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Rapid Responses: Rapid Responses published:
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Celiac and schizophrenia - not convinced
- Eugene B Campbell, Stephen Foley (23 February 2004)
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Not yet an appropriate screening issue
- Gerry Waldron, Michael Devine, Pamela Hannigan, Madeline Heaney, Joanne McClean, Pat Purvis (5 March 2004)
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Coeliac disease and schizophrenia
- Anita Sainsbury (6 March 2004)
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Struggle in Many Forms
- Ned Hoke (6 March 2004)
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An entangled duo with much to be learned
- Giovanni Gambassi, Raffaele Manna, Giovanni Gasbarrini (9 March 2004)
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Gluten and schizophrenia
- F. Curtis Dohan, Jr., Peter H. Dohan, Elisabeth H. Harper (18 March 2004)
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COELIAC DISEASE AND PSYCHIATRIC DISORDERS: ARE THEY ASSOCIATED BY BRAIN PERFUSION CHANGES?
- Giovanni Addolorato, Daniela Di Giuda, Giovanni Gasbarrini (26 March 2004)
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Coeliac Disease: Psychiatric Ramifications!
- Dr.Naseem A. Qureshi MD, IMAPA, LMIPS, Dr.Abdulhameed Al-Habeeb, BMHH, Saudi Arabia (3 May 2004)
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Rheumatoid arthritis and schizophrenia:there is also a well documented inverse correlation between the two diseases?
- AK Al-Sheikhli (4 May 2004)
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Eugene B Campbell, Research Fellow University of Nottingham, Stephen Foley
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Editor- Eaton et al report a strong risk relation between schizophrenia and celiac disease.(1) We do not believe their data supports this hypothesis. They define their case sample as 7997 patients with schizophrenia, in whom they found four cases of celiac disease. Eaton et al then include the data on parents’ celiac status ( 8 cases) in their analysis and this is potentially misleading. If the parent data is excluded from the analysis, then the prevalence of celiac disease in new onset schizophrenics is only 0.5 per 1000, which is the same as in their control group. They describe celiac disease as rare in Denmark and this was the traditional view. Their sample population dated from 1981-1998, during which time diagnostic testing for celiac disease has advanced. Recent data using endomysial antibody to screen the Danish population suggests a prevalence of 1 in 400, more akin to neighbouring Scandinavian countries.(2) Therefore, underascertainment of the true prevalence of celiac disease is a real possibility and a potential confounding factor. 1. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ. 2004 Feb 21;328(7437):438-9. 2. Weile I, Grodzinsky E, Skogh T et al. High prevalence rates of adult silent coeliac disease, as seen in Sweden, must be expected in Denmark. APMIS. 2001 Nov;109(11):745-50. Competing interests: None declared |
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Gerry Waldron, Consultant in Public Health Medicine Northern Health & Social Services Board, County Hall, Ballymena, Northern Ireland BT42 1QB, Michael Devine, Pamela Hannigan, Madeline Heaney, Joanne McClean, Pat Purvis
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William Eaton and colleagues have demonstrated an interesting association between coeliac disease and schizophrenia (1). However much more research is needed before screening for coeliac disease can be recommended as part of the routine assessment of people with schizophrenia, not to speak of the recommendation of a gluten free diet for those who screen positive for coeliac disease but are free of clinical symptoms. A gluten free diet may well be safe and inexpensive, but, in the absence of evidence of any benefit, it would impose a considerable additional burden on patients who are already coping with a serious mental illness and possibly the side effects of antipsychotic medication. The tests for coeliac disease may be inexpensive in themselves and “carry minimal risk and discomfort” in their application, but much more than this needs to be taken into consideration. We believe that simply applying the Wilson and Jungner criteria (2) provides ample reasons to reject this as a screening test. 1 Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ 2004;328:438-439 2 Wilson JM, Jungner G. Principles and practice of screening for disease. Geneva: World Health Organization, 1968. (Public Health Paper Number 34.) Competing interests: None declared |
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Anita Sainsbury, SpR Gastroenterology St James's Hospital, Leeds, Yorkshire, LS9 7TF
