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

Primary Purpose

Schizophrenia

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Oral Glucose Tolerance Test (OGTT)

About this trial

This is an interventional basic science trial for Schizophrenia focused on measuring Inflammation, Magnetic Resonance Imaging (MRI), Negative Symptoms

Eligibility Criteria

18 Years - 59 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Emory University Department of Psychiatry and Behavioral Sciences
Grady Health System (non-CRN), Grady Health System (CRN), Ponce Center
Emory Clinic, Emory University Hospital
Emory University Clinical Research Network
Emory University
Emory Universtiy

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Oral Glucose Tolerance Test (OGTT)

Arm Description

Medically stable participants with schizophrenia and a range of insulin resistance will have an oral glucose tolerance test.

Outcomes

Primary Outcome Measures

Change in Fasting Blood Glucose

Fasting blood glucose will be assessed to determine the impact of insulin resistance on inflammatory markers.

Change in Fasting Blood Insulin

Fasting blood insulin will be assessed to determine the impact of insulin resistance on inflammatory markers.

Change in Plasma C-reactive Protein (CRP) Levels

Plasma CRP will be assessed to determine the impact of insulin resistance on inflammatory markers.

Change in Tumor Necrosis Factor (TNF)-alpha Levels

Fluorokine MultiAnalyte Profiling (MAP) Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. TNF-alpha levels before and after the OGTT will be examined.

Change in Soluble TNF Receptor 2 (sTNFR2) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. sTNFR2 levels before and after the OGTT will be examined.

Change in Interleukin-1 receptor antagonist (IL-1RA) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. IL-1RA levels before and after the OGTT will be examined.

Change in Interleukin-1beta (IL-1beta) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. IL-1beta levels before and after the OGTT will be examined.

Change in Interleukin-6 (IL-6) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. IL-6 levels before and after the OGTT will be examined.

Change in Soluble Interleukin-6 Receptor (sIL-6R) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. sIL-6R levels before and after the OGTT will be examined.

Change in Interleukin-10 (IL-10) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. IL-10 levels before and after the OGTT will be examined.

Change in Monocyte Chemoattractant Protein-1 (MCP-1) Levels

Fluorokine MAP Multiplex Human Biomarker Panels will be used to measure plasma inflammatory markers that have been found to be altered in schizophrenia. MCP-1 levels before and after the OGTT will be examined.

Secondary Outcome Measures

Change in Finger Tapping Task (FTT) Score

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.

Change in Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time Score

This reaction time test includes simple and choice reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses and providing distinction between reaction (or decision) time and movement latencies. Movement times on the CANTAB reaction time task have been slowed during interferon-alpha (IFN-α) treatment and correlated with IFN-alpha-induced depression and fatigue.

Change in Trail Making Test Part A (TMT-A) Score

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.

Change in Digit Symbol Substitution Task (DSST) Score

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.

Change in Effort-Expenditure for Rewards Task (EEfRT) Score

EEfRT is a multi-trial game task assessing motivation in which participants choose between two different task difficulty levels in order 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' task 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. The proportion of hard-task choices across each level of probability is calculated. Lower proportions of hard task choices indicate decreased motivation.

Change in Profile of Mood States (POMS) Brief Score

The POMS is a 30-item rating scale designed to measure mood states across short periods of time. 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.

Change in neural response to anticipating and receiving monetary rewards assessed by Monetary Incentive Delay (MID) Task

Assessment of reward anticipation will be achieved using the MID task, conducted during functional MRI (fMRI) neuroimaging. Briefly, during this task participants have the opportunity to win or lose money by making a rapid button press in response to a target visual stimulus. The primary epoch of interest is the "anticipatory delay" - a period of ~2000ms that occurs after participants have been informed how much money they can win or lose on a given trial, but prior to the presentation of the target. This epoch has repeatedly been associated with robust ventral striatal activity. Participants will complete 2 functional runs of between 50 and 200 trials each (the number of trials will be decided at the discretion of the PI), with evenly distributed reward magnitudes.

Change in Resting State Scan

For the resting state and task based functional connectivity analysis, whole brain, subject-level correlation maps indicating regional similarity with the striatal seed region time series will be generated and Fisher transformed to Z-score maps. In addition, data reduction strategies will be employed to address inflammatory marker collinearity in analyses combining relevant inflammatory markers. To assess significance of correlated activity with each bilateral seed region, paired t-tests will be conducted on participants' Z-score maps, adjusted for multiple comparisons. For significant brain regions, descriptive statistics will be used to characterize the mean, standard deviation, and standard error of the Z scores.

