Celiac Disease: An Overlooked Cause of Mental Illness in Children

SPECIAL REPORT: CHILD AND ADOLESCENT PSYCHIATRY

Mental health assessment and treatment are often focused heavily on a patient’s symptoms, a process that typically leads to a DSM-5 diagnosis and treatment with medication. This process can help some patients; however, many continue to struggle with residual symptoms. Often missing from the standard treatment approach is an evaluation of physiological and biochemical causes or factors that can contribute to mental health. One commonly overlooked condition that can contribute to a host of mental health challenges is celiac disease.

Celiac disease is an inflammatory, autoimmune-type reaction to the consumption of gluten, a protein found in wheat and related grains.¹ When gluten is consumed, the ensuing inflammation damages the enterocytes lining the small intestine, leading to smoothing of the villi necessary for nutrient absorption.

Beyond the Gut: Hidden Manifestations of Celiac Disease

Typical symptoms of celiac disease include abdominal pain, weight loss, and diarrhea. Complicating matters is that many patients present with minimal symptoms or are misdiagnosed with irritable bowel syndrome.² Estimates suggest that almost half of patients with celiac disease do not present with classical symptoms, frequently delaying diagnosis.³

It is believed that around 1% of the population have celiac disease.⁴ Unfortunately, a large percentage of individuals with the condition are unaware, with research showing more than 80% of patients with celiac disease are undiagnosed.⁵

Celiac Disease and Mental Health

The fact that celiac disease has effects on the brain is recognized but not completely understood. As a condition, celiac disease causes nutritional deficiencies, autoimmune antibodies, and direct neurotoxicity that are all likely relevant in contributing to neurological problems and the increasing incidence of mental illness found in children with the condition.

Nutrient Deficiencies

Patients with celiac disease are commonly deficient in B vitamins, including vitamin B12 and folate.⁶ Deficiencies in both of these nutrients can cause elevated homocysteine, a toxic amino acid that can lead to neurological damage.⁷ Elevated levels of homocysteine have been found in patients with celiac disease and may even be implicated in the progression of the condition.⁸

Deficiencies in vitamin D are also commonly encountered in this patient population.⁹ As a nutrient, vitamin D has numerous important roles in maintaining brain health, normal behavior, and neurological function.¹⁰ Iron, magnesium, and zinc are also known to be more commonly deficient in celiac disease and can have effects on mental health.^11-13

Autoimmune Antibodies

Autoimmune antibodies that can cause damage to the central nervous system are also known to occur in celiac disease. In 1 study of patients, 21% were found to have antineuronal antibodies.¹⁴ In this same set of patients, those with neurological manifestations of the condition had an even higher incidence of antineuronal antibodies, reaching almost 50%, showing the potential real-world consequences and neurological damage from their presence.

Direct Neurotoxicity

Peptides derived from gluten have also been found to have neurotoxic effects on the brain.¹⁵ Studies suggest that gliadin peptides can stimulate kainate receptors (a type of glutamate receptor) and induce excitotoxicity and inflammation. The connection is mostly well documented in animal studies of epilepsy, a condition also shown to be increased in incidence for patients with celiac disease.¹⁶

Due to these effects, it should come as no surprise that children with celiac disease often struggle with mental illness. Numerous mental health conditions are known to be more common among patients with celiac disease. As a child psychiatrist, I firmly believe that celiac disease should be ruled out in every child presenting with major psychiatric illness, especially in those with a poor response to traditional treatments.

Mood Disorders

Results of a study of 152 children and adolescents with biopsy-confirmed celiac disease showed concerning levels of anxiety and depression in 39% of patients. A meta-analysis of the literature found that patients with celiac disease have a 2.26 times higher risk of having anxiety and a 3.36 times higher risk of developing depression.¹⁷ Even with these results, controversy exists as to whether depression and anxiety are consequences of the challenges of living with celiac disease or a deeper manifestation of the condition itself. In all likelihood, it is a combination of both.