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Eaton et al propose that Coeliac disease is a significant risk factor for schizophrenia based on their large case-control trial. However, I suggest that there is likely to be a degree of selection bias in the cases of schizophrenia. Those requiring admission to a psychiatric facility may represent a more severely affected group than those with schizophrenia overall. Conversely, they may be more willing to accept medical help and agree to participate in a clinical trial. Such a group may also be more likely to present themselves for investigation of gastrintestinal symptoms leading to the diagnosis of Coeliac disease. As the authors infer, the concept of a 'Coeliac Iceberg' exists, whereby most cases of the disease remain undiscovered. Coeliac disease can be diagnosed at almost any age, making it feasible that the diagnosis of schizophrenia could precede that of Coeliac disease by as much as six decades. This prompts questions regarding the validity of using a case- control study to examine the relationship between these two diseases. Furthermore, the use of odds ratios rather than relative risks would have been more appropriate, given the case-control design of the study. Competing interests: None declared |
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Ned Hoke, ecological medicine/private Calif/USA
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While the immediate science of this assertion is unconvincing the principles within the inquiry are indeed intriguing. Given the chaos and processing challenges represented in both situations coherent links appear to me as worth consideration and observation. Given the frequency I find wheat flour & gluten sensitivity unappreciated even by the most modern testing I don't myself believe science can realistically limit itself in study to the presumed certainty of lab methods in this matter. Competing interests: None declared |
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Giovanni Gambassi, Associate Professor Università Cattolica, 00168 Rome, Italy, Raffaele Manna, Giovanni Gasbarrini
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The study by Eaton and colleagues suggests that a history of coeliac disease is a risk factor for schizophrenia possibly in relation to the vicinity of respective genetic markers on chromosome 6. While the study is thought-provoking, we believe that the true validity of the causal relationship remains to be demonstrated. In 1997, we have reported the case of young woman with a four-year history of schizophrenia receiving a pharmacological treatment with a combination of two conventional antipsychotics and a benzodiazepine, who came to our attention because of severe diarrhoea and weight loss.1 She would eventually receive a diagnosis of coeliac disease based on the presence of anti-endomysial antibodies and on a jejunal biopsy showing subtotal villous atrophy with Lieberkuhn crypts hyperplasia. She was then put on a gluten-free diet and her physical and psychiatric symptoms improved rapidly. Most notably, SPECT-documented areas of hypoperfusion in the left frontal and temporal cortex also normalized, and pharmacologic treatment was discontinued without recurrence of schizophrenic symptoms. After several years now, she remains symptom-free and well. This case demonstrates that schizophrenia may indeed represents even the exclusive clinical expression of a coeliac disease rather than be a primary psychiatric illness. This case also illustrates that a gluten-free diet could dramatically improve symptoms in patients with schizophrenia who screen positive for coeliac disease. 1. De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997;242:421-3 Competing interests: None declared |
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F. Curtis Dohan, Jr., Director, Division of Neuropathology, Associate Professor of Pathology University of Tennessee, Memphis, TN 38103, Peter H. Dohan, Elisabeth H. Harper
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Eaton et al. (1) are to be commended for their convincing demonstration of the association between celiac disease and schizophrenia. While in patients with both celiac disease and schizophrenia, the celiac disease-associated schizophrenia may respond dramatically to a gluten-free diet (2), the work of the late F. C. Dohan and others indicates that a gluten-free diet may also benefit a significant number of patients with the more common, idiopathic form of schizophrenia. Dohan believed that the genotype for idiopathic schizophrenia overlaps somewhat with that of celiac disease, and on the basis of extensive epidemiological studies correlating grain consumption with the incidence of schizophrenia (3,4) he concluded