This study purpose is to conduct a confirmatory double-blind randomized controlled trial in an inpatient setting of the effects of a tightly controlled gluten-free diet (GFD) to improve negative symptoms in people with schizophrenia or schizoaffective disorder who have antibodies to gliadin (AGA IgG). As part of the project investigators will also confirm outcomes such as cognitive symptoms, changes in peripheral and central inflammation as well as gut/blood brain barrier permeability.

This study is a randomized double blind clinical trial being funded by NIMH. Investigators will need to enroll 40 cases with AGA IgG positivity in order to present a powered and convincing result about the efficacy of gluten withdrawal in the subpopulation of persons with schizophrenia with elevated AGA IgG levels. Investigators will recruit a minimum 50 to ensure they are well powered without question, and to account for dropouts. Investigators will use a battery of measures of peripheral and central inflammation as well as gut permeability at baseline and endpoint to confirm the relationship of these outcomes to changes in AGA IgG and symptom changes in the clinical trial. Investigators will test negative symptoms as a primary outcome but will test changes in other symptom domains such as positive symptoms. After the completion of the 5 week confirmatory study, investigators will discharge participants and follow them for 8 weeks in their own environment to test the maintenance of the effect following the stringent GFD, and provide education on gluten free shopping, cooking and eating.

Inclusion Criteria:

1. DSM-IV/DSM 5 diagnosis of schizophrenia or schizoaffective disorder
2. Positive for antibodies to gliadin (IgG > 20 U)
3. SANS total score ≥ 20 and the affective flattening or alogia global item ≥ 3
4. Age 18- 64 years
5. Same antipsychotic for at least 4 weeks
6. Ability to consent determined by a score of 10 or greater on the Evaluation to Sign Consent.

Exclusion Criteria:

1. Persons already on gluten free diets

2. Positivity to tissue transglutaminase (tTg) antibodies or known history of Celiac Disease

3. Pregnant or lactating females

4. Medical condition whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol

5. Meets DSM-5 criteria for alcohol or substance use disorder (other than nicotine) within the last month

6. Gluten ataxia, as measured by the Brief Ataxia Rating Scale

   Additional exclusion for those participating in optional imaging component:

7. Non-removable ferromagnetic metal on or within the body

8. Current claustrophobia

9. Inability to lie supine for 1.5 hours