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

This study will recruit persons with schizophrenia or schizoaffective disorder and will use an oral glucose tolerance test to test the hypothesis that insulin resistance drives inflammation.

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. Increased inflammation has been reliably linked to deficits in reward processing and decreased motivation via effects of inflammatory cytokines on regions of the basal ganglia, including the ventral striatum. 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. Relevant to the impact of inflammation on insulin signaling, measures of insulin sensitivity are significantly worse in patients with schizophrenia, including at illness onset. Moreover, antipsychotic medications lead to metabolic syndrome, contributing to risk for insulin resistance and ultimately diabetes. Insulin resistance is believed to be caused by increased inflammation, and in turn can contribute to inflammation through alterations in glucose metabolism.

This study uses an oral glucose tolerance test to test the hypothesis that insulin resistance drives inflammation. The researchers will recruit subjects with a range of insulin resistance, as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). This will allow the researchers to investigate the contributions of metabolic dysfunction and inflammation on inflammatory and metabolic markers, brain reward circuitry, motivational deficits, and negative symptoms.

Eligibility Criteria:
Inclusion Criteria:

* Willing and able to give written informed consent
* A primary diagnosis of schizophrenia, per the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5), or schizoaffective disorder as diagnosed by the Mini International Neuropsychiatric Interview (MINI) 7.0
* Mini Mental Status Examination Score ≥24
* Brief Negative Symptom Scale Score ≥25
* 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)

Exclusion Criteria:

* Evidence of untreated or poorly controlled endocrine, thyroid, cardiovascular, hematological, renal, neurological disease, hepatitis B or C or HIV
* Current HbA1C ≥ 8.5%
* 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 (patients may still be included with a positive tetrahydrocannabinol (THC) result at the discretion of the PI)
* 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 central nervous system trauma or active seizure disorder requiring medication
* Positive pregnancy test
* Presence of metal in the body (excludes from MRI scan only)
* Active suicidal ideation as determined by the PI and/or study staff
* Diagnosis of diabetes mellitus