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Psychosomatics 45:325-335, August 2004
© 2004 The Academy of Psychosomatic Medicine

Mental Disorders in Adolescents With Celiac Disease

Päivi A. Pynnönen, M.D., Erkki T. Isometsä, M.D., Ph.D., Eeva T. Aronen, M.D., Ph.D., Matti A. Verkasalo, M.D., Ph.D., Erkki Savilahti, M.D., Ph.D., and Veikko A. Aalberg, M.D., Ph.D.

Received Aug. 10, 2003; revision received Feb. 15, 2004; accepted March 10, 2004. From the Hospital for Children and Adolescents, Helsinki University Central Hospital; and the Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland. Address reprint requests to Dr. Pynnönen, Department of Adolescent Psychiatry, Hospital for Children and Adolescents, Helsinki University Central Hospital, P.O. Box 282, 00029 HUCH, Finland; paivi.pynnonen{at}hus.fi (e-mail).


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects. Relative to the comparison subjects, the celiac disease patients had significantly higher lifetime prevalences of major depressive disorder (31% versus 7%) and disruptive behavior disorders (28% versus 3%). In most cases these disorders preceded the diagnosis of celiac disease and its treatment with a gluten-free diet. The prevalence of current mental disorders was similar in both groups. Celiac disease in adolescents is associated with an increased prevalence of depressive and disruptive behavioral disorders, particularly in the phase before diet treatment.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have suggested a high prevalence of depressive symptoms and depressive disorders among adults with celiac disease1–5 and a high prevalence of vaguely defined "emotional symptoms" among children and adolescents with celiac disease.6 Celiac disease is an underdiagnosed inflammatory disease of the upper small intestine that results from gluten ingestion in genetically susceptible individuals. Inflammation causes atrophy of the villous structure of the jejunum and may lead to malabsorption of several important nutrients.7 Diagnosis is based on villous atrophy confirmed by small-bowel biopsy, and permanent withdrawal of gluten from the diet is the current essential treatment. Hereditary factors alone do not explain the development of celiac disease, although 90% of celiac disease patients have the HLA DR3-DQ2 haplotype. Immunological factors, infectious agents, and hormonal status may also be involved.7–9

In a recent screening study, the prevalence of biopsy-proved celiac disease among Finnish schoolchildren (N=3,654) was estimated to be at least one case among 99 children.9 In another screening study, the ratio of known to undiagnosed cases of celiac disease was found to be 1:7.10 For unknown reasons, the clinical presentations of the disease appear to have changed over recent decades: minor symptoms such as dyspepsia, anemia, slight weight loss, failure to thrive, and fatigue have been found to be increasingly common. The disease may even be clinically silent, despite manifest small-bowel lesions.7–9 Undetected or neglected, celiac disease may cause considerable later complications.7,8,11

Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy.8,12 According to Hadjivassilou et al.,12 ataxia may be the sole manifestation of celiac disease in some individuals with genetic susceptibility to the disease and with serological evidence of gluten sensitivity. In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%)2–4 and depressive disorders (42%)5 has been reported in adult celiac disease patients, compared to medical and normal comparison subjects. A prior history of psychiatric treatment was described in nine of 42 (21%) adult patients with celiac disease, compared to 5% of a medical comparison group, and six of the 42 (14%) celiac disease patients had been granted a disability pension because of psychiatric disorders.1 Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet.13

The mechanisms involved in the origin and pathogenesis of mental and behavioral disorders related to celiac disease are unknown. Previous studies suggested the possibility of impaired availability of tryptophan and disturbances in central serotonergic function.14,15 Low plasma tryptophan levels and a low ratio of tryptophan to other large neutral amino acids were reported in four of 11 adult celiac disease patients,14 and significantly lower plasma tryptophan concentrations and ratios were reported in untreated and treated children with celiac disease, relative to comparison subjects without celiac disease.15 The plasma tryptophan ratio was lowest in untreated children with symptoms of behavioral disturbances, and mood and mental activity improved in some of these patients after they started a gluten-free diet. Hallert and Sedvall16 found a significant increase (mean=33%) in the concentration of major monoamine metabolites (5-hydroxyindole acetic acid, homovanillic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol) and an insignificant 10% increase in tryptophan concentration in CSF in seven adult celiac disease patients after 1 year of maintaining a gluten-free diet. More recently, subclinical thyroid disease was found to represent a significant risk factor for major depressive disorder and panic disorder in patients with celiac disease.5 However, to our knowledge, these findings have not been replicated.

