Schizophrenia

PET scan showing schizophrenia. Courtesy Wikimedia.

What Is Schizophrenia?

Schizophrenia is a thought disorder characterized by psychotic symptoms and inappropriate and bizarre behavior.

Schizophrenia involves dysfunction in any of these areas:

• Cognition which are thinking skills that include intellect, language, mathematical ability, memory, perception, reasoning, judgment, learning, and imagination.
• Interpersonal relationships.
• Ability to work or attend education.
• Ability to take care of physical and financial needs.

Q: What are psychotic symptoms?

A: In psychosis the symptoms vary but include loss of contact with reality shown by hallucinations, delusions, disorganized speech, and disorientation. Some may be depressed or manic. Some may be withdrawn and mute while others may become violent if frustrated or thwarted.

In hallucinations, affected persons see what is not real such as a burgler in the process of robbing them but which is not really happening or hear voices that are not real.

In delusions, affected persons may express strange ideas, claim to read minds or that they are a famous person living or dead.

Early-onset schizophrenia with onset before age 18 is defined by the same diagnostic criteria as in adults because it is continuous with adult schizophrenia. The onset before age 12 years comprises less than 1% of adult cases, and onset from age 12–18 years constitutes about 12–33% of all adult cases of schizophrenia.1

What Is Schizophrenia In Celiac Disease and/or Gluten Sensitivity?

• Relationship between schizophrenia and celiac disease. Schizophrenia is an associated psychiatric disorder of celiac disease with a robust relationship.2
• Relationship between schizophrenia and genes. Both schizophrenia and celiac disease involve a genetic component. A study investigating increased immune sensitivity to gluten in schizophrenia found that individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.
• Relationship between schizophrenia and antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to celiac disease and gluten sensitivity.3
• Relationship between schizophrenia and gluten sensitivity. A meta-analysis of 12 original articles show that not all serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. However, the specific immune response to gluten in this population differs from that found in patients with celiac disease. The following 5 biomarkers (antibodies) of gluten sensitivity were found to be significantly elevated in patients with non-affective psychoses compared to controls: Anti-Gliadin IgG, Anti-Gliadin IgA, Anti-TTG2 IgA, Anti-Gliadin (unspecified isotype), and Anti-Wheat.

  Four biomarkers for gluten sensitivity, Anti-EMA IgA, Anti-TTG2 IgG, Anti-DGP IgG, and Anti-Gluten, were not found to be associated with schizophrenia.4

• Relationship between schizophrenia and inheritance. The conditional test looking at the combined effect of the CLDN5 gene, involved in forming permeability barriers, and the DQB1 genetic marker associated with celiac disease demonstrated these two genes possibly work together in conferring a susceptibility to schizophrenia.5
• Relationship between schizophrenia and Hypoperfusion (low blood flow) of the left frontal brain area without structural cerebral abnormalities was demonstrated in a patient with schizophrenia, and the dysfunction disappeared after gluten free diet.6
• Relationship between schizophrenia and wheat exomorphines. Wheat gluten hydrolysates, called exomorphines, exhibit a high opioid-like activity in isolated peptides. While some peptides showed no activity, 0.5 mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay and were derived from the gliadin fraction of gluten.7

How Prevalent Is Schizophrenia In Celiac Disease and/or Gluten Sensitivity?

• Gluten sensitivity is common in schizophrenia.8
• Psychotic symptoms often occur in adult celiac disease.9
• A prevalence study among schizophrenia patients showed that 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group.  Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group.3

What Are The Symptoms Of Schizophrenia?

Schizophrenia is marked by the following symptoms:

• Confusion.
• Delusions.
• Hallucinations.
• Disorganized speech and behavior.
• Lack of insight.
• Flat affect.
• Social withdrawal.
• Absence of volition (desire to act).

How Does Schizophrenia In Celiac Disease and/or Gluten Sensitivity Develop?

