- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05748990
Does Abnormal Insulin Action in the Brain Underlie Cognitive and Metabolic Dysfunction in Schizophrenia
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
i) Schizophrenia and cognition: Cognitive impairment is a core aspect of schizophrenia (SCZ), contributing to disability and poor functional outcomes. Antipsychotics reduce positive symptoms but there are no currently approved treatments for cognitive impairment, creating a large unmet need.
ii) Schizophrenia and metabolic dysfunction: Patients with SCZ also have exceedingly high rates of metabolic comorbidity. Almost half of patients are obese and the prevalence of type 2 diabetes is 3-9 fold higher than the general population. Patients with SCZ die on average 15-20 years earlier than the general population from cardiovascular disease. Thus, metabolic health represents another large unmet need.
iii) Association between cognitive and metabolic dysfunction: These two domains of dysfunction interact in an additive manner to worsen outcomes. Metabolic syndrome and diabetes are both associated with worse cognition among SCZ patients. Recent knowledge elucidating the interactions between metabolic health, cognition, and functioning have encouraged a reconceptualization of SCZ as both a metabolic and cognitive disorder, prompting search for treatment strategies that address abnormalities in both these aspects.
iv) Brain insulin as a unifying link: There has been recent recognition that insulin plays an important role in the brain. Brain insulin is implicated in several processes relevant to SCZ. Abnormal brain insulin action may help explain both cognitive and metabolic aberrations in patients with SCZ. Moreover, it is now clear that glucose uptake in the brain is partially dependent on insulin in brain regions relevant to SCZ, such as the hippocampus, hypothalamus, and striatum.
v) Evidence and promise in SCZ: There is preliminary evidence to suggest that brain insulin resistance is associated with worse cognition. A magnetic resonance spectroscopy (1H-MRS) study found higher brain glucose and lower glucose utilization in SCZ patients, suggesting brain insulin resistance, that were associated with memory impairment. Initial intervention studies using intranasal insulin have not been successful, likely because resistance to insulin in the brain prevents any benefits of intranasal insulin from accruing. However, this has not been conclusively demonstrated. This study seeks to answer this question directly.
vi) Role of 18-fluorodeoxyglucose ([18F]-FDG)-positron emission tomography (PET): 1H-MRS is an indirect and imprecise measure of glucose in the brain (it combines intra- and extracellular glucose). This is also true for other MRI based measures, which have recently been employed to indirectly study insulin action in the brain. Currently, there are no PET ligands able to reliably quantify insulin or its receptors in the brain. However, using [18F]-FDG PET, it is possible to measure differences in glucose uptake, with and without an insulin challenge, into insulin sensitive regions of the brain (e.g. hippocampus and striatum). This can serve as a surrogate marker of brain insulin action. This principle has already been used successfully in rodents and healthy humans, and offers a more direct method of quantifying brain insulin action.
In this study, [18F]-FDG PET will be employed to examine whether abnormal brain insulin action is a feature of SCZ. The study examines young antipsychotic-naïve/free SCZ patients to minimize medication-related confounds. Insulin (160 IU; shown to be safe and effective previously) will be delivered intranasally as it has been shown to be reliable method of delivering insulin to the brain.
Primary hypothesis: SCZ patients will have reduced [18F]-FDG uptake, in response to an intranasal insulin challenge, compared to healthy controls.
Study Type
Enrollment (Estimated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Mahavir Agarwal, MD, PhD
- Phone Number: 30546 416-535-8501
- Email: mahavir.agarwal@camh.ca
Study Contact Backup
- Name: Laurie Hamel, MA
- Phone Number: 30544 416-535-8501
- Email: laurie.hamel@camh.ca
Study Locations
-
-
Ontario
-
Toronto, Ontario, Canada, M6J1H3
- Recruiting
- Centre for Addiction and Mental Health
-
Principal Investigator:
- Mahavir Agarwal, PhD, MBBS, MD
-
Contact:
- Laurie Hamel
- Phone Number: 4165358501
- Email: laurie.hamel@camh.ca
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
i) Experimental group (participants with a diagnosis of schizophrenia spectrum disorder):
- Antipsychotic naïve or antipsychotic treatment for equal to or less than 3 weeks within the past 3 months
- (Medications can be confirmed via CAMH chart review). Participants do not need to remain off of antipsychotics for the duration of the study.
- 17-45 years
- both sexes;
- Patients with first-episode schizophrenia spectrum illness: Primary DSM-5 diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, brief psychotic disorder, psychotic disorder NOS, major depressive disorder with psychotic symptoms, bipolar I disorder, and bipolar II disorder, OR substance-induced psychosis, and antipsychotic treatment for schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum, other psychotic disorder, major depressive disorder with psychotic symptoms, bipolar I disorder, and bipolar II. (Diagnosis willbe confirmed via CAMH chart review).