Behavioral Disorders

Notably, the findings for attention-deficit/hyperactivity disorder (ADHD) are not as robust as for depression and anxiety, yet the available evidence still appears to indicate a potential relationship between celiac disease and ADHD. Whereas results of a systematic review from 2020 of 8 studies found no association,¹⁸ studies published since then have continued to add weight to the connection. A more comprehensive systematic review of 23 studies from 2022 reversed the findings, noting a correlation between ADHD and celiac disease, with a recommendation for further research that analyzes the relationship between celiac disease and ADHD subtypes.¹⁹ Results of a meta-analysis on mental health comorbidities also showed that celiac disease raised the risk of ADHD by a factor of 1.39, lower than some of the other mental health conditions, but still significant.²⁰

A study on adherence to a gluten-free diet in children showed that those who were less adherent had more problems with behavior and cognitive regulation.²¹ A separate study showed how untreated celiac disease can mimic ADHD and should not be overlooked as a potential diagnosis.²² A large population study of more than 10,000 children with celiac disease found that this population had a 1.4-fold increased propensity for having behavioral disorders.²³

Eating Disorders

The relationship between eating disorders and celiac disease appears to be bidirectional. For children with undiagnosed celiac symptoms, eating can cause abdominal pain, bloating, and diarrhea—all of which can lead to a problematic relationship with food. Alternatively, disordered eating patterns can cause damage to the digestive tract, which can increase the likelihood of the development of celiac disease in children with a genetic predisposition.

Further complicating the relationship is the fact that anorexia nervosa and celiac disease share many similarities, including gastrointestinal (GI) symptoms and life-threatening weight loss. Results of a meta-analysis exploring the relationship showed that patients with celiac disease had a 1.48 increased risk for anorexia nervosa.²⁴ Conversely, patients with anorexia nervosa had a 2.35 increased risk for developing celiac disease.²⁴ In patients with anorexia who do not seem to be responding to the reintroduction of adequate calories with appropriate weight gain or when GI or other symptoms are suggestive, celiac disease should be ruled out.

It is also worth bearing in mind the complexity of treating celiac disease in a young patient who is already restricting food intake. A gluten-free diet should only be attempted in patients with eating disorders where it is clearly indicated. A skilled nutritionist, familiar with both eating disorders and celiac disease, can be a vital team member for providing supportive care.

The data on bulimia also show a potential correlation. For patients with celiac disease, the incidence of bulimia nervosa is just over 7%.²⁴

Schizophrenia

From my own experience, other mental health conditions should also be considered, even if the published clinical evidence is somewhat mixed. For schizophrenia, results of an analysis from 2018 concluded that patients with celiac disease had double the risk of developing the condition.²⁵ However, a more recent analysis concluded the data do not support a relationship, although the authors note that the lack of studies is a valid criticism weighing on their conclusion.²⁰

Approximately one-third of patients with schizophrenia have been shown to have IgG anti-gliadin antibodies, raising the possibility that for at least a subset of patients, gluten could be a factor.²⁶ Other authors have proposed a new diagnostic entity based on the existing evidence: gluten psychosis.²⁷

A separate systematic review on the use of a gluten-free diet in psychotic disorders is further evidence of a potential connection, although again, more data are needed for full confirmation.²⁸ Published case reports also lend additional credence to the idea that a subset of patients can react to gluten in ways that contribute to their psychotic symptoms.

A case from 2009 is particularly dramatic, with a woman who had struggled with long-standing schizophrenia since age 17 having complete resolution of her symptoms on a gluten-free, ketogenic diet. While on the diet, the patient was able to stop her psychotropic medications without the reemergence of symptoms.²⁹

A separate case of a 33-year-old patient diagnosed with schizophrenia who had severe diarrhea and weight loss has also been published. Due to the GI symptoms, a celiac disease evaluation was initiated and came back positive. At the time of diagnosis, a single-photon emission computed tomography showed frontal lobe dysfunction that reversed, along with the patient’s psychotic symptoms, on a gluten-free diet.³⁰

Screening for celiac disease and a trial of a gluten-free diet are both worth considering in any child or adolescent struggling with symptoms of psychosis.

Obsessive-Compulsive Disorder

A study from 2024 found correlations in a subset of patients with celiac disease between disordered eating and obsessive-compulsive disorder (OCD) symptom severity. In patients with the most disordered eating behaviors, compliance with a gluten-free diet was worse.²² While the authors do not claim that gluten was the cause of the symptoms, the correlation of worse OCD with worse adherence to a gluten-free diet raises obvious questions and concerns about the influence of gluten on OCD behaviors.