• Gluten exerts a primary schizophrenia-promoting effect evidenced by improvement with gluten withdrawal and exacerbation with reinstatement.10,11
• Schizophrenia in celiac disease results from exposure to gluten through increased intestinal permeability of the small intestine and malnutrition in celiac disease involving deficiencies of vitamin C, vitamin B12 (causing paranoia in particular), magnesium, and EPA (omega-3 fatty acid). Beta-lactoglobulin and casein from cow’s milk are also involved in producing symptoms.12
• Gluten appears to exert an innate immune response.13 An innate response involves inflamation caused by gluten but does not involve the production of celiac antobodies.

Does Schizophrenic Symptoms Respond To Gluten-Free Diet?

Yes. Schizophrenia improves and may resolve on gluten free diet.14,9,15

6 Steps To Improve Schizophrenia In Celiac Disease and/or Gluten Sensitivity:

• 1Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

• 2 Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

• 3 Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• 4 Manage Your Medications Safely:

• 5Nutritional Supplements To Help Correct Deficiencies:

• 6Manage Natural Remedies: 

What Do Medical Research Studies Tell About Schizophrenia In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia.” This study investigating the relationship between gluten sensitivity and schizophrenia shows that identifying people in schizophrenia who may benefit from a gluten-free diet remains possible by blood test only.

100 people with schizophrenia compared to 100 matched controls replicates a higher prevalence of gluten sensitivity and higher mean antigliadin IgG antibody levels in schizophrenia (2.9±7.7 vs. 1.3±1.3, p=0.046, controlled for age).

Additionally, examination of symptoms within the schizophrenia group found that while positive symptoms are significantly lower in people who have elevated antigliadin antibodies (AGA; 4.11±1.36 vs. 6.39±2.99, p=0.020), no robust clinical profile (set of symptoms) differentiates between positive and negative antibody groups.18

“Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis.” This systematic literature review investigated which serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia in original articles that measured biomarkers of gluten sensitivity in patients with schizophrenia and non-affective psychoses compared to a control group. Findings show that not all serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. However, the specific immune response to gluten in this population differs from that found in patients with celiac disease.

Three databases were used: Ovid MEDLINE, Psych INFO, and Embase, dating back to 1946. Forward tracking and backward tracking were undertaken on retrieved papers. A meta-analysis was performed of specific biomarkers and reported according to MOOSE guidelines.

In 12 relevant original articles 5 biomarkers of gluten sensitivity were found to be significantly elevated in patients with non-affective psychoses compared to controls: Anti-Gliadin IgG , Anti-Gliadin IgA , Anti-TTG2 IgA, Anti-Gliadin (unspecified isotype), and Anti-Wheat.

Four biomarkers for gluten sensitivity, Anti-EMA IgA, Anti-TTG2 IgG, Anti-DGP IgG, and Anti-Gluten were not found to be associated with schizophrenia.4

“Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients.” This analysis focuses on transglutaminase 6 (tTG6) antibodies (show brain inflammation) in schizophrenia (SZ) and its relationships to raised tTG2 and to antigliadin antibodies to try to understand why an increased prevalence of tTG2 antibodies in gluten sensitive SZ patients compared with healthy controls was not paralleled by an increased prevalence of antiendomysial antibody which is a marker for celiac disease.

To elucidate this discrepancy, researchers examined those tTG2 positive SZ patients from a previous study for the presence of tTG6 antibody and also searched for tTG6 antibodies in their sample of antigliadin (AGA) positive and AGA and tTG2 negative SZ patients. Seventy-four tTG2 positive SZ patients were compared with 148 age and gender-matched healthy controls. Of the 74 tTG2 positive SZ patients, 16 were positive for tTG6 IgA for a prevalence of 22%. Only 4 healthy controls were positive for tTG6 IgA for a prevalence of 2.7%.