that gluten is a major factor in causing this disorder in genetically susceptible individuals within the general population. The results of trials of a gluten-free diet in the treatment of idiopathic schizophrenia have been inconsistent but have been well reviewed by Lorenz (5). In two trials, a statistically significant beneficial effect of the diet was noted. In other trials, some patients responded favorably, but the overall results were not statistically significant. In still other trials, the diet had no discernible beneficial effect. These studies varied considerably in a number of important parameters including their duration, the number of patients studied, and the subtype and stage of schizophrenia in the treated patients. In most of the trials, milk (casein) was also omitted from the diet, an omission that benefits some patients with celiac disease. Although his gluten hypothesis remains as yet unproven, Dohan's epidemiological studies and the overall results of the gluten-free diet trials indicate that a gluten-free diet may benefit a significant number of patients with idiopathic schizophrenia, particularly those in an early stage of their illness and those who are acutely psychotic. For this reason, future studies using a gluten-free diet to treat celiac disease-associated schizophrenia should include as well a group of patients with idiopathic schizophrenia, some of whom may also respond to the diet. References 1. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ 2004;328:438-9. 2. De Santis A. Addolorato G. Romito A. et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med. 1997;242(5):421-3. 3. Dohan FC. Wartime changes in hospital admissions for schizophrenia. A comparison of admission for schizophrenia and other psychoses in six countries during World War II. Acta Psychiatrica Scandinavica. 1966;42(1):1-23. 4. Dohan FC. Cereals and schizophrenia: data and hypothesis. Acta Psychiatrica Scandinavica. 1966;42(2):125-52.. 5. Lorenz K. Cereals and schizophrenia. In: Pomeranz Y, editor. Advances in Cereal Science and Technology, Vol. X. St. Paul: American Association of Cereal Chemists;1990, p. 435-469. Competing interests: None declared |
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Giovanni Addolorato, Institute of Internal Medicine, Catholic University of Rome, Italy Gemelli Hospital, Largo A. Gemelli 8, 00168-Rome-Italy, Daniela Di Giuda, Giovanni Gasbarrini
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TO THE EDITOR: We read with great interest the recent paper by Eaton et al (1) on the association between coeliac disease (CD) and schizophrenia. The authors conclude with an important question about the start of gluten-free diet (GFD) in the small proportion of patients affected by schizophrenia who screen posetively for CD but not show its classic symptoms. Several neurological, psychiatric (including schizophrenia) and affective disorders have been reported in coeliac patients; these complication occurr in approximatively 8%-10% of subjects affected by coeliac disease (CD) (2). At present the etiology and pathogenesis of these disorders is uncertain. In a recent study our group evaluated regional cerebral perfusion assessed by single photon emission computed tomography (SPECT) in untreated CD patients, comparing them with CD patients on GFD and with healthy controls. The study showed the the presence of regional cerebral hypoperfusion in 73% of the untreated CD patients, compared with only 7% of CD patients on GFD and none of the controls (3). An overall multivariate test showed a significant difference in cerebral perfusion among the three groups of subjects. (p = 0.01). Considering each single region, a significant lower cerebral perfusion was found in untreated celiac patients compared to controls in seven of the 26 cerebral regions evaluated. There were no significant differences in cerebral perfusion between untreated patients and those on GFD, or between patients on GFD and healthy controls, reflecting a beneficial effect of a GFD on these alterations (3). Perfusion defects were predominant in the superior and anterior areas of the frontal cortex with the involvement of the adjacent anterior cingulated cortex. Similar cerebral blood flow changes have been reported in patients suffering from different psychiatric disorders (4). Our previous paper reported a case of brain perfusion abnormalities, assessed by SPECT examination, in a CD patient with schizophrenia; regression of both cerebral hypoperfusion and schizophrenic symptoms was observed after 6 months of a GFD (5). In conclusion psychiatric and/or neurological disorders in CD patients could be related, in part, to brain perfusion alterations. These hemodynamic changes seems to be linked to disease activity, and resolved after GFD. For these reasons GFD should started as soon as possible, also in patients which do not show the classic form of CD. REFERENCES 1. Eaton WW, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national register. BMJ 2004; 328: 438-9. 