Diagnostic Considerations

For any child or adolescent with symptoms of diarrhea, weight loss, or irritable bowel syndrome, celiac disease should be ruled out, regardless of mental health status.

Non-GI symptoms that can also indicate the need for screening include dermatitis herpetiformis, a blistering, itchy skin rash that is pathognomonic for celiac disease. Interestingly, patients with dermatitis herpetiformis rarely have GI symptoms.³¹ Fatigue and iron deficiency anemia are also common and should raise concerns. Thyroid problems and type 1 diabetes are frequent comorbidities with celiac disease.³² Headaches and migraines are also known to occur in patients with celiac disease with 1 in 5 having migraines.³³

In children with first-degree relatives who have celiac disease, suspicions regarding the condition should also be heightened. A persistent misconception among clinicians is that the absence of GI symptoms rules out celiac disease. This belief is false, and potentially dangerous, delaying diagnosis while celiac disease continues to damage the brain and body.

Treatment

The standard treatment for celiac disease is the complete elimination of gluten from the diet. Wheat, barley, rye, triticale, spelt, kamut, and other related grains and grain products contain gluten.³⁴ Some patients may tolerate oats, but due to cross-contamination, oats should be approached cautiously.

Nutrient repletion is also critical for patients with celiac disease because absorption is typically compromised. In children, before diagnosis, deficiencies in iron, calcium, vitamin D, vitamin B12, vitamin B6, folic acid, zinc, and magnesium are more common.¹¹ On a gluten-free diet, not all nutrient deficiencies resolve, and iron, vitamin D, and magnesium, among other deficiencies, should still be considered and treated with appropriate supplementation.¹¹

Gut flora issues are another common problem in children and adolescents with celiac disease. Although the evidence is preliminary, due to their safety and potential efficacy, probiotics can be an effective method to help decrease inflammation and modulate gut flora populations in an attempt to improve symptoms.³⁵

Concluding Thoughts

In children and adolescents, celiac disease is a condition that is commonly overlooked. Providers often wrongly assume that if a patient does not have GI symptoms, they cannot have celiac disease. This is far from the truth, as half of patients with celiac disease do not present with classical symptoms.

When present, celiac disease can damage the brain and nervous system through several different mechanisms. Due to this damage, mental health conditions are more common. As child psychiatrists, we must think beyond the DSM-5. For children and adolescents with resistant psychiatric symptoms, screening for celiac disease should be the rule, not the exception. The stakes are too high for us to ignore.

Dr Greenblatt is the chief medical officer of Psychiatry Redefined, an online educational platform for integrative and functional psychiatry.

References

1. Iversen R, Sollid LM. The immunobiology and pathogenesis of celiac disease. Annu Rev Pathol. 2023;18:47-70.

2. Ford AC, Chey WD, Talley NJ, et al. Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med. 2009;169(7):651-658.

3. Parra-Medina R, Cherñavsky AC. Celiac disease. In: Autoimmunity: From Bench to Bedside [Internet]. El Rosario University Press; 2013. Accessed December 30, 2024. https://www.ncbi.nlm.nih.gov/books/NBK459453/

4. Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2.

5. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538-1544; quiz 1537, 1545.

6. Wierdsma NJ, van Bokhorst-de van der Schueren MAE, Berkenpas M, et al. Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients. Nutrients. 2013;5(10):3975-3992.

7. Varshney KK, Gupta JK, Mujwar S. Homocysteine induced neurological dysfunctions: a link to neurodegenerative disorders. Int J Med Res. 2019;8(4):135-146.

8. Yaseen FT, Al-Jumaily RMK. Evaluation of global DNA methylation, homocysteine and vitamin B12 levels among patients with celiac disease. Gastroenterology. 2024;58(4):258-263.

9. Lu C, Zhou W, He X, et al. Vitamin D status and vitamin D receptor genotypes in celiac disease: a meta-analysis. Crit Rev Food Sci Nutr. 2021;61(12):2098-2106.

