-reported diet adherence was compared among groups based on self-reported depressive symptoms (categorized into current [1-month], remitted, and never). Results: The life-time prevalence rate of self-reported depressive symptoms was 39.0% (n = 883), of whom 270 (11.9%) suffered from current depressive symptoms. Adherence to gluten-free diet was strict in 50.2% of patients, sufficient in 46.3%, and insufficient in 3.6%. Insufficient adherence was not associated with current depressive symptoms (odds ratio [OR] 0.95; 95% confidence interval [CI]: 0.48–1.92). Keeping a gluten-free diet for longer than five years was associated with lower OR of current depressive symptoms compared to being on a diet for less than two years (OR 0.69; 95% CI: 0.50–0.95). Conclusions: Lifetime depressive symptoms may be present in one third of the CD patients who adhere to gluten-free diet. Long-term adherence to the gluten-free diet may reduce the risk of current depressive symptoms. © 2012 Elsevier Inc. All rights reserved.
Introduction Coeliac disease (CD) is an immune-mediated intolerance for gluten in genetically predisposed individuals and is characterized by an inappropriate immune response of the T-lymphocytes of the small intestines to gluten peptides. This results in intestinal malabsorption, atrophy of the intestinal villi and chronic inflammation of the jejunal mucosa of the small intestine. The clinical presentation varies widely, as CD is now considered a multisystem disorder affecting multiple organs, such as the skin, thyroid, heart, nervous system, pancreas, spleen, liver [1], as well as the brain. CD has a prevalence rate in Europe and the USA of about 1:100 [2] and is associated with an increased prevalence of psychopathology [3,4]. The only available treatment is a strict gluten-free diet (GFD), which leads to restoration of the atrophied intestinal villi. It may, however, take years to achieve complete recovery of the intestinal villi [5], and the effects of the diet on mood and psychiatric symptoms are largely unknown. Common psychiatric symptoms in untreated CD are depressive symptoms, apathy, anxiety, and irritability [6–9]. A cross-sectional, case–control study in 36 CD patients and 144 controls used the Composite International Diagnostic Interview (CIDI) to assess lifetime psychopathology [7]. They found that the risks of major depression (MD; 41.7%), dysthymic disorder (8.3%), adjustment disorders ⁎ Corresponding author at: Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands. Tel.: +31 71 527 6751; fax: +31 71 527 3932. E-mail address: [email protected] (N.J.M. van Hees). 0022-3999/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpsychores.2012.11.007
(30.5%), and panic disorder (13.9%) were increased in CD. Increased rates of depressive and anxiety symptoms were also found in CD patients on a GFD [4,10,11]. The reported prevalence of depressive symptoms in CD patients varies widely across studies, ranging from 6 to 69% [8,12–17]. Differences in patient characteristics, cultural background, and study design may account for the large variability [3,18,19]. In a large longitudinal population-based cohort study, CD patients were at an 80% increased risk of depression compared to controls [19]. Only one case–control study found equal prevalence rates of depression (17.2% versus 16%) [20]. However, diagnoses for depression in this study were solely based on notes from primary care providers or gastroenterologists and reliability may be questioned. The increased risk of depressive symptoms in CD patients could be explained by several mechanisms. Firstly, dietary non-compliance and sustained malabsorption may play a role [18], which could lead to sustained nutritional deficiencies (e.g. of vitamin B6, vitamin B12, and folic acid) which in turn may have increased the risk of depression [21]. Secondly, nutritional deficiencies may be a consequence of the strict restrictive GFD. Many of the gluten-free grains do not inherently contain thiamin, riboflavin, niacin, folate, and iron, nor are gluten-free food products in general required to be enriched with these micronutrients by food authorities [22–24]. Whether nutritional deficiencies caused by the daily diet in general contribute to the risk of depression is unknown at this time. There might also be reductions in brain monoamine availability and metabolism [27] and regional cerebral hypoperfusion [28] in patients with CD that may subsequently have induced depression. Thirdly, psychosocial
