This 16 week clinical trial investigates a precision-medicine approach to schizophrenia by targeting a biologically distinct subgroup,-approximately one-third of patients-characterized by the presence of anti-gliadin antibodies (AGA IgG+) which is associated with elevated inflammation in the IL-23/IL-17 immune axis (Th17 pathway). This specific biotype is associated with pronounced negative symptoms, cognitive deficits, and reduced white matter integrity. Building on evidence that this pathway can be modulated to improve clinical outcomes, we are conducting a randomized, double-blind clinical trial of mirikizumab, an FDA-approved monoclonal antibody targeting IL-23, in addition to current antipsychotics, in schizophrenia patients who are positive for AGA IgG.

The primary objective is to determine whether mirikizumab - a repurposed FDA approved monoclonal antibody treatment inhibiting IL-23-- will be superior to placebo in treating experiential (e.g., anhedonia and asociality) negative symptoms and cognitive impairments. Secondary aims will be to assess changes in T-cell subtypes and relative abundance by gene expression, peripheral cytokines, and neuroimaging markers (in a smaller subset). By focusing on this patient subgroup, who are identified by their immune status, the research aims to provide a targeted, revolutionary treatment for symptoms that have traditionally remained resistant to standard antipsychotic therapies.

This protocol includes a screening phase, with a separate consent form which is intended to identify those with AGA IgG antibodies. This screening portion will also serve to compare other aspects of immune functioning and the TH17 pathway between patient groups and controls in order to further characterize and show that Th17 (and similar immune cell lines) are different between AGA IgG positive, AGA IgG negative and healthy controls of either status.

Inclusion Criteria: Screening

• Age range of 18-64
• Schizophrenia Group: Meet meet DSM 5 criteria for schizophrenia or schizoaffective disorder
• Healthy Control Group: Does NOT meet DSM 5 criteria for schizophrenia or schizoaffective disorder, bipolar disorder, or major depressive disorder.

Exclusion Criteria: Screening

• Known current active infection, or taking an immunosuppressive medications (e.g. oral scheduled corticosteroids, chemotherapy or transplantation or HIV/AIDs associated drugs), or the scheduled use of anti-inflammatory medications, including NSAIDs (e.g. ibuprofen, celecoxib, or naproxen) or aspirin > 81 mg on a daily basis will be excluded.
• Score of less than 10/12 on the ESC

Inclusion Criteria: Clinical Trial

• Age range of 18-64
• Meet meet DSM 5 criteria for schizophrenia or schizoaffective disorder
• Personal and Social Performance (PSP) Scale score of ≤70.
• Treated with the same antipsychotic for at least 30 days and having received a constant therapeutic dose for at least 15 days prior to study entry
• One test in the past of elevated AGA IgG antibodies (AGA IgG > 15)

Exclusion Criteria: Clinical Trial

• Current infection, including HIV, and Hepatitis C (blood draw) or tuberculosis (TB*); or an organic brain disorder or 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.
• Currently taking immunosuppressive medications (e.g. oral scheduled corticosteroids, chemotherapy or transplantation or HIV/AIDs associated drugs); or the scheduled use of anti-inflammatory medications, including NSAIDs (e.g. ibuprofen, celecoxib, or naproxen) or aspirin > 81 mg on a daily basis will be excluded. The use of PRN anti-inflammatory agents will be allowed
• Score of less than 10/12 on the ESC