10. Eyles DW. Vitamin D: brain and behavior. JBMR Plus. 2020;5(1):e10419.

11. Kreutz JM, Adriaanse MPM, van der Ploeg EMC, Vreugdenhil ACE. Narrative review: nutrient deficiencies in adults and children with treated and untreated celiac disease. Nutrients. 2020;12(2):500.

12. Kim J, Wessling-Resnick M. Iron and mechanisms of emotional behavior. J Nutr Biochem. 2014;25(11):1101-1107.

13. Wang J, Um P, Dickerman BA, Liu J. Zinc, magnesium, selenium and depression: a review of the evidence, potential mechanisms and implications. Nutrients. 2018;10(5):584.

14. Caio G, De Giorgio R, Venturi A, et al. Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations. Gastroenterol Hepatol Bed Bench. 2015;8(2):146-152.

15. Gerace E, Resta F, Curti L, et al. Differential pattern of neurotoxicity induced by the gliadin peptides p31-43 and p57-68 in in vitro model of epilepsy. Biochem Pharmacol. 2024;226:116409.

16. Gerace E, Resta F, Landucci E, et al. The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models. Sci Rep. 2017;7(1):15146.

17. Moawad MHE, Serag I, Shalaby MM, et al. Anxiety and depression among adults and children with celiac disease: a meta-analysis of different psychiatry scales. Psychiatr Res Clin Pract. 2024;6(4):124-133.

18. Ertürk E, Wouters S, Imeraj L, Lampo A. Association of ADHD and celiac disease: what is the evidence? A systematic review of the literature. J Atten Disord. 2020;24(10):1371-1376.

19. Gaur S. The association between ADHD and celiac disease in children. Children (Basel). 2022;9(6):781.

20. Clappison E, Hadjivassiliou M, Zis P. Psychiatric manifestations of coeliac disease, a systematic review and meta-analysis. Nutrients. 2020;12(1):142.

21. Sady M, Coburn SS, Kramer Z, et al. Associations between executive functioning and adherence in pediatric celiac disease. Child Health Care. 2023:1-15.

22. Efe A, Tok A. A clinical investigation on ADHD-traits in childhood celiac disease. J Atten Disord. 2023;27(4):381-393.

23. Butwicka A, Lichtenstein P, Frisén L, et al. Celiac disease is associated with childhood psychiatric disorders: a population-based study. J Pediatr. 2017;184:87-93.e1.

24. Nikniaz Z, Beheshti S, Abbasalizad Farhangi M, Nikniaz L. A systematic review and meta-analysis of the prevalence and odds of eating disorders in patients with celiac disease and vice-versa. Int J Eat Disord. 2021;54(9):1563-1574.

25. Wijarnpreecha K, Jaruvongvanich V, Cheungpasitporn W, Ungprasert P. Association between celiac disease and schizophrenia: a meta-analysis. Eur J Gastroenterol Hepatol. 2018;30(4):442-446.

26. Kelly DL, Buchanan RW. Can the current schizophrenia construct endure? Schizophr Res. 2022;242:64-66.

27. Lionetti E, Leonardi S, Franzonello C, et al. Gluten psychosis: confirmation of a new clinical entity. Nutrients. 2015;7(7):5532-5539.

28. Levinta A, Mukovozov I, Tsoutsoulas C. Use of a gluten-free diet in schizophrenia: a systematic review. Adv Nutr. 2018;9(6):824-832.

29. Kraft BD, Westman EC. Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and review of the literature. Nutr Metab (Lond). 2009;6:10.

30. 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):421-423.

31. Reunala T. Dermatitis herpetiformis: coeliac disease of the skin. Ann Med. 1998;30(5):416-418.

32. Pinto-Sánchez MI, Bercik P, Verdu EF, Bai JC. Extraintestinal manifestations of celiac disease. Dig Dis. 2015;33(2):147-154.

33. Fanaeian MM, Alibeik N, Ganji A, et al. Prevalence of migraine in adults with celiac disease: a case control cross-sectional study. PLoS One. 2021;16(11):e0259502.

34. Buriánek F, Gege C, Marinković P. New developments in celiac disease treatments. Drug Discov Today. 2024;29(9):104113.

35. Saviano A, Petruzziello C, Brigida M, et al. Gut microbiota alteration and its modulation with probiotics in celiac disease. Biomedicines. 2023;11(10):2638.