It has been suggested that emotional symptoms are common among children with celiac disease,6 and numerous adult celiac disease patients with psychiatric symptoms have histories that suggest undetected celiac disease in childhood.1,5,13,17 However, few studies have focused on psychiatric symptoms in children and adolescents with celiac disease. Ljungman and Myrdal18 reported that adolescents with a diagnosis of celiac disease before 2 years of age were otherwise as healthy as matched comparison subjects, with the exception of being significantly more likely to have a sleep disorder and to have difficulty relaxing. Hernanz and Polanco15 reported more behavioral disorders and depressive symptoms in children with untreated celiac disease, compared to children with treated celiac disease and to healthy comparison subjects. In a large Italian screening study (N=17,201 patients age 6–16 years), most of the detected celiac disease cases showed illness of low-grade intensity that was often associated with poorly defined "decreased psychophysical well-being."10 However, none of these studies involving children and adolescents applied current diagnostic criteria or used structured psychiatric interviews. Therefore, the validity of the diagnoses and the prevalence of mental disorders in the patients with celiac disease, as well as the effects of a gluten-free diet on psychiatric symptoms, remain uncertain.

In the present study the prevalence of current and lifetime mental disorders in adolescents with celiac disease confirmed by small-bowel biopsy and a comparison group without celiac disease was studied by using semistructured psychiatric interviews.


  METHOD

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Study Design
The study was performed in the Hospital for Children and Adolescents of Helsinki University Central Hospital in Helsinki, Finland. The hospital has a catchment area of about 500,000 inhabitants. Thirty-seven celiac disease patients age 12–17 years were identified from the Department of Gastrointestinal Services' records of small-bowel biopsies for children and adolescents conducted during the years 1982–1999 (N=414). In all cases of celiac disease, the diagnosis was based on villous atrophy demonstrated in a small-bowel biopsy. Four of 37 celiac disease patients were excluded; three male patients were excluded because they had Down's syndrome, and one female patient was excluded because she was not Finnish speaking. Four girls refused to participate; according to a parent, two of those patients had psychiatric symptoms. Of the eligible celiac disease patients, 29 of 33 (88%)—16 girls and 13 boys—participated. The study was approved by the hospital's institutional ethics committee. Written informed consent for each patient was obtained from the patient and a parent.

The comparison patients had serological evidence and clinical symptoms that suggested celiac disease (Table 1), and the suspicion of celiac disease had been strong enough to indicate a diagnostic biopsy. Most of the comparison patients with abdominal complaints had experienced recurrent abdominal pain, loose stools, or other functional gastrointestinal symptoms. Patients with inflammatory bowel disease were excluded. The comparison patients were currently age 12–18 years and were identified by using the same biopsy records that were used to identify the celiac disease patients (from the 414 records for biopsies conducted in 1982–1999). The comparison patients were matched for gender, age at the time of biopsy (+/–6 months in patients younger than age 12 years), and age at the time of psychiatric evaluation in adolescence (+/–1.2 years). All celiac disease patients had between one and three possible comparison subjects who were ordered in priority according to how closely they met the age criteria. After the recruitment process (a letter followed by a phone call), 23 of 29 (79%) comparison patients were the best suited to meet the age criteria, and the remaining six (21%) were the second-best suited. The characteristics of the celiac disease group and the comparison group are shown in Table 1.


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TABLE 1. Characteristics of Adolescent Patients With a Diagnosis of Celiac Disease Confirmed by Small-Bowel Biopsy and Matched Comparison Patients Without Celiac Diseasea



Psychiatric Evaluation
The present and lifetime psychiatric diagnostic evaluation was conducted with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL),19,20 a semistructured diagnostic interview. At assessment, first the adolescent and then a parent were interviewed separately by the first author, who is an experienced adolescent psychiatrist. The final DSM-IV diagnoses were based on the interview and were made as consensus diagnoses by the interviewer and an experienced child psychiatrist (E.A.). Neither of them was blind to the diagnosis of celiac disease. A comorbid diagnosis of disruptive behavior disorder was assigned to patients with unusual irritability and explosive anger (had physically harmed others) who met the DSM-IV criteria for disruptive behavior disorder, although all the patients who met the criteria for the disorder also had a diagnosis of a depressive disorder.

