Impact of Inflammation on Reward Circuits, Motivational Deficits and Negative Symptoms in Schizophrenia

Schizophrenia is a severe mental illness that affects 1% of the population, but accounts for
over $60 billion in costs to the national healthcare system. Negative symptoms of
schizophrenia, including motivational deficits, are some of the most debilitating aspects of
the disorder, being both difficult to treat and representing one of the most significant
barriers to functional recovery.One pathophysiologic pathway that may contribute to these
alterations in reward circuitry in schizophrenia is inflammation.

Previous work has demonstrated that inflammatory stimuli decrease neural activity in the
ventral striatum and decrease connectivity in reward-relevant neural circuitry. Previous
findings show that some patients with schizophrenia reliably exhibit elevated concentrations
of inflammatory markers and that inflammatory cytokines may be related to negative symptoms
including decreased motivation. Based on these findings the study wants to determine the
impact of inflammation on reward circuitry in patients with schizophrenia using both
task-based and resting state functional magnetic resonance imaging and also the impact of
inflammation on objective and clinical measures of motivation and negative symptoms. The
study also wants to evaluate the effect of an anti-inflammatory challenge on reward
circuitry, motivational deficits, and negative symptoms in a subset of patients with high
inflammation. This study aims to inform future studies of novel therapeutic strategies to
treat negative symptoms in patients with schizophrenia.

Inclusion Criteria:

- willing and able to give written informed consent;

- a primary diagnosis of Diagnostic and Statistical Manual -V schizophrenia or
schizoaffective disorder as diagnosed by the Mini International Neuropsychiatric
Interview for Schizophrenia and Psychotic Disorders (MINI) 6.0;

- Mini Mental Status Examination Score ≥24; e. no psychotropic medication changes for
one month prior to study enrollment; may be taking other psychotropic
non-antipsychotic medications (i.e., antidepressants, mood stabilizers,
benzodiazepines);

- will have a CRP >3 mg/L.

Exclusion Criteria:Exclusion criteria will be split between those related to data quality
and those related to subject safety. Data quality exclusion criteria may be waived at the
discretion of the PI, though those exclusion criteria for subject safety may not be waived
under any circumstances

- Data Quality Exclusion Criteria:

- evidence of untreated or poorly controlled endocrine, thyroid, cardiovascular,
hematological, renal, neurological disease, hepatitis B or C or HIV;

- prior treatment with antiviral or immunomodulatory drugs, including
corticosteroids within six months of study entry;

- current treatment with antibiotics;

- primary diagnosis of major depressive disorder or bipolar disorder;

- active abuse of alcohol or illicit/prescription drugs within the past 6 months
including a urine toxicology screen positive for drugs of abuse;

- predominant left-handedness excluded for portions of the MRI scan;

- Wide Range Achievement Test-3 Reading Scale (WRAT-3) score indicating less than
8th grade reading level, unless otherwise approved by the PI or PI's designee;

- any other condition which in the opinion of the investigator would make the
patient unsuitable for enrollment, or could interfere with participating in or
completing the protocol.

- history of tuberculosis or high risk of tuberculosis exposure;

- history of fungal infection;

- history of any type of cancer;

- women of child bearing potential who are not using a medically accepted means of
contraception;

- heterosexual males and their partners who do not agree to practice appropriate
birth control;

- known allergy to murine products or other biologic therapies;

- previous organ transplant; h) treatment with clozapine (given increased risk of
neutropenia/agranulocytosis).

- Subject Safety Exclusion Criteria:

- history of central nervous system trauma or active seizure disorder requiring
medication;

- positive pregnancy test;

- presence of metal in the body;

- active suicidal ideation as determined by the PI and/or study staff.