Revisiting evidence for

recommending a Gluten-
Free Diet in Schizophrenia

Catalina Argüello Gutiérrez, PhD.

Introduction
“Let food be thy medicine, and let medicine be
thy food.” Hippocrates.

Growing interest in the relationship between

neuroinflammation and immune system
activation in psychiatric conditions.

(Bauer & Teixeira, 2021; Lurie, 2018; Rhie, et al., 2020; Najjar et al, 2013)
 Dr. William Davis
Cardiologist

Dr. Jean Seignalet

Clinician, clinical
pathologist,
lecturer and
researcher Dr. David
Perlmutter
Neurologist
Introduction
Altered immune and nervous function
linked to:

• neurological harm through a combination of

cross reacting antibodies
• dysregulation of the autonomic nervous system,
cerebella ataxia, hypotonia
• immune complex disease and direct toxicity

(Busby, et al. 2018; Golofast & Vales, 2019; Rhie, et al., 2020)
Introduction
Immune response to gluten may play an
important role in altered immune function
in schizophrenia

(Patrono, et al., 2021; Szeligowski, Lennox & Burnet, 2020)

Introduction
• strong connection between SCZ and altered gut
microbiota (Golofast et al., 2020; Lv et al, 2017; Zheng et al, 2019).
• association between schizophrenia and CD was
noted in reports spanning back to the 1960s (Dohan,
1966)

(Szeligowski et al.,2020)
Research
Aim
• Review existing literature to determine whether
adherence to a gluten-free diet (GFD) could be a
recommended intervention for patients with
schizophrenia (SCZ)
Research
Schizophrenia
• psychiatric diagnosis that brings together severe
chronic mental changes and is characterised by
unusual behaviour and a modified perception of
reality

(Saha, et al., 2005)

Research
Gluten
storage protein made up of a complex mixture of
proteins, mainly gliadin and glutenin.
Present in of wheat, rye, barley or oats are also
referred to as gluten.
Also added to processed food to improve its
texture and moisture characteristics.

(Biesiekierski, 2017)
Method
Literature review. The searched was performed using
Pubmed, Web of Science and Scopus databases using
the terms “schizophrenia” and “gluten” or “gluten
free” or “gluten-free” or "cereal-free" or "wheat".
 Inclusion criteria Exclusion criteria
• RCTs, cohort studies, case
series, pre-post • Editorials, reviews,
interventions, single case commentaries, gray
study with follow up literature
• Prospective and • Single case studies
retrospective studies
English and Non–English without follow up
language studies • In vitro or animal studies
• Diagnosis of schizophrenia
• Pediatrics schizophrenia
• Adult male or female
patients, any age • Other mental disorders.
• GFD intervention OR
gluten challenge after GFD
14 PAPERS
published between 1969
and 2020 presented data
showing evidence of the
effects of GFD.
Year Authors Title Sample size Length Study Outcome of GFD
& age of GFD design
1969 Dohan et al. Relapsed schizophrenics: more 102 male 175 d Crossover, Faster release from locked to open
rapid improvement on a m= 38y randomized ward with GFD.
milk- and cereal-free diet
1973 Dohan and Relapsed schizophrenics: earlier 115 male 175 d Crossover, Faster release from locked to open
Grasberger discharge from the hospital after m = 38y randomized ward with GFD. Gluten is pathogenic to
cereal free, milk free diet those with schizophrenia.
1976 Singh and Kay Wheat gluten as a pathogenic 14 (3 male, 4 wk. Crossover Psychopathology measures
factor in schizophrenia 11 female) deterioration after the administration
m= 19,57 of gluten. Gluten exacerbated
symptomology of schizophrenia and
diminished response to treatment.

1978 Rice et al Another look at gluten in 16 male 14 wk. Crossover Improvement proved in their levels of
schizophrenia m= 38 functioning above baseline on the BPRS
and clinical observations.

1981 Potkin et al. Wheat gluten challenge in 8 (5 male, 3 8 wk Crossover, No effect. No deterioration in clinical
schizophrenic patients female) randomized status as measured by the BPRS was
m= 25 noted on gluten challenge.