Current psychiatric status and symptoms were assessed by using the Youth Self-Report21 and the Child Behavior Checklist.22 Current depressive symptoms were evaluated with the Beck Depression Inventory23 and the Hamilton Depression Rating Scale,24 and anxiety symptoms were assessed with the Beck Anxiety Inventory25 and the Hamilton Anxiety Rating Scale.26 Data on psychiatric and somatic symptoms and laboratory test results before the small-bowel biopsy (and for celiac disease patients, after starting a gluten-free diet), as well as data on the effects of a gluten-free diet as reported by the patient or by a parent,were gathered from the pediatric case records and as a part of the clinical interview.

Because there is no systematic method for collecting family history data of mental disorders within a K-SADS-PL interview, questions about family history were included in a supplementary interview. Only data on parental mental disorders (a history of functional impairment as evidenced by having taken extended sick leave or having had a psychiatric consultation or treatment) were used in the statistical analyses. The interviewer, who was both an adolescent and adult psychiatrist, classified the parental mental disorders into the four categories of depressive, anxiety, psychotic, or severe alcohol abuse disorders.

Statistical Methods
Statistical analyses were performed by using both matched and unmatched group procedures as appropriate (e.g., repeated-measures and one-way analysis of variance, dependent and independent group t tests, Wilcoxon signed ranks test, Fisher's exact test, and cross-tabulation with the ordinary chi-square test and McNemar test). Reflecting the study design, the results reported in the tables are from matched analyses, although statistically significant results were provided mostly by the unmatched analyses. Binary logistic regression and a linear probability model were used to test the effects of celiac disease and of sociodemographic and clinical characteristics (e.g., divorce of parents, family history of psychiatric disorders or celiac disease, and somatic symptoms before the biopsy) on the occurrence of mental disorders. In these analyses, p values (two-tailed) <0.05 were considered significant.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
The characteristics of the celiac disease group and the comparison group are shown in Table 1. All subjects were Caucasian and of Finnish nationality. Eighty-six percent (25 of 29) of the celiac disease patients and 62% (18 of 29) of the comparison patients were living with two biological parents. Twenty-one percent (six of 29) of the celiac disease patients and 17% (five of 29) of the comparison patients had a history of psychiatric treatment as outpatients, but none had received any psychopharmacological treatment. Type 1 diabetes (known to be associated with celiac disease) had been diagnosed in 12% of all subjects (7% of the celiac disease patients and 17% of the comparison patients). The age at the time of small-bowel biopsy varied from 0.7 to 18.1 years (median=10.3). Current laboratory test results showed that the celiac disease patients were more likely to have positive endomysium antibody titers (10 of 28) than the comparison subjects (three of 29), but a positive transglutaminase antibody titer (≥8 AU) was found for only two of the 28 celiac disease patients for whom the data were available and one of the 29 comparison patients, which indicated that the treatment of celiac disease with diet has succeeded.

Lifetime Mental Disorders
The lifetime prevalence of major depressive disorder was markedly higher in the celiac disease patients (31%) than in the comparison patients (7%) (p<0.05, Fisher's exact test), and the prevalence of double depression (dysthymic disorder superimposed with major depressive disorder episode) was significantly greater in the celiac disease patients (21%) than in the comparison patients (0%) (Table 2). The risk for lifetime major depressive disorder was significantly greater in the celiac disease patients than in the comparison patients (odds ratio=6.06, 95% confidence interval (CI)=1.18–31.23, p<0.04). Of the nine celiac disease patients with major depressive disorder, five had a recurrent episode of the disorder; the mean age at onset of first major depressive disorder episode was 11.8 years (SD=2.3). Three of the nine celiac disease patients with major depressive disorder received the diagnosis of celiac disease before age 1.5 years. Only one of the nine celiac disease patients with major depressive disorder had a first-degree relative with a diagnosis of celiac disease, compared with 10 of all 28 celiac disease patients for whom these data were available.