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mechanisms may be involved. Due to the strict dietary regimen CD patients may avoid social situations which involve eating and also may experience more psychological distress due to daily hassles, negative responses to the diet by their social surroundings, and continued worrying about dietary mistakes and negative health outcomes [25–28]. Distress, social isolation and loneliness may subsequently lead to depression [29]. Fourthly, depression in CD may be secondary to an association between CD and other auto-immune diseases that carry a high risk of depression, such as thyroid disease and diabetes mellitus [7,20]. It is often assumed that dietary non-compliance increases the risk of depressive symptoms. It is common practice to refer CD patients to a dietician for a diet review. The literature on the relationship between adherence to gluten-free diet and depression however is inconclusive and long term dietary compliance in relation to depression has not been studied in depth. Two case series found that psychiatric disturbances and depressive symptoms improved rapidly after the introduction of a gluten-free diet [30,31], but several other studies found no improvement [7,25,32]. One study even reported more depressive symptoms for GFD-treated versus untreated CD patients [33]. In addition, one study found a small significant correlation between non-compliance and depressive symptoms [34], one study found diet adherence not to be a predictor of depressive symptoms [35], and one study found that strict diet adherence was related to an increase in depressive symptoms independent from duration of diet [12]. Most studies included recently diagnosed CD patients and did not study patients who were on a diet for more than one year, while the restoration of the absorption function may take two [36] to five years [5]. In the present study, we investigated the association of duration and stringency of the GFD with the prevalence of depressive symptoms. We performed a cross-sectional survey on a representative sample, comparing groups of adult CD patients who report never having had depressive symptoms, who are remitted from depressive symptoms or who currently experience depressive symptoms. We hypothesized that CD patients who adhere badly to the GFD have an increased risk of currently having depressive symptoms compared to CD patients who strictly adhere to the GFD. We also expected that increased length of the GFD is associated with a lower risk of depressive symptoms. Methods Patients Participants were recruited from the 7119 adult members of the Dutch Coeliac Association (NCV). The NCV comprises CD patients with varying treatment history and severity of illness. According to self-report, 87% of this population had the diagnosis of coeliac disease confirmed by a biopsy of the intestinal lining. In 7% the diagnosis was made by other means and 5% was on GFD for other medical reasons [37]. Instruments Adherence to gluten-free diet Diet adherence of the GFD was assessed by one self-report reply to the question: “I keep my diet: very stringent/simply right/moderately well/not well”. Similar questions and methodology have been used in other studies [8,28,35,38–41]. Self-reported depressive symptoms Self-reported current and past depressive symptoms were assessed with the Major Depression Questionnaire (MDQ) [42], an 18 item self-reported questionnaire which assesses the diagnostic criteria for MD according to the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV-TR) [43] criteria for MD. A previous validation study in a small sample (n = 39) showed excellent sensitivity (100%) and negative predictive value (100%), good positive predictive value (79%), specificity (75%) and overall kappa (0.75), compared with interview-based diagnoses [44]. The MDQ consists of a series of questions that cover all DSM-IV diagnostic criteria for current and past major depression [43], including impact on functioning and exclusion criteria (e.g., mourning). The scoring criteria and the cut-off for caseness versus noncaseness also follow DSM-IV, in other words no case of depression is assumed when both core symptoms of depression are absent or