- BMI under or equal to 27
- Right-handed
ii) Control group (healthy controls):
- 17-45 years of age
- sex-,
- hand dominance (right-handed) -and
- body mass index (BMI)-matched
- Absence of DSM-5 diagnosis other than a specific phobia according to MINI
Exclusion Criteria:
1) moderate or severe substance use according to MINI (per PI discretion in the case of moderate alcohol or cannabis use)
- prediabetes, diabetes, or evidence of impaired glucose tolerance on screening OGTT
- acute suicidal risk
- use of weight, lipid, antidiabetic or blood pressure reducing agents
- liver or kidney disease
- pregnancy
- nursing
- pacemakers
- metallic cardiac valves
- magnetic material such as surgical clips, implanted electronic infusion pumps or any other conditions that would preclude the MRI scan
- clinically significant claustrophobia (determined from MRI screening form; significance evaluated as per QI's discretion).
- history of head trauma resulting in loss of consciousness > 30 minutes that required medical attention;
- size of head, neck, precluding to fit in the MRI or PET scanners
- weight over 350lbs (limit for MRI scanner bed)
- unstable physical illness
- significant neurological disorder including a seizure disorder;
- Received maximum allowed radiation in the past 12 months (20 mSv)
- Completed more than 6 PET scans/ lifetime, that, together with the PET scanning procedures under this protocol will bring the total number of PET scans to more than the allowed/lifetime (8 PET scans per lifetime). These limits are set by the Centre for Addiction and Mental Health Brain Health Imaging Centre Guideline.
- clinically relevant abnormality observed in medical history,
- current intake of any medication that may interfere with participation in the study or may confound the results of PET imaging (e.g. anti-diabetic medication).
- Disorders of coagulation, blood or ongoing use of anticoagulant medication
Control group: Exclusionary criteria are as listed above for participants, in addition to:
1) First degree family member with primary psychotic disorder.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Schizophrenia Group
Insulin (160IU) or placebo is administered intranasally 15 minutes prior to the PET scan.
|
160 IU insulin (Humalog) is administered intranasally using a metered spray bottle 15 minutes prior to the PET scan.
Other Names:
0.9% saline is administered intranasally using a metered spray bottle 15 minutes prior to the PET scan.
Other Names:
|
Experimental: Healthy Control Group
Insulin (160 IU) or placebo is administered intranasally 15 minutes prior to the PET scan.
|
160 IU insulin (Humalog) is administered intranasally using a metered spray bottle 15 minutes prior to the PET scan.
Other Names:
0.9% saline is administered intranasally using a metered spray bottle 15 minutes prior to the PET scan.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
[18F]-FDG brain uptake
Time Frame: Scan duration is ~90 minutes
|
Change in [18F]-FDG uptake in striatum and hippocampus is measured in response to intranasal insulin challenge or placebo
|
Scan duration is ~90 minutes
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 154-2020
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Healthy
-
Prevent Age Resort "Pervaya Liniya"RecruitingHealthy Aging | Healthy Diet | Healthy LifestyleRussian Federation
-
Maastricht University Medical CenterCompletedHealthy Volunteers | Healthy Subjects | Healthy AdultsNetherlands
-
Yale UniversityNot yet recruitingHealth-related Benefits of Introducing Table Olives Into the Diet of Young Adults: Olives For HealthHealthy Diet | Healthy Lifestyle | Healthy Nutrition | CholesterolUnited States
-
Hasselt UniversityRecruitingHealthy | Healthy AgingBelgium
-
Galera Therapeutics, Inc.Syneos HealthCompleted
-
Galera Therapeutics, Inc.Syneos HealthCompletedHealthy | Healthy VolunteersAustralia
-
University of PennsylvaniaActive, not recruitingHealthy | Healthy AgingUnited States
-
Chalmers University of TechnologyGöteborg UniversityCompletedHealthy | Nutrition, HealthySweden
-
University of ManitobaNot yet recruitingHealthy | Healthy Diet
Clinical Trials on Intranasal insulin
-
Michigan State UniversityCompletedExercise | InsulinUnited States
-
Wake Forest University Health SciencesCompleted
-
University Health Network, TorontoCompleted
-
Texas Tech University Health Sciences CenterCompletedHypogonadotropic HypogonadismUnited States
-
University of BirminghamQueen Elizabeth Hospital NHS Foundation TrustCompleted
-
Johns Hopkins UniversityTerminatedHIV Dementia | HIV-Associated Cognitive Motor ComplexUnited States
-
University Health Network, TorontoCompletedInsulin Resistance, DiabetesCanada
-
Centre for Addiction and Mental HealthRecruitingDepression | Major Depressive DisorderCanada
-
HealthPartners InstituteJuvenile Diabetes Research Foundation; International Diabetes Center at Park...TerminatedType1diabetesUnited States
-
Rutgers, The State University of New JerseyAlzheimer's AssociationRecruitingMetabolic Syndrome | Alzheimer Disease | Mild Cognitive ImpairmentIsrael