Among the AGA positive SZ patients, the prevalence of tTG6 IgA was 21.3% while 13.1% of the AGA and tTG2 negative SZ patients were positive for tTG6 IgA. The healthy controls  had a prevalence of 6%. Results indicate a higher prevalence of tTG6 antibodies in SZ that may represent a biomarker useful to identify SZ patients who would benefit from a gluten-free diet.19

“Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population.” This study investigating antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group found that persons with schizophrenia have higher than expected titers of antibodies related to celiac disease and gluten sensitivity.

AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race.

Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group.  Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group.  Adjustments for sex, age, and race had trivial effects on the differences.20

“Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia.” This study investigating increased immune sensitivity to gluten in schizophrenia found that individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

The sample of 471 individuals included 129 with recent-onset psychosis, 191 with multi-episode schizophrenia, and 151 controls. Immunoglobulin (Ig)G and IgA antibodies to gliadin and to tissue transglutaminase, and IgG antibodies to deamidated gliadin were measured. Quantitative levels of antibodies in the psychiatric groups were compared with controls. All participants were categorized as to whether their levels of antibodies met standardized cutoffs for celiac disease. HLA DQ2 and HLA DQ8 alleles were detected by real-time polymerase chain reaction.

Individuals with recent-onset psychosis had increased levels of IgG (odds ratio [OR] 5.50; 95% confidence interval [CI] 2.65-11.42) and IgA (OR 2.75; 95% CI 1.31-5.75) antibodies to gliadin compared with control subjects. Individuals with multi-episode schizophrenia also had significantly increased levels of IgG antibodies to gliadin (OR 6.19; 95% CI 2.70-14.16).
IgG antibodies to deamidated gliadin and IgA antibodies to tissue transglutaminase (tTG) were not elevated in either psychiatric group, and fewer than 1% of individuals in each of the groups had levels of these antibodies predictive of celiac disease. There were no significant differences in the distribution of the HLA DQ2/8 alleles among the groups.21

“Specific IgA antibody increases in schizophrenia.” This study demonstrated more schizophrenics than controls showed IgA antibody levels above the upper limit to gliadin from wheat and beta-lactoglobulin and casein from cow’s milk.22

“Is schizophrenia rare if grain is rare?” This study testing the hypothesis that neuroactive peptides from gluten grains are major agents evoking schizophrenia in those with the genotypes demonstrated gluten is harmful.23

“Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates.” This study determining the origin of peptides that exhibit opioid activity demonstrated a high opioid-like activity in isolated peptides from wheat gluten hydrolysates. While some peptides showed no activity, 0.5mg of the most active peptides were equivalent to 1 nM of morphine in the binding assay and were derived from the gliadin fraction of gluten.7

“Wheat gluten as a pathogenic factor in schizophrenia.” This study demonstrated that gluten exerts a primary schizophrenia-promoting effect evidenced by improvement with gluten withdrawal and exacerbation with reinstatement.15

CASE REPORT SUMMARIES

“Psychosis revealing a silent celiac disease in a young woman with trisomy 21.” This case report of a patient with Down’s syndrome with psychosis, describes subsequent diagnosis of Celiac Disease with spectacular and lasting improvement after 12 months on a Gluten Free Diet.24

“Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet.” This case report of SPECT examination of a patient with “schizophrenic disorder” with undiagnosed and untreated Celiac Disease demonstrated hypoperfusion (low blood flow) of the left frontal brain area, without structural cerebral abnormalities. Dysfunction disappeared after Gluten Free Diet.25