1982 Storms et al. Effects of gluten on 26 male 10 d RCT (n = 13 No effect. Improvement of Profile on
schizophrenics aged 18-55 in each Mood States measures of tension-
group) anxiety and anger-hostility in gluten
condition.
1982 Osborne et al. Lack of effect of a gluten-free 5 (n/a) 36 wk Crossover No effects on Brief Psychiatric Rating
diet on neuroleptic blood Scale or plasma levels of butaperazine
levels in schizophrenic
patients
Year Authors Title Sample size Length Study design Outcome of GFD
& age of GFD
1986 Vlissides et al. A double-blind gluten-free/gluten- 17 (10 male 14 wk Crossover, Improvement in Psychotic In-Patient
load controlled trial in a secure 7 female) double profile (PIP) in GFD
ward population aged 23–59 blind
1990 Reichelt et al. The effect of gluten-free diet on 10 male 8 wk Crossover, Improvement in NOSIE, CPRS, WIST
urinary peptide excretion and aged 22-38 randomized; Urinary peptide concentrations
clinical state in schizophrenia optional reversibly altered by a GFD.
open-label
1997 De Santi et al Schizophrenic symptoms and SPECT 1 female, 7 dy + Case study Improvement of physical and psychiatric
abnormalities in a coeliac patient: aged 33 follow symptoms.
regression after a gluten-free diet up
2009 Kraft & Schizophrenia, gluten, and low- 1 female 2 wk + Case study Improvement of symptoms, no
Westman carbohydrate, ketogenic diets: a aged 70 follow recurrence of her auditory or visual
case report and review of the up hallucinations.
literature
2012 Jackson et al. A gluten-free diet in people with 2 (a male, 1 2wk Open-label Improvement in BPRS scores, SANS, and
schizophrenia and anti-tissue female) pilot in extrapyramidal symptoms.
transglutaminase or anti-gliadin
antibodies
2019 Kelly et al. Randomized controlled trial of a 16 (n/a) 5 wk RCT (n =7 Improvement on the Clinical Global
gluten-free diet in patients with aged 37.9 GFD, 9 Impressions scale and in negative
schizophrenia positive for antigliadin containing symptoms. Robust improvements in
antibodies (AGA IgG): a pilot gluten) Gastrointestinal Symptom Rating Scale
feasibility study in GFD
2020 Friendshuh et The Effects of a Gluten-Free Diet on 15 aged 18 - 5 wk RCT (n =7 Improvement in negative symptoms.
al Immune Markers and Kynurenic Acid 64 GFD, 9 There may be modulation directly or
Pathway Metabolites in Patients with containing indirectly through inflammatory markers
Schizophrenia Positive for Anti- gluten) which can activate IDO, stimulating KYN
Gliadin Antibodies (AGA IgG) metabolism and potentiate the
Balance
Results demonstrate a strong association between gluten
elimination and improved outcomes in SCZ patients.

• 11 out of 14 showed improvement in GFD

• No negative effects were associated to a GFD in
SCZ.
• Only 1 study showed a positive impact in mood
during GD.
• The earliest reported improvements were noted to
occur 1 and 2 wk into the GFD
Balance

These results suggest that ingestion of cereals

may play a role in the pathogenesis of
schizophrenia by showing that a GFD may lead
to an improvement of acutely exacerbated
symptom
Analysis
Inflammation has been Beneficial effect of GFD
proposed as a link between may be achieved via
gluten consumption and circulating food-derived
schizophrenia exacerbation, peptides (exorphins)
by disrupting the blood-brain exerting an influence on
barrier and increase its physiological processes
in the brain.
permeability to exogenous
peptides.

(Levinta et al.,2018; Sapone et al., 2010)

(Cascella et al. 2013)
Analysis
1/3 people with SCZ have antigliadin antibodies of
the immunoglobulin G (IgG) type
(Cascella, et al., 2011; Kalaydjian et al, 2006)

Psychiatric Manifestations of CD
(Clappison et al 2020)

NC Gluten sensitivity may also play a role, not

accompanied by the intestinal mucosal changes, but can
show variable changes in gluten related antibody titers
(Bonder et al.2016; David et al, 2014; De Palma et al., 2009).
Conclusions
There is insufficient evidence to recommend a
standard GFD intervention in schizophrenia.
(Brietzke et al., 2018; Levinta et al 2018)

However, there is an association between mood

disorders and gluten intake in susceptible individuals.
(Busby et al, 2018; Ergün et al., 2018; Lerner et al, 2019; Rhie, et al., 2020).

No negative or detrimental effects on GFD , were

observed in any of the studies.
Conclusions

Patients with comorbid dermatological, neurological,

and gastrointestinal conditions may have the
greatest chance of benefit from a GFD.
(Rubin, 2020; Liester & Liester, 2017)

