PI moved to another institution before enrollment could start.

In a double-blinded, randomized, parallel controlled design, patients with schizophrenia spectrum disorder will be exposed to a single dose of lipopolysaccharide (LPS) (LPS-patient). Clinical symptoms, blood samples, and brain imaging will be assessed at baseline and after LPS. There will be two comparison groups. Comparison groups include an age- and sex-matched healthy control group also exposed to the same LPS (LPS-control), and an age- and sex-matched sample of patients with schizophrenia on placebo (Placebo-patient). As in Phase I studies, multiple interim analyses are expected so the current design may be modified, which will be communicated during annual reports (21CFR312.30).

Schizophrenia spectrum disorders are a major public health burden due to functional and cognitive impairment, psychosis and other symptoms, and high comorbidity. Unfortunately, current therapies have limited effectiveness in treating some of the symptoms and most of the cognitive deficits. Alternative biological models of the disease are needed for developing new and more effective treatment. Neuroinflammation has increasingly been implicated in the pathophysiology of schizophrenia. Patients with schizophrenia have signs of low-grade, chronic inflammation, including elevated blood levels of pro-inflammatory cytokines and other immune markers. Administration of LPS is the standard immune challenge to investigate the body's immune response in a wide range of disorders. Our goal is to use LPS to investigate whether schizophrenia patients have abnormal immune response to LPS and whether the abnormality is associated with specific brain imaging biomarkers.

Inclusion Criteria:

1. Age 18-55
2. Patients must be on antipsychotic medication and clinically stable, defined as no hospitalization or major change in antipsychotic medication in the past 4 weeks
3. Patients must pass the ESC with score 10 or above
4. BMI 35 or less -

Exclusion Criteria:

1. History of major medical illness including, but not limited to, history of heart attack, stroke, TIA (transient ischemic attack)

2. History of organic brain disorders that may affect neurophysiological measurements, including seizure disorder, brain tumor, head injury with evidence of significant cognitive deterioration

3. DSM diagnosis of substance use disorder within 6 months except nicotine and marijuana

4. Prior suicide attempt or frequent suicidal ideations, or current suicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)

5. Women who have positive urine pregnancy tests; Women who plan to become pregnant, or are breastfeeding

6. Frequent (more than once) history of syncope (fainting) of unknown reason

7. Unable to undergo MRI scanning due to metallic devices or objects or claustrophobia

8. Presence of co-morbid inflammatory disorders such as rheumatoid arthritis

9. Presence of acute or chronic infection; have received flu or similar vaccine in the past 4 weeks

10. Current regular use of non-steroidal anti-inflammatory drugs or immune modifying drugs

11. Clinically significant abnormalities on screening laboratory tests

12. Blood pressure <90/60 or > 150/100, or pulse <55 or > 100 beats/minute, or temperature > 99.5°F

13. 12-Lead ECG demonstrating QTcF >450 msec or a QRS interval >120 msec. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject's eligibility

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