Change in neural response to reward motivation assessed by fMRI-adapted version of the EEfRT

Assessment of effort based decision making will be made using the EEfRT task adapted for fMRI. During each trial, subjects are presented with a choice between two levels of task difficulty, a High Effort option and a Low Effort option. Unlike in the behavioral version of the task, subjects will not be required to make button presses during the scan. The reward magnitude for a No Effort option remains constant, while the reward magnitude for the High Effort option varies. Additionally, the amount of effort required for the High Effort option will vary between 20%, 50%, 80% and 100% of the subject's maximum effort (set for each individual prior to scan).

Full Information

NCT ID

NCT03818516

First Posted

January 19, 2019

Last Updated

August 22, 2023

Sponsor

Emory University

Collaborators

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT03818516

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

August 31, 2020 (Actual)

Primary Completion Date

March 1, 2022 (Actual)

Study Completion Date

March 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

Collaborators

National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia

Keywords

Inflammation, Magnetic Resonance Imaging (MRI), Negative Symptoms

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Oral Glucose Tolerance Test (OGTT)

Arm Type

Experimental

Arm Description

Medically stable participants with schizophrenia and a range of insulin resistance will have an oral glucose tolerance test.

Intervention Type

Other

Intervention Name(s)

Oral Glucose Tolerance Test (OGTT)

Intervention Description

Participants will undergo a fasting blood draw for inflammatory and metabolic markers before a 75gm oral glucose tolerance test (OGTT) and at 1, 2 and 3 hours post-OGTT. Behavioral assessments will also be administered pre- and post-OGTT administration.

Primary Outcome Measure Information:

Title

Change in Fasting Blood Glucose

Description

Fasting blood glucose will be assessed to determine the impact of insulin resistance on inflammatory markers.

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Fasting Blood Insulin

Description

Fasting blood insulin will be assessed to determine the impact of insulin resistance on inflammatory markers.

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Plasma C-reactive Protein (CRP) Levels

Description

Plasma CRP will be assessed to determine the impact of insulin resistance on inflammatory markers.

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Tumor Necrosis Factor (TNF)-alpha Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Soluble TNF Receptor 2 (sTNFR2) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Interleukin-1 receptor antagonist (IL-1RA) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Interleukin-1beta (IL-1beta) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Interleukin-6 (IL-6) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Soluble Interleukin-6 Receptor (sIL-6R) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Interleukin-10 (IL-10) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Title

Change in Monocyte Chemoattractant Protein-1 (MCP-1) Levels

Description

Time Frame

Baseline, Hours 1, 2, and 3

Secondary Outcome Measure Information:

Title

Change in Finger Tapping Task (FTT) Score

Description

Time Frame

Baseline, Hour 1

Title

Change in Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time Score

Description

Time Frame

Baseline, Hour 1

Title

Change in Trail Making Test Part A (TMT-A) Score

Description

Time Frame

Baseline, Hour 1

Title

Change in Digit Symbol Substitution Task (DSST) Score

Description

Time Frame

Baseline, Hour 1

Title

Change in Effort-Expenditure for Rewards Task (EEfRT) Score

Description

Time Frame

Baseline, Hour 1

Title

Change in Profile of Mood States (POMS) Brief Score

Description

Time Frame

Baseline, Hour 1

Title

Change in neural response to anticipating and receiving monetary rewards assessed by Monetary Incentive Delay (MID) Task

Description

Time Frame

Baseline, Hour 3

Title

Change in Resting State Scan

Description

Time Frame

Baseline, Hour 3

Title

Change in neural response to reward motivation assessed by fMRI-adapted version of the EEfRT

Description

Time Frame

Baseline, Hour 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

59 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Goldsmith, MD

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University Department of Psychiatry and Behavioral Sciences

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30030

Country

United States

Facility Name

Grady Health System (non-CRN), Grady Health System (CRN), Ponce Center

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30303

Country

United States

Facility Name

Emory Clinic, Emory University Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Emory University Clinical Research Network

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Emory University

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Emory Universtiy

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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

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