self-reported impact on functioning is low. This leads to self-reported depressive symptoms which can be categorized as MDQ cases and MDQ noncases. MDQ caseness can be further subdivided in never, remitted and current cases. The items that make up a positive caseness score in the MDQ include an item on changes in quality of sleep and an item on changes in body weight. As these symptoms may overlap with those of CD, we made an attempt to exclude the most profound physical consequences of CD through additional instructions and item-wording. Although participants were instructed to disregard the cause of physical symptoms and just report whether the symptom was present or not, they were asked to only report weight change achieved without intent and caused by increased or decreased appetite and only to report sleep disturbance leading to at least a 2 hour change from usual for most of the time during a 2 week period. Symptoms of anxiety and depression The Hospital Anxiety and Depression Scale (HADS) [45] is a 14 item self-reported questionnaire for the assessment of symptoms of anxiety and depression with good case-finding ability. Cronbach's alpha is .83 for the HADS anxiety scale (HADS-A) and .82 for the HADS depression scale (HADS-D). The optimal cut-off score is 8 and the concurrent validity of the HADS was found to be good to very high [46]. The Dutch version has good internal consistency in medical outpatients (HADS total score, α = .90). The sensitivity and specificity to detect MD with a cut-off point of 8 on the depression subscale are 56% and 82%, respectively [47]. The HADS is designed to screen non-psychiatric hospital outpatients for possible anxiety or depressive disorder and items referring to eating and sleep disturbances are not included in the scale making it a fitting tool for populations with somatic illness such as CD. It has been suggested in a recent review that the results of the HADS should be interpreted as a unidimensional measure of “emotional distress” [48] and therefore we reported both the HADS subscale scores as well as total scores. Vulnerability to depression Cognitive vulnerability to depression was measured with the short (6-item) version of the self-report Leiden Index of Depression Sensitivity (Leids-R-SF), derived from the 34 item Leids-R [49]. The Leids-R consists of questions like “When I am feeling down, I more often think about how I am unable to make anyone happy” and “I can only think positive when I feel well” followed by a five point Likert scale. The Leids-R-SF in our sample had good internal consistency (α = 0.87). Procedure The questionnaires were bundled in a questionnaire-booklet, which was sent out as unsolicited mail accompanying a 2007 issue of the NCV quarterly magazine. The questionnaires were also handed out during five NCV events, were made available online, and were announced on various Dutch CD websites, forums and mailing lists. Articles about the questionnaire and the study were published in four issues of the quarterly magazine and these articles were also made available through the online questionnaire website. This study was approved by the ethics committee of the institute of psychology of
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Leiden University. All patients gave written informed consent to participate in the study when returning the completed questionnaire. Statistical analysis Records were excluded on the basis of one or more missing values on the main variables of interest. Data imputation was not performed in any of the measures except the HADS. Data imputation with case means per subscale was performed for records with 3 or less missing values per subscale (n = 74, 3.1%). Records with more than 3 missing values per subscale were excluded (n = 14, 0.6%). Patients were categorized into the three groups (i.e., absent, remitted or current depressive symptoms) based on MDQ scores. Differences between these study groups were analyzed for socio-demographic characteristics, comorbid disorders, other depression assessment variables, characteristics of depressive symptom episodes and dietary habits by analysis of variance (ANOVA) or Pearson chi-squared (χ2) tests for categorical variables. Hochberg's GT2 and Games–Howell post-hoc tests were used, when appropriate. Kruskal–Wallis test (H) was used to assess length of depressive symptom