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TABLE 2. Prevalence of Mental Disorders in Adolescent Patients With a Diagnosis of Celiac Disease Confirmed by Small-Bowel Biopsy and Matched Comparison Patients Without Celiac Diseasea



The risk for lifetime disruptive behavior disorder (identified in eight of celiac disease patients and one of 29 comparison patients) was significantly greater in the celiac disease patients than in the comparison patients (odds ratio=10.67, 95% CI=1.24–92.00, p<0.04). Among the nine celiac disease patients with major depressive disorder, six had comorbid dysthymic disorder (67%) and six had comorbid disruptive behavior disorder (67%) (four [44%] had both comorbid dysthymic disorder and comorbid disruptive behavior disorder). The lifetime prevalence of anxiety disorders was similar in the celiac disease patients (21%) and the comparison subjects (24%). No significant differences between the groups were found in the lifetime prevalence of attention deficit hyperactivity disorder (based on the K-SADS-PL interview) or of dysphasia or learning disorders (based on case records and clinical interview).

Mental Disorders Preceding Diagnostic Small-Bowel Biopsy
The prevalence of any depressive disorder (major depressive disorder, dysthymic disorder, depressive disorder not otherwise specified) before the diagnostic biopsy was significantly higher in the celiac disease group (seven of the 19 patients for whom these data were available, 37%) than in the comparison group (none of 19 patients, 0% (Table 2). The prevalence of major depressive disorder was markedly greater among the celiac disease patients (five of 19 patients, 26%) than among the comparison patients (0%) (p<0.05, Fisher's exact test). Recurrent episodes were diagnosed in two patients with major depressive disorder. All celiac disease patients with major depressive disorder were characterized as withdrawn and lonely, and all had reports of a period of unusual irritability and explosive anger before receiving the celiac disease diagnosis. Two had learning disorders. The age of the patients who had major depressive disorder before the diagnostic biopsy varied from 11.3 to 15.3 years, and at the time of the psychiatric evaluation, the patients had been following a gluten-free diet for 1.0–1.8 years (mean=1.4 years).

Disruptive behavior disorder was diagnosed in five of 19 celiac disease patients before the biopsy, but in none of the comparison patients (p<0.05, Fisher's exact test). Four of the celiac disease patients with disruptive behavior disorder had major depressive disorder, and one had dysthymic disorder. The prevalence of anxiety disorders before the small-bowel biopsy was similar in both groups. No significant differences in suicidal ideation or tendencies were found between the groups, and none of the subjects reported suicide attempts in the K-SADS-PL interview.

Current Mental Disorders and Psychiatric Symptoms
No significant differences were found in the prevalence of current depressive, anxiety, or disruptive behavior disorders between the celiac disease patients and the comparison patients (Table 2). Both the celiac disease patients with current major depressive disorder (two of 29 patients, both of whom had recurrent episodes) had received the diagnosis of celiac disease before age 1.5 years, and the first episode of major depressive disorder had occurred at 8–9 years. After following a gluten-free diet for 1.0–1.8 years none of the five celiac patients with a prebiopsy diagnosis of major depressive disorder or double depression fulfilled the criteria for current major depressive disorder, although one female patient (with double depression diagnosed before the biopsy) had a diagnosis of dysthymic disorder and another had an anxiety disorder.

Reflecting the relatively asymptomatic current state of the adolescents with celiac disease, significant differences did not emerge between the groups in the scores on the Youth Self-Report, the Child Behavior Checklist, the Beck Depression Inventory, the Beck Anxiety Inventory, Hamilton depression scale, or Hamilton anxiety scale. Current Children's Global Assessment Scale scores (obtained as part of the K-SADS-PL interview) were similar in the celiac disease patients and the comparison patients. No significant differences between the groups were found for success or problems at school, current suicidal tendencies, or aggression problems on the basis of responses to the Youth Self-Report, Child Behavior Checklist, and K-SADS-PL. Endomysium and transglutaminase antibody levels had no correlation with scores on any of the scales used in the study.