inform yourself and discuss updated info

with your patients
Recomendations

• More RCT studies to provide more evidence

• Characterization of inflammatory markers to help in
the selection of patients who may benefit from an
intervention.
• The differential impact on age and sex needs more
exploration.
• Clarify the utility of this diet in certain patient
populations or stages of illness.
Contact info: catalina.arguello@unir.net
Download Presentation at:
https://www.researchgate.net/profile/Catalina-Argueello-2
References Barbaro, M. R., Cremon, C., Wrona, D., Fuschi, D., Marasco, G., Stanghellini, V., & Barbara, G. (2020). Non-Celiac
Gluten Sensitivity in the Context of Functional Gastrointestinal Disorders. Nutrients, 12(12), 3735.
https://doi.org/10.3390/nu12123735
Biesiekierski, J.R. (2017). What is gluten? J. Gastroenterol. Hepatol. 32, 78–81.
Bonder, M.J., Tigchelaar, E.F., Cai, X. et al. (2016). The influence of a short-term gluten-free diet on the human gut
microbiome. Genome Med 8, 45 https://doi.org/10.1186/s13073-016-0295-y
Brietzke, E., Cerqueira, R. O., Mansur, R. B., & McIntyre, R. S. (2018). Gluten related illnesses and severe mental
disorders: a comprehensive review. Neuroscience and biobehavioral reviews, 84, 368–375.
https://doi.org/10.1016/j.neubiorev.2017.08.009
Busby, E., Bold, J., Fellows, L., & Rostami, K. (2018). Mood Disorders and Gluten: It's Not All in Your Mind! A
Systematic Review with Meta-Analysis. Nutrients. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266949/.
Cascella, N.G.; Kryszak, D.; Bhatti, B.; Gregory, P.; Kelly, D.L.; Mc Evoy, J.P.; Fasano, A.; Eaton, W.W. (2011).
Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention
effectiveness study population. Schizophr. Bull. 37, 94–100.
Cascella, N.G.; Santora, D.; Gregory, P.; Kelly, D.L.; Fasano, A.; Eaton, W.W. (2013). Increased prevalence of
transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull. 39, 867–871.
Clappison, E., Hadjivassiliou, M., & Zis, P. (2020). Psychiatric Manifestations of Coeliac Disease, a Systematic Review
and Meta-Analysis. Nutrients, 12(1), 142. https://doi.org/10.3390/nu12010142
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. (2014). Diet rapidly and
reproducibly alters the human gut microbiome. Nature; 505:559–63.
De Palma G, Nadal I, Collado MC, Sanz Y. (2009). Effects of a gluten-free diet on gut microbiota and immune
function in healthy adult human subjects. Br J Nutr, 102:1154–60.
De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G. (1997).
Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern
Med; 242: 421–23.
References Dickerson, F.; Stallings, C.; Origoni, A.; Vaughan, C.; Khushalani, S.; Leister, F.; Yang, S.; Krivogorsky, B.; Alaedini, A.;
Yolken, R. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode
schizophrenia. Biol. Psychiatry 2010, 68, 100–104.Bauer, M. E, & Teixeira A, L. (2021) Neuroinflammation in Mood
Disorders: Role of Regulatory Immune Cells. Neuroimmunomodulation;28:99-107. doi: 10.1159/000515594
Dohan, F.C.(1966). Cereals and schizophrenia data and hypothesis. Acta Psychiatr. Scand. 42, 125–152.
Ergün, C., Urhan, M., & Ayer, A. (2018). A review on the relationship between gluten and schizophrenia: Is gluten
the cause?. Nutritional neuroscience, 21(7), 455–466. https://doi.org/10.1080/1028415X.2017.1313569
Friendshuh, C. R., Pocivavsek, A., Demyonovich, H., Rodriguez, K. M., Cihakova, D., Talor, M. V., Richardson, C. M.,
Vyas, G., Adams, H. A., Baratta, A. B., Fasano, A., Cascella, N., Feldman, S., Liu, F., Sayer, M., Powell, M. M.,
Wehring, H. J., Buchanan, R. W., Carpenter, W. T., Jr, Eaton, W. W., …Kelly, D. L. (2020). The Effects of a Gluten-Free
Diet on Immune Markers and Kynurenic Acid Pathway Metabolites in Patients With Schizophrenia Positive for
Antigliadin Antibodies Immunoglobulin G. Journal of clinical psychopharmacology, 40(3), 317–319.
https://doi.org/10.1097/JCP.0000000000001197
Golofast B, Vales K. (2019). The connection between microbiome and schizophrenia. Neurosci Biobehav Rev.
2020;108:712–31. https://doi.org/10.1016/j.neubiorev.2019.12.011.
Jackson, J., Eaton, W., Cascella, N., Fasano, A., Warfel, D., Feldman, S., … Kelly, D. L. (2012). A gluten-free diet in
people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophrenia research.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641835/.