episode and length of diet per depression category. Jonckheere–Terpstra and Mann–Whitney post-hoc tests were used, when appropriate. Associations between GFD characteristics and current depressive symptoms were analyzed using multivariate logistic regression analysis, which yielded odds ratios (OR) with 95% confidence intervals (CI). Multivariate analyses were adjusted for potential confounding by age, gender, and level of education (in Model 1) and additionally for number of other chronic diseases (in Model 2). Statistical significance was inferred at p b .05. All analyses were done with SPSS software (SPSS Inc., Chicago, IL) [50]. Results Participant flow In total we received 2407 valid responses (response rate of 33.8%). 1793 participants returned the paper questionnaire and 614 completed it online. During a brief interview on the reasons for dropout among 30 subjects, a lack of time was most frequently reported. A small minority indicated never having had depressive symptoms and therefore thought themselves unsuitable, and others anticipated that participation
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would be too depressing. Records with missing data on the variables age (n = 8), level of education (n=8), gender (n=14), status of GFD (n=2), length of GFD (n=50), total MDQ (n=50), total HADS (n=14), and dietary adherence (n=51) were excluded from analysis. Records of CD patients who were not on a GFD and had not been on a GFD in the past (patient is in the process of receiving a diagnosis), were also excluded (n=32). The total number of excluded records was 142 (5.9%). The total sample therefore consisted of 2265 (94.1%) CD patients. However, some of these participants had missing data on the variables describing psychiatric characteristics. The sample size was therefore smaller for analyses involving description of: vulnerability to depression (n = 2081); age at first depressive symptom onset (n = 2173); number of lifetime depressive symptom episodes (n = 2135); and length of the most severe episode (n = 1980). Patient characteristics Patients were on average 52 years old (range 18–93 years), 75.5% was female, and they had above average educational attainment (Table 1). Comorbid disorders were reported by 882 patients (38.9%), most often mentioned were chronic pulmonary disease (n = 168), osteoporosis (n = 123), hypothyroidism (n = 116) and cardiovascular disease (n = 110). Table 1 shows the results for 11 comorbid disorders in relation to depression categories (never, remitted and current). Comorbid chronic pulmonary disease and hypothyroidism were significantly associated with depressive symptom categories (p b .001 and p = .008, respectively). The results for inflammatory bowel disease (Chron's disease, colitis ulcerosa, collagenous-, lymphocytic-, microcytic colitis) should be interpreted with some caution since the expected cell count was below five for the currently depressed category (n = 30, p = .66). Table 1 also shows that there was an overall effect of number of comorbid diseases on depressive symptoms (χ2 (4) = 30.4; p b .001). Having one comorbid disorder raised the OR of having current depressive symptoms compared to having no comorbid disorder (1.43, 95% CI: 1.06–1.93). Having more than one comorbid disorder in addition to CD doubled the OR of having current depressive symptoms (2.15; 95% CI: 1.54–3.01). Characteristics of depressive symptoms The life-time prevalence rate of depressive symptoms (i.e., current plus remitted) was 39.0% (n = 883), of whom 270 (11.9%) suffered from current depressive symptoms. Table 1 shows demographic and medical characteristics of CD patients according to the three depressive symptom categories. The mean age differed among the three groups (F (2, 2265)=56.7; pb .001). Post-hoc tests revealed that the group who never experienced depressive symptoms was significantly older than the groups with current and remitted depressive symptoms. The gender distribution also differed among groups (χ2 (2) = 63.8; p b .001), driven by the higher OR of female versus male CD patients in the remitted or current groups (2.37; 95% CI: 1.91–2.94). The level of education also significantly differed among the groups (χ2 (4) = 42.6; p b .001), driven by the higher OR for high versus low-educated CD patients in the remitted or current groups (3.26; 95% CI: 2.64–4.04).
Table 1 Socio-demographic and medical characteristics of the study patients with coeliac disease according to categories of depressive symptoms
Number of patients—n (%) Age (years)—mean (SD) Gender: n (%) • Male • Female Level of education: n (%) • Low • Intermediate • High Comorbidity (% total n):b n (%) • Cardiovascular disease • Diabetes mellitus • Chronic pulmonary disease • Rheumatoid disease • Arthrosis • Hypothyroidism • Other thyroid diseases • Osteoporosis • Cancer • IBD Number of comorbid disorders:b n (%) • No comorbidity • 1 comorbid disorder • ≥2 comorbid disorders
Total
Never
Remitted
Current
p-Value
2265 51.8 ± 16.1
1382 54.6 ± 16.1
613 47.7 ± 15.0
270 46.6 ± 15.3
b.001
556 (24.5%) 1709 (75.5%)
419 (30.3%) 963 (69.7%)
94 (15.3%) 519 (84.7%)
43 (15.9%) 227 (84.1%)
b.001
627 (27.7%) 691 (30.5%) 947 (41.8%)
432 (31.3%) 386 (27.9%) 564 (40.8%)
116 (18.9%) 204 (33.3%) 293 (47.8%)
79 (29.3%) 101 (37.4%) 90 (33.3%)
b.001
110 (4.9%) 81 (3.6%) 168 (7.4%) 59 (2.6%) 44 (1.9%) 116 (5.1%) 46 (2%) 123 (5.4%) 42 (1.9%) 30 (1.3%)
66 (4.8%) 51 (3.7%) 91 (6.6%) 34 (2.5%) 19 (1.4%) 55 (4%) 34 (2.5%) 72 (5.2%) 23 (1.7%) 19 (1.4%)
24 (3.9%) 18 (2.9%) 41 (6.7%) 17 (2.8%) 17 (2.8%) 43 (7%) 6 (1%) 35 (5.7%) 14 (2.3%) 9 (1.5%)
20 (7.4%) 12 (4.4%) 36 (13.3%) 8 (3%) 8 (3%) 18 (6.7%) 6 (2.2%) 16 (5.9%) 5 (1.9%) 2 (0.7%)
.08 .50 b.001 .85 .49 .008 .09 .84 .64 .66
1383 (61.1%) 575 (25.4%) 307 (13.6%)
888 (64.3%) 341 (24.7%) 153 (11.1%)
360 (58.7%) 157 (25.6%) 96 (15.7%)
135 (50%) 77 (28.5%) 58 (21.5%)
b.001
Data are presented as n (%) or mean (± SD), when appropriate. IBD denotes Inflammatory Bowel Disease. a p-Values by chi-squared test for categorical variables and by ANOVA for continuous variables. b Comorbidity is self-reported and defined as being diagnosed by a physician.
a
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Table 2 Psychiatric characteristics of the study patients with coeliac disease according to categories of depressive symptoms
Number of patients HADS—mean ± SD • HADS Depression • HADS Anxiety • HADS Total Cognitive vulnerability—mean ± SD First onset of depressive symptomsb—n • Before introduction of GFD • During the first 2 years on GFD • During the 2nd to 5th year on GFD • After more than 5 years on GFD Number of lifetime episodes—Mdn (Q1–Q3) Length of most severe episode (years)—Mdn (Q1–Q3)
Total
Never
Remitted
Current
2265
1382
613
270
4.5 ± 3.9 6.1 ± 4.0 10.6 ± 7.3 8.4 ± 5.6 791 590 (74.6%) 10 (1.3%) 39 (4.9%) 152 (19.2%) 3.0 (1.0–10.0) 1.0 (0.5–3.0)
3.3 ± 3.2 4.7 ± 3.4 8.0 ± 6.0 6.3 ± 5.0
5.2 ± 3.9 7.3 ± 3.7 12.5 ± 6.9 10.2 ± 4.7 527 424 (74.1%) 7 (1.2%) 30 (5.2%) 111 (19.4%) 2.0 (1.0–5.8) 1.0 (0.4–2.5)
9.2 ± 3.4 10.6 ± 3.3 19.8 ± 5.8 14.2 ± 4.6 219 166 (75.8%) 3 (1.4%) 9 (4.1%) 41 (18.7%) 8.0 (3.5–20.0) 2.0 (0.5–5.4)
– – – –
p-Value
a
b0.001 b0.001 b0.001 b0.001 0.89
b0.001 b.03
Data are presented as n (%), mean (± SD) and median (Q1–Q3) when appropriate. HADS denotes the Hospital Anxiety and Depression Questionnaire; GFD, gluten-free diet. a p-Values based on chi-square test for categorical variables, F-test for continuous variables and Kruskall–Wallis H for non-parametric continuous variables. b First onset of depressive symptoms was calculated in a smaller sample (n = 2173) due to missing data.
As expected, there was a significant overall difference in the mean HADS-Depression (F (2, 667)=366.2; pb .001), HADS-Anxiety (F (2, 687)=398.6, pb .001), and HADS-Total (F (2, 688)=496.2, pb .001) symptom scores among the three depressive symptom groups. Post-hoc tests showed that the mean HADS-D, HADS-A, and HADS-Total scores differed significantly in one-by-one comparisons (all psb .001). The biserial correlation coefficient between HADS-D scores and the category of current depressive symptoms defined by MDQ results showed a strong and significant correlation (rb =0.71, pb .001). There was a significant overall difference in the mean LEIDS-R-SF scores (H(2) = 357.0, p b .001), and all one-by-one comparisons were significant (all ps b .001). Of the 883 CD patients with lifetime depressive symptoms, 74.6% had the onset of their first depressive symptoms before introduction of the GFD (Table 2). Patients with current depressive symptoms reported more lifetime episodes of depressive symptoms than patients with remitted depressive symptoms (H(1) = 97.0; p b .001), and they also reported longer episodes (H(1) = 4.94; p b .03). Dietary adherence to the GFD On average, patients were maintaining a GFD for an uninterrupted period of 8.2 years, ranging between one week and sixty years (Table 3). Length of current GFD differed significantly among the three groups (H(2) = 31.80; p b .001). The Mann–Whitney test showed that duration of the GFD differed significantly between the never and remitted depressive symptom groups (p b .001), as well as between the remitted and current depressive symptom groups (p = .019), with the shortest duration of the GFD for the current depressive symptom group. The dietary adherence categories “moderately well” and “not well” were collapsed for the purpose of analyses, because of small numbers. There was no significant overall difference in categories of self-reported dietary adherence among the never, remitted and current groups (χ2 (4) = 1.185; p = .89). Associations between GFD characteristics and depressive symptoms The associations between GFD characteristics and depressive symptoms are presented in Table 4. The duration of the GFD related to the three depressive symptom categories. Although a duration of the GFD of 2 up to 5 years was not significantly associated with a reduced risk of current depressive symptoms, it was decreased in those CD patients being on a GFD longer than 5 years versus shorter than 2 years
(adjusted OR: 0.69, 95% CI: 0.50–0.95; Wald χ2(1) = 5.28, p = .02). The adherence to the GFD was not associated with current depressive symptoms in the fully adjusted model 2 (Wald χ2(1) = 0.01, p= .92).
Discussion In our group of 2265 adult CD patients, a lifetime prevalence of depressive symptom cases of 39% was found, based on MDQ questionnaire scores. This is in line with previous findings of high rates of MD [7] and depressive symptoms [8,25]. Long-term adherence to the gluten-free diet (over 5 years) was associated with a reduced risk of current depressive symptoms, which is in line with findings from an Italian study [27]. We found no association of self-reported diet stringency and depressive symptoms in our population, which is also in line with results found in Italy and Germany [8,35].
Why is the prevalence of depressive symptoms increased in CD? The one-month and lifetime prevalences of depressive symptom cases based on MDQ questionnaire scores observed in our study (i.e., 11.8% and 39.0%, respectively) appear to be higher than the rates of MD in the general Dutch population (2.7% and 15.4%, respectively) [51]. CD patients with current depressive symptoms also reported increased anxiety symptoms. This may be due to the well-established relationship between anxiety and mood disorders and the overlap between anxiety and depressive symptoms, or may signal an independent association between anxiety disorders and CD [4,7,10,25,35]. Cognitive vulnerability to depression scores were also increased in CD patients with remitted and current depressive symptoms [49].
Table 3 Dietary habits of the study patients according to categories of depressive symptoms
Number of patients Length of gluten-free diet—Mdn (Q1–Q3) Length of present diet • 0 to 2 years • 2 to 5 years • 5 years and longer Dietary adherence by self-report: “I keep my diet:” • Very stringent diet • Sufficient diet • Moderately well/not well
Total
Never
Remitted
Current
p-Value
2265 5.8 (2.3–12.0)
1382 6.4 (2.8–12.9)
613 5.0 (2.0–11.3)
270 4.0 (1.5–10.0)
b.001
466 (20.6%) 535 (23.6%) 1264 (55.8%)
248 (17.9%) 307 (22.2%) 827 (59.8%)
144 (23.5%) 154 (25.1%) 315 (51.4%)
74 (27.4%) 74 (27.4%) 122 (45.2%)
b.001
1136 (50.2%) 1048 (46.3%) 81 (3.6%)
687 (49.7%) 647 (46.8%) 48 (3.5%)
306 (49.9%) 284 (46.3%) 23 (3.8%)
143 (53.0%) 117 (43.3%) 10 (3.7%)
.89
Data are presented as n (%) or median (Q1–Q3), when appropriate. a p-Values based on chi-square test for categorical variables and Kruskall–Wallis H for non-parametric continuous variables.
a
N.J.M. van Hees et al. / Journal of Psychosomatic Research 74 (2013) 155–160 Table 4 Associations between the characteristics of the gluten-free diet and depressive symptoms Length of gluten-free diet
Total number of patients No. with current symptoms—n (%) - Crude association - Model 1a - Model 2b
b2 years
2–5 years
≥5 years
466 74 (15.9%)
535 74 (13.8%)
1264 122 (9.7%)
1.0 (ref) 1.0 (ref) 1.0 (ref)
0.85 (0.60–1.21) 0.93 (0.65–1.32) 0.94 (0.66–1.34)
0.56 (0.42–0.77)c 0.68 (0.49–0.93)c 0.69 (0.50–0.95)c
Dietary adherence by self-report
Total number of patients No. with current symptoms—n (%) - Crude association - Model 1a - Model 2b
Very stringent diet
Sufficient diet
Insufficient or no real diet
1136 143 (12.6%)
1048 117 (11.2%)
81 10 (12.3%)
1.0 (ref) 1.0 (ref) 1.0 (ref)
0.87 (0.67–1.13) 0.84 (0.65–1.10) 0.89 (0.68–1.16)
0.98 (0.49–1.94) 0.94 (0.47–1.89) 0.95 (0.48–1.92)
Odds ratios are presented (with 95% confidence intervals). a Adjusted for age, gender, and level of education. b Additionally adjusted for number of comorbid chronic diseases. c p b 0.05.
One of the hypotheses under study was that insufficient adherence to the GFD increases the risk of depressive symptoms in CD patients [8,19]. This was not supported by our data. However, only 3.8% of our patients kept an insufficient diet, which limited the power to detect any effects of insufficient dietary adherence. The high prevalence of depressive symptoms may also be explained by a general burden of suffering from a chronic disease [17,26,28,35,52]. Finally, depression and CD may share underlying biological causal factors, similar to the link between depression and cardiovascular diseases that may be explained by underlying atherosclerotic and inflammatory processes [53]. We also tested the hypothesis that a longer duration of the GFD is linked to a lower risk of depressive symptoms. This was supported by our findings, but only after more than five years of keeping a GFD. This may be a consequence of restoration of the intestinal lining [5] and a subsequent general improvement in health, which may take several years [54,55]. Continuing malabsorption problems, which take longer to dissipate than previously assumed, may induce depressive symptoms. Strengths and limitations of this study By using the survey methodology we were able to investigate a large sample of patients with CD representative of the NCV membership [37]. The response rate was a satisfactory 34% [37]. The sample was largely representative of the entire CD population, which in most studies was found to be skewed towards women and people with higher education [27,56]. Only 3.8% of our patients reported keeping an insufficient diet. Nevertheless, it is possible that poor adherence to the GFD was underreported as participants may tend to give socially desirable answers. Although assessment of GFD adherence by a specialized dietician is the most reliable instrument [40], self-report ratings of dietary adherence have been used in a range of studies in adults and children with CD. A French study found higher rates of non-compliance and dietary mistakes (28%) using an estimated intake of 18 g gluten in 2 months as a cut-off. Direct enquiries by experts uncovered more frequent occasional lapses of gluten intake [57]. In a study in which participants were interviewed by an expert, 7% transgressed at least once a week [27]. Another study using a four-point scale on a self-report survey showed that 8% of participants adhered to the GFD rarely to sometimes