Effects of Family Factors on the Prevalence of Mental Disorders
Celiac disease and parental history of depressive disorders were the only factors that were significantly associated with the prevalence of prebiopsy or lifetime major depressive disorder. Among the celiac disease patients with lifetime major depressive disorder, a history of parental depressive disorder was reported in four of eight patients (data were missing for one patient) and in none of the celiac disease patients without major depressive disorder (data were missing for one of the 20 patients in this group) (p=0.004, Fisher's exact test). Parental educational level, divorce of parents, poor weight or height gain, and somatic symptoms such as diarrhea, abdominal pain, or anemia preceding the biopsy were not related to mental disorders.

The risk for lifetime major depressive disorder associated with parental depressive disorder (odds ratio=6.80, 95% CI=1.45–31.72, p<0.02) was comparable to the risk for lifetime major depressive disorder associated with celiac disease (odds ratio=6.06, 95% CI=1.18–31.23, p<0.04). In a correlated linear probability model, parental depressive disorders and celiac disease each significantly predicted prebiopsy and lifetime major depressive disorder, as did the interaction of the two factors. Among celiac disease patients, a history of parental depressive disorder was associated with significantly higher risk for prebiopsy major depressive disorder (odds ratio=7.79, 95% CI=1.03–59.3, p<0.05) and for lifetime major depressive disorder (odds ratio=5.71, 95% CI=2.36–14.08, p=0.004) but was not associated with lifetime or current anxiety disorders. However, as parental history of depressive disorders was actually more common in the comparison group, it did not explain the increased risk for depressive disorders in the celiac disease group, relative to the comparison group.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents, relative to matched comparison subjects without celiac disease. In most cases depressive disorders and comorbid disruptive behavior disorder manifested before the small-bowel biopsy used to diagnose celiac disease, and significant differences were not found in the prevalence of current mental disorders in adolescents with celiac disease, relative to the comparison subjects. It seems possible that at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet.

To our knowledge, this report describes the first controlled study that has used a semistructured psychiatric diagnostic interview to examine the relationship between celiac disease and mental disorders in adolescents. To control the effects of gender, age, and somatic symptoms, we carefully matched the comparison group patients with the celiac disease patients, and thus our findings on depressive and behavioral disorders are unlikely to be explained by these factors. Moreover, even if the characteristics of the comparison group patients—for example, a high prevalence of anxiety disorders among patients who formerly had recurrent abdominal pain27—made them different from unselected, healthy adolescents, these characteristics do not explain the increased prevalence of lifetime and prediet depressive and disruptive disorders found in the celiac patients.

The lifetime prevalence of major depressive disorder in the adolescent celiac disease patients (31%) is concordant with a recently reported prevalence of lifetime major depressive disorder in adult celiac disease patients (42%)5 and higher than the corresponding rates from adolescent population studies (15%–20%).28 The rates of current major depressive disorder (7% in the celiac disease group versus 3% in the comparison group) are comparable with the prevalence rates found in general adolescent populations (0.4%–8.3%).28 The relatively asymptomatic current state of the celiac disease patients in the present study was rather unexpected, since depressive symptoms and disorders are common among adult celiac disease patients, even during diet treatment.1–5 Moreover, the adolescents with lifetime double depression (21% of the celiac disease patients in the current study) tended to have more severe and longer depressive episodes and worse social impairment than the adolescents with major depressive disorder or dysthymic disorder alone, and the findings of earlier research suggested that depressed patients with comorbid disruptive behavior disorders (24% of the celiac disease patients in the current study) have a worse short-term outcome and persisting conduct problems after the depression has remitted.28 Thus, even though the patients with prediet major depressive disorder had a relatively short period of treatment with a gluten-free diet, it seems possible that early diagnosis and diet treatment may decrease the vulnerability to depression, as also recently suggested by Carta et al.5

The risk of psychological disorders is substantially higher in children with a chronic disease29 and, for unknown reasons, particularly in patients with inflammatory bowel disease.30 Burke et al.31 reported a higher lifetime prevalence of depression in children with Crohn's disease (29%) and ulcerative colitis (21%), compared to children with cystic fibrosis (11.5%), without significant differences in the lifetime prevalence of anxiety disorders or of current mental disorders. We also did not find significant differences in the prevalence of anxiety disorders or of current mental disorders between the celiac disease patients and the comparison patients. Thus, our findings, like those of Burke et al.,31,32 suggest a specific increase in the prevalence of depressive disorders rather than a generalized increase in psychopathology. Among the patients in our study, depressive disorders preceded the diagnosis of celiac disease and diet treatment, and it is likely that the majority of the patients had had celiac disease for years before they received the diagnosis.9 It seems possible that depressive disorders are more specifically related to the disease process in celiac disease than in inflammatory bowel disease. In children with inflammatory bowel disease the delay in diagnosis is normally relatively short, and—contrary to our findings among patients with celiac disease—depression generally follows the diagnosis of the bowel disease.31,32

According to Ciacci et al.,4 depressive symptoms in treated adult celiac disease patients (N=92) were equally represented in patients who received the diagnosis in childhood and those who received the diagnosis in adulthood, and the presence of these symptoms did not correlate with age at diagnosis or with the duration of or adherence to a gluten-free diet. Depressive symptoms were also not influenced by age, gender, or socioeconomic variables. In our study, gender, parental educational level, divorce of the parents, and prebiopsy physical illness symptoms, such as abdominal pain or diarrhea, were not statistically associated with major depressive disorder. Moreover, psychosocial risk factors, such as death of a parent, divorce, and a parental history of psychiatric disorder, were actually more common in the comparison group. Some previous studies suggested that depression in celiac disease patients may be related to the "burden of illness" associated with dietary restrictions.3 We find this an unlikely explanation of our findings, since, at least in children and adolescents, depressive and behavioral disorders usually preceded the diagnosis of celiac disease and improved after the patients started a gluten-free diet.

In the present study parental depressive disorders were the only factors found to be statistically associated with depressive disorders in the adolescent celiac disease patients. Family history of depression is known to be a significant risk factor for depression in general and among children and adolescents with a chronic illness. This effect has been attributed to the influence of family history of depression on biological-genetic vulnerabilities or on cognitive and social-behavioral vulnerabilities.29 Our findings among adolescents with celiac disease appear to support the findings of Goldberg,2 who reported that celiac disease patients with a family history of psychiatric illness were more likely to become mentally ill in the survey year, compared with other celiac patients. The hypothesis that affective illness in patients with celiac disease could be related to genetic vulnerability to affective disorders is interesting in light of the possibility that untreated celiac disease may lead to impaired availability of tryptophan in the central nervous system.14–16 In tryptophan depletion experiments, clinical depressive states are seen as a consequence of rapid reduction of plasma tryptophan, which is followed by impaired brain serotonin synthesis. In these experiments, greater vulnerability to depressive states during tryptophan depletion in otherwise euthymic subjects has been associated with past depressive episode33 and with a family history of affective illness.34 Among adults, tryptophan depletion has been reported to reduce plasma tryptophan levels by about 80%.35 In a study by Hernanz and Polanco,15 the mean plasma tryptophan levels of children with untreated celiac disease (mean=13 µmol/liter, SD=4) and children with treated celiac disease (mean=31 µmol/liter, SD=13) were 84% and 62% lower, respectively, than that of children without celiac disease (mean=81 µmol/liter, SD=22). The lowest tryptophan levels were found in children with behavioral problems and mood disturbance.

Complete removal of tryptophan from the diet reduces plasma tryptophan by only 15%–20%,35 suggesting that the lower plasma tryptophan concentrations found in children with celiac disease are unlikely to be fully explained in terms of dietary intake or malabsorption. The role of immune activation with T-cell-mediated immune response to dietary gluten and cytokine release is important in the pathogenesis of celiac disease,7–9 and interferon-{gamma} is the predominant cytokine produced by gluten-specific T-cells in active celiac disease.36 It is of theoretical interest that increased interferon-{gamma} production can suppress serotonin function both directly and indirectly, e.g., by enhancing tryptophan as well as serotonin turnover by means of increased activity of the kynurenine-niacin pathway,37 and as much as a 90% reduction of plasma tryptophan levels may be produced by interferon administration.38 Besides its effects on plasma tryptophan levels, cytokine activation is known to enhance hypothalamus-pituitary-adrenal axis hyperactivity, which has been associated with major depressive disorder in adults.39 Behavioral changes encountered in a considerable number of patients treated with interferon (depressed mood, fatigue, irritability, short temper, emotional lability, social withdrawal, lack of concentration, and even full-blown major depressive disorder)40,41 were also common among children and adolescents with untreated celiac disease. Thus, immune activation could play a role in depressive and behavioral disorders in patients with untreated celiac disease and perhaps even in some of the patients who adhere to a gluten-free diet.

The neuroendocrine perturbations identified in adolescents with depressive disorders have generally been consistent with dysregulation of brain serotonin system functioning,42 although only a few studies, e.g., studies of peripheral markers of serotonergic systems in children and adolescents, have examined this possible mechanism.15,43 Among adults, disturbances in the central serotonergic system are associated with vulnerability to depressive and impulse control disorders, aggression dysregulation, and higher risk of suicidal ideation or behavior.43–45 Thus, even if the increased prevalence of depressive and disruptive disorders found in adolescent celiac disease patients appears to be consistent with the hypothesis that untreated celiac disease is associated with disturbances in central serotonergic function, the mechanisms involved remain unclear and need to be studied further.

Limitations
Our aim in this study was to examine the specific effects of celiac disease. To control the influence of developmental phase and symptoms such as abdominal pain, the comparison group consisted of children with abdominal complaints matched for gender and for age at the time of psychiatric evaluation and at the time of the diagnostic biopsy. The design probably provided a rather insensitive test of potential moderate differences between groups. The number of subjects was too small to allow investigation of the developmental effects of untreated celiac disease in different age groups. However, the subject group was highly representative of adolescent patients with celiac disease in the catchment area, because it was based on the group of all patients with a diagnosis of celiac disease included in the catchment area's register, and 88% of the identified eligible patients participated.

Some methodological limitations need to be noted. First, the interviewer was not blind to the presence or absence of celiac disease. Second, the K-SADS-PL is designed to identify present and lifetime diagnoses, and even when it is used alone, it generates reliable and valid psychiatric diagnoses.20 However, in this study, prebiopsy mental disorders were investigated retrospectively, which unavoidably compromised the validity of the assessment. Finally, there is no systematic method for collecting data on family history of mental disorders by using the K-SADS-PL. To eliminate these weaknesses, we used several symptoms scales and obtained data from pediatric case records. We used data from clinical notes recorded during the prospective medical follow-up of the celiac disease patients, and in most cases the follow-up was performed by experienced pediatric gastroenterologists (M.V. or E.S.). In the psychiatric interview, data were gathered from both the adolescent and a parent, and the interviewer was a psychiatrist who specialized in adolescent psychiatry (P.A.P.). Final DSM-IV diagnoses were given as consensus diagnoses by the interviewer and a child psychiatrist (E.A.).

Clinical Implications
Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential. Although our clinical findings appear to be consistent with the hypothesis that untreated celiac disease is associated with disturbances in central serotonergic function, the mechanisms involved remain unresolved and need to be studied further.


  ACKNOWLEDGMENTS

 
The authors thank Hanna Oksanen, M.Sc., Ph.D., and Erkki Komulainen, M.A., Ph.D., for statistical advice.

This study was supported by the Yrjö Jahnsson Foundation and the Finnish Association of Adolescent Psychiatry. The authors report no competing interests.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hallert C, Derefeldt T: Psychic disturbances in adult coeliac disease, I: clinical observations. Scand J Gastroenterol 1982; 17:17–19[Medline]
  2. Goldberg D: A psychiatric study of patients with diseases of the small intestine. Gut 1970; 11:459–465[Abstract/Free Full Text]
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  5. 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; 53:789–793[CrossRef][Medline]
  6. Walker-Smith JA: Celiac disease, in Pediatric Gastrointestinal Disease, 2nd ed. St Louis, Mosby, 1996, pp 840–861
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A. Karwautz, G. Wagner, G. Berger, U. Sinnreich, V. Grylli, and W.-D. Huber
Eating Pathology in Adolescents With Celiac Disease
Psychosomatics, September 1, 2008; 49(5): 399 - 406.
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