Kalaydjian AE, Eaton W, Cascella N, Fasano A. (2006). The gluten connection: the association between
schizophrenia and celiac disease.Acta Psychiatr Scand 113(2):82–90.
Kelly DL, Demyanovich HK, Rodriguez KM, et al. (2019). Randomized controlled trial of a gluten-free diet in patients
with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci
;44:1–9.
Kraft, B & Westman, E. (2009). Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: A case report and
review of the literature. Nutrition & metabolism. 6. 10. 10.1186/1743-7075-6-10.
Lerner, B. A., Green, P., & Lebwohl, B. (2019). Going Against the Grains: Gluten-Free Diets in Patients Without
Celiac Disease-Worthwhile or Not?. Digestive diseases and sciences, 64(7), 1740–1747.
https://doi.org/10.1007/s10620-019-05663-x
References Levinta, A., Mukovozov, I., & Tsoutsoulas, C. (2018). Use of a Gluten-Free Diet in Schizophrenia: A Systematic
Review. Advances in nutrition (Bethesda, Md.), 9(6), 824–832. https://doi.org/10.1093/advances/nmy056
Liester MB, Liester MG. (2017). A review of psychiatric disorders associated with celiac disease. Dual Diagn; 2(2):1
Lurie D. I. (2018). An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain.
Journal of experimental neuroscience, 12, 1179069518793639. https://doi.org/10.1177/1179069518793639
Lv F, Chen S, Wang L, et al. (2017). The role of microbiota in the pathogenesis of schizophrenia and major
depressive disorder and the possibility of targeting microbiota as a treatment option. Oncotarget ; 8(59):100899–
907. https://doi.org/10.18632/oncotarget.21284.
Najjar, S., Pearlman, D.M., Alper, K. et al. (2013). Neuroinflammation and psychiatric illness. J Neuroinflammation
10, 816 https://doi.org/10.1186/1742-2094-10-43
Osborne, M., Crayton, J. W., Javaid, J., & Davis, J. M. (1982). Lack of effect of a gluten-free diet on neuroleptic
blood levels in schizophrenic patients. Biological Psychiatry, 17(5), 627–629.
Patrono, E., Svoboda, J. & Stuchlík, A. Schizophrenia, the gut microbiota, and new opportunities from optogenetic
manipulations of the gut-brain axis. Behav Brain Funct 17, 7 (2021). https://doi.org/10.1186/s12993-021-00180-2
Potkin, S.G.; Weinberger, D.; Kleinman, J.; Potkin, S.G.; Weinberger, D.; Kleinman, J.; Nasrallah, H.; Luchins, D.;
Bigelow, L.; Linnoila, M.; et al. (1981). Wheat gluten challenge in schizophrenic patients. Am. J. Psychiatry 138,
1208–1211.
Reichelt KL, Sagedal E, Landmark J, Sangvik BT, Eggen O, Scott H. (1990). The effect of gluten-free diet on urinary
peptide excretion and clinical state in schizophrenia. J Orthomol Med;5(4):223–39.
Rhie, S. J., Jung, E. Y., & Shim, I. (2020). The role of neuroinflammation on pathogenesis of affective disorders.
Journal of exercise rehabilitation, 16(1), 2–9. https://doi.org/10.12965/jer.2040016.008
Rice, J. R., Ham, C. H., & Gore, W. E. (1978). Another look at gluten in schizophrenia. The American Journal of
Psychiatry, 135(11), 1417–1418. https://doi.org/10.1176/ajp.135.11.1417
Rubin, A. (2020). Gluten-Free Intervention for Schizophrenia. American Journal of Psychiatry, 16(1); 7-8
https://doi.org/10.1176/appi.ajp-rj.2020.150303
References Saha S, Chant, D., Welham, J, & McGrath, J. (2005). A systematic review of the prevalence of schizophrenia. PLoS
Med. 2, e141.
Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A. (2010). Differential mucosal
IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac
disease. Int Arch Allergy. Immunol ,152(1):75–80.
SinghM, Kay SR. (1976). Wheat gluten as a pathogenic factor in schizophrenia. Science, 191(4225):401–2.
Storms, L. H., Clopton, J. M., & Wright, C. (1982). Effects of gluten on schizophrenics. Archives of general
psychiatry, 39(3), 323–327. https://doi.org/10.1001/archpsyc.1982.04290030055010
Szeligowski T, Yun AL, Lennox BR & Burnet PWJ (2020) The Gut Microbiome and Schizophrenia: The Current State
of the Field and Clinical Applications. Front. Psychiatry 11:156. doi: 10.3389/fpsyt.2020.00156
Vlissides, D.M.; Venulet, A.; Jenner, F.A. (1986). A double-blind gluten free/gluten-load controlled trial in a secure
ward population. Br. J. Psychiatry, 148, 447–452.
Zheng P, Zeng B, Liu M, Chen J, Pan J, Han Y, et al. The gut microbiome from patients with schizophrenia modulates
the glutamate-glutamine-GABA cycle and schizophrenia-relevant behaviors in mice. Sci Adv. 2019;5:eaau8317.