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[27,28]. Comparisons among studies are difficult, however, because of differences in cut-off points for compliance, and more agreement and guidelines on this matter are needed. Our study was limited by the cross-sectional design. A potential source of bias is the reliance on self-report questionnaires. We used self-report questionnaires for CD diagnoses and for psychiatric diagnoses, rather than medical file analysis or structured interviews. Although attempts have been made to exclude the most profound physical symptoms of CD that overlap with depressive symptoms, a self-report survey is not a suitable instrument for accurately differentiating between these symptoms. In addition, the MDQ should be validated more extensively. The HADS on the other hand has been extensively validated, although some debate has recently arisen on its subscales [58]. We focused in our survey on depressive symptoms as these were found to be prevalent in CD [8,25], the risk of other forms of psychopathology may also be increased [7]. Clinical implications and future research Depressive symptom rates were found to be high in CD patients. Depressed CD patients may benefit from available treatments for depression in addition to the GFD. In turn, improving depressive symptoms in CD patients may improve these patients' adherence to the GFD [59] as depression is a risk factor for non-adherence to medical advice and subsequent poor outcomes [60,61]. Future prospective studies and trials are needed to confirm the beneficial effects of long-term adherence to the gluten-free diet on depressive symptoms and MD. Prospective studies—with prolonged follow-up spanning at least five years—may help to unravel the time sequence between changes in the GFD habits and the onset and remission of depressive symptoms and MD. Acknowledgments This project was funded by a grant from the Netherlands Science Foundation (N.W.O-MaGW Vici) grant # 453-06-005 to WVdD, and grants from the Leiden University Fund (LUF) and Gratama Foundation. The research was conducted independently of the funding agencies. Appendix A. Supplementary data Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.jpsychores.2012.11.007. References [1] Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006;131(6):1981-2002. [2] Tommasini A, Not T, Kiren V, Baldas V, Santon D, Trevisiol C, et al. Mass screening for coeliac disease using antihuman transglutaminase antibody assay. Arch Dis Child 2004;89(6):512-5. [3] Addolorato G, Leggio L, D'Angelo C, Mirijello A, Ferrulli A, Cardone S, et al. Affective and psychiatric disorders in celiac disease. Dig Dis 2008;26(2):140-8. [4] Addolorato G, Mirijello A, D'Angelo C, Leggio L, Ferrulli A, Abenavoli L, et al. State and trait anxiety and depression in patients affected by gastrointestinal diseases: psychometric evaluation of 1641 patients referred to an internal medicine outpatient setting. Int J Clin Pract 2008;62(7):1063-9. [5] Rubio-Tapia A, Rahim M, See J, Lahr B, Wu T-T, Murray J. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol 2010;105(6):1412-20. [6] Addolorato G, Stefanini G F, Capristo E, Caputo F, Gasbarrini A, Gasbarrini G. Anxiety and depression in adult untreated celiac subjects and in patients affected by inflammatory bowel disease: a personality “trait” or a reactive illness? Hepatogastroenterology 1996,Nov–Dec;43(12):1513-7. [7] Carta MG, Hardoy MC, Boi MF, Mariotti S, Carpiniello B, Usai P. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res 2002 Sep;53(3):789-93. [8] Ciacci C, Iavarone A, Mazzacca G, De Rosa A. Depressive symptoms in adult coeliac disease. Scand J Gastroenterol 1998 Mar;33(3):247-50. [9] Hernanz A, Polanco I. Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. Gut 1991 Dec;32(12):1478-81.
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