Intranasal Insulin and Olanzapine Study in Healthy Volunteers (INI/OLA)

Effect of Antipsychotics on Central Insulin Action in Relation to Glucose Metabolism and Cognition in Healthy Volunteers

Antipsychotic (AP) medications are considered to be the gold standard treatment for psychotic disorders including schizophrenia. However, APs have also been commonly associated with serious metabolic adverse effects including weight gain and Type 2 Diabetes, with younger populations disproