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

Not Applicable

Completed

• Conditions: Schizophrenia
• Interventions: Other: Oral Glucose Tolerance Test (OGTT)

• Registration Number: NCT03818516
• Lead Sponsor: Emory University

Brief Summary

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.

Detailed Description

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-01-19
• Study First Submitted QC: 2019-01-24
• Study First Posted: 2019-01-28
• Study Start: 2020-08-31
• Primary Completion: 2022-03-01
• Study Completion: 2022-03-01
• Results First Submitted: 2023-12-14
• Status Verified: 2024-04
• Results First Submitted QC: 2024-04-08
• Last Update Submitted: 2024-04-08
• Results First Posted: 2024-05-02
• Last Update Posted: 2024-05-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Oral Glucose Tolerance Test (OGTT)	Oral Glucose Tolerance Test (OGTT)	Medically stable participants with schizophrenia and a range of insulin resistance will have an oral glucose tolerance test.

Primary Outcome Measures

Name	Time	Method
Effort-Expenditure for Rewards Task (EEfRT) Score	Baseline, Hour 1	EEfRT is a multitrial game task assessing motivation in which participants choose between 2 different task difficulty levels to obtain monetary rewards. For all trials, participants make repeated manual button presses which raises the level of a virtual ''bar'' viewed onscreen by the participant. Participants are eligible to win the money allotted for each trial if they raise the bar to the ''top''. Each trial presents subjects with a choice between 'high effort' and 'low effort' tasks that require different amounts of button pressing. Reward magnitudes for the high-effort task vary between amounts, while reward magnitudes for the low-effort task remain constant. Trials also vary in terms of 3 levels of probability of winning the amount associated with the choice selected. The first 50 trials are used for analysis. Percentage of hard-task choices across all levels of probability is calculated from all hard choices. Lower percentages of hard task choices indicate decreased motivation.

Secondary Outcome Measures

Name	Time	Method
Finger Tapping Task (FTT) Score	Baseline, Hour 1	The Finger Tapping Task (FTT) uses a specially adapted tapper that the subject is asked to tap as fast as possible. The subject is given 5 consecutive 10-second trials for the preferred and non-preferred hands.The FTT is design to assess subtle motor impairment and found to be altered in subjects with basal ganglia disorders and lesions. The finger tapping score is the mean number of taps of 5 trials and is computed for each hand.
Profile of Mood States (POMS) Brief Score	Baseline, Hour 1	The POMS is a 30-item rating scale designed to measure mood states across short periods. The POMS assess six mood factors: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. Each item is rated on a 5-point scale where 0 = not at all and 4 = extremely. Total scores range from 0 to 120 and lower scores indicate a better state of mood.
Trail Making Test Part A (TMT-A) Score	Baseline, Hour 1	The Trail Making Test-A is a timed task that provides information on motor function and speed of processing. In Part A of the TMT participants connect circles labeled with numbers, in ascending order. The score is the amount of time it takes for the participant to complete the task. The average time it takes to complete the task is 29 seconds and times longer than 78 seconds suggest a deficiency.
Digit Symbol Substitution Task (DSST) Score	Baseline, Hour 1	The DSST is a subtest of the Wechsler Adult Intelligence Scale and involves graphimotor speed, visual scanning and memory, with about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% by memory. Performance on the Digit Symbol Test has been found to correlate with subcortical (caudate) atrophy in disorders involving the basal ganglia. Respondents match symbols to numbers using a key presented at the top of the test page. The score is the number of correctly entered symbols in the given time period and higher scores indicate better performance.

Trial Locations

Locations (6)

Emory University Clinical Research Network; 🇺🇸 Atlanta, Georgia, United States

Emory Clinic, Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States

Emory University Department of Psychiatry and Behavioral Sciences; 🇺🇸 Atlanta, Georgia, United States

Grady Health System (non-CRN), Grady Health System (CRN), Ponce Center; 🇺🇸 Atlanta, Georgia, United States

Emory Universtiy; 🇺🇸 Atlanta, Georgia, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States