1. Pagsberg AK, Tarp S, Glintborg D, Stenstrøm AD, Fink-Jensen A, Correll CU, Christensen R. Antipsychotic treatment for children and adolescents with schizophrenia spectrum disorders: protocol for a network meta-analysis of randomised trials. BMJ Open. 2014 Oct 10;4(10):e005708. doi: 10.1136/bmjopen-2014-005708. [↩]
2. Jessica R. Jackson, William W. Eaton, Nicola G. Cascella, Alessio Fasano, and Deanna L. Kelly Neurologic and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivity. Psychiatr Q. Mar 2012; 83(1): 91–102. doi:  10.1007/s11126-011-9186-y [↩]
3. Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, Fasano A, Eaton WW. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2011 Jan;37(1):94-100. doi: 10.1093/schbul/sbp055. [↩] [↩]
4. Lachance LR, McKenzie K. Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis. Schizophr Res. 2014 Feb;152(2-3):521-7. doi: 10.1016/j.schres.2013.12.001. [↩] [↩]
5. Wei J, Hemmings GP. Gene, gut and schizophrenia: the meeting point for the gene-environment interaction in developing schizophrenia. Medical Hypotheses. 2005;64(3):547-52. [↩]
6. De Santis A, Addolarato G, Romito A, et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. Journal of Internal Medicine. Nov 1997;242(5):421-3. [↩]
7. Huebner FR, Lieberman KW, Rubino RP, Wall JS. Demonstration of high opioid-like activity in isolated peptides from wheat gluten hydrolysates. Peptides. Nov-Dec 1984;5(6):1139-47. [↩] [↩]
8. Potocki P, Hozyasz K. Psychiatric symptoms and coeliac disease. Psychiatria Polska. Jul-Aug 2002;36(4):567-78. [↩]
9. Wei J, Hemmings GP. Gene, gut and schizophrenia: the meeting point for the gene-environment interaction in developing schizophrenia. Medical Hypotheses. 2005;64(3):547-52. [↩] [↩]
10. Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science. Jan 30, 1976;191(4225):401-2. [↩]
11. Rudin DO. The choroid plexus and system disease in mental illness. III. The exogenous peptide hypothesis of mental illness. Biological Psychiatry. May 1981;16(5):489-512. [↩]
12. Reichelt KL, Landmark J. Specific IgA antibody increases in schizophrenia. Biological psychiatry. Mar 15, 1995;37(6):410-3. [↩]
13. Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull. 2013 Jul;39(4):867-71. doi: 10.1093/schbul/sbs064. [↩]
14. Serratrice J, Disdier P, Kaladjian A, et al. Psychosis revealing a silent celiac disease in a young woman with trisomy 21. La Presse Medicale. Oct 12, 2002;31(33):1551-3. [↩]
15. Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science. Jan 30, 1976;191(4225):401-2. [↩] [↩]
16. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
17. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩] [↩]
18. Jackson J, Eaton W, Cascella N, Fasano A, Santora D, Sullivan K, Feldman S, Raley H, McMahon RP, Carpenter WT Jr, Demyanovich H, Kelly DL. Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophr Res. 2014 Oct 10. pii: S0920-9964(14)00511-8. doi: 10.1016/j.schres.2014.09.023. [↩]
19. Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull. 2013 Jul;39(4):867-71. doi: 10.1093/schbul/sbs064. [↩]
20. Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, Fasano A, Eaton WW. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr Bull. 2011 Jan;37(1):94-100. doi: 10.1093/schbul/sbp055. [↩]
21. 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 Jul 1;68(1):100-4. doi: 10.1016/j.biopsych.2010.03.021. [↩]
22. Reichelt KL, Landmark J. Specific IgA antibody increases in schizophrenia. Biological psychiatry. Mar 15, 1995;37(6):410-3. [↩]
23. Dohan FC, Harper EH, Clark MH, Rodriguez RB, Zigas V. Is schizophrenia rare if grain is rare?Biological Psychiatry. Mar 1984;19(3):385-99. [↩]
24. Serratrice J, Disdier P, Kaladjian A, et al. Psychosis revealing a silent celiac disease in a young woman with trisomy 21.La Presse Medicale. Oct 12, 2002;31(33):1551-3. [↩]
25. De Santis A, Addolarato G, Romito A, et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. Journal of Internal Medicine. Nov 1997;242(5):421-3. [↩]