2. Finelli PF, McEntee WJ, Ambler M, Kestenbaum D. Adult celiac disease presenting as cerebellar syndrome. Neurology 1980; 30:245-9. 3. Addolorato G, DiGiuda D, DeRossi G, Valenza V, Domenicali M, Caputo F, Gasbarrini A, Capristo E, Gasbarrini G. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med 2004; 116: 312-7. 4. O’Connel RA. SPECT brain imaging in psychiatric disorders: current clinical status. In Grünwald F, Kasper S, Biersack H-J, Möller H-J, Eds. Brain SPECT Imaging in Psychiatry. De Gruiter W, Berlin, New York 1995: 35 -57. 5. De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med 1997; 242: 421-3. Competing interests: None declared |
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Dr.Naseem A. Qureshi MD, IMAPA, LMIPS, Medical Director(A), Director CME&R Buraidah Mental Health Hospital, Postcode:2292, Saudi Arabia, Dr.Abdulhameed Al-Habeeb, BMHH, Saudi Arabia
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Dear Sir: By and large, coeliac disease (CD) is reported to be a very rare disease. It is silent in early part of human life cycle including among children and adults but its incidence tends to increase in old age. It has well defined clinical and diagnostic criteria; diarrhoea, weight loss, anti-glidin and anti-dymosial antibodies, jejunal villous atrophy and other features. This disease is reported to have a very interesting but controversial co-morbid relationship with a variety of psychiatric disorders in particular schizophrenia, pervasive developmental disorder that is autistic disorder (AD), attention-deficit-hyperactive disorder (ADHD), and mood disorders (MDs). Notably, there are numerous implications of co-morbidity of coeliac disease with schizophrenia. These implications may include epidemiological trends, genetic etiological pooling and sharing, phenomenological overlapping, diagnostic clues, therapeutic relationship and finally prognostic and outcome trajectories. With regard to schizophrenia, CD is reported to share genetic pool (chromosome 6) and can precipitate psychotic decompensation in terms of schizophrenia-like psychosis. Likewise, psychosis may also precipitate the onset of coeliac disease. Patients with CD are sensitive to cereals containing gluten and milk, which contain casein. There could be exacerbations both of coeliac and psychotic symptoms after use of gluten-load diet. Conversely, gluten free diet (also casein free milk)certainly improves coeliac symptomatology as well as psychotic manifestations. However, gluten free diet has no therapeutic role in the treatment of schizophrenia without coeliac disease and likewise gluten is not a pathogenic risk factor for the development of schizophrenia. Hence when both disorders have mutual causative relationship as regards gluten, they may improve with gluten free diet. Notably, gluten free diet is reported to have some adverse psychological effects in various trials that recruited patients with schizophrenia. The therapeutic role of gluten free diet in AD, MDs and ADHD is equivocal and now better drug options like effective atypical antipsychotics, SSRIs and mood stabilizers are available in the market. Reference: William Eaton, Preben Bo Mortensen, Esben Agerbo, Majella Byrne, Ole Mors, and Henrik Ewald. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ 2004; 328: 438-439 Competing interests: None declared |
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AK Al-Sheikhli, Psychiatrist Medical Centre,Nuneaton,CV11 5HX,UK.
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EDITOR--It was interesting to read the paper of Eaton et al[BMJ 2004;328:438 -439], Coeliac disease and schizophrenia:population based case control study with linkage of Danish national registers. My comment: It is well known for long time that schizophrenia is unknown among patients with rheumatoid arthritis[1]. It was suggested that it might be due to the possibility that both of them share a common infectious or immune etiology and that once a person gets one of the diseaes then they are relatively immune to the other[2], so further research work in those areas might help us to reach a firm conclusion about the etiology of schizophrenia. Thanking
you,
References, 1.Gorwood P, Pouchot J, Vinceneux P, et al, Rheumatoid arthritis and schizophrenia: a negative association at a dimensional level,Schizophr Res, 2004,66(1);21-9 2.Torrey EF and Yolken RH,The schizophrenia-rheumatoid arthritis connection :infectious,immune,or both?,Brain Behav Immun,2001;15(4):401-10 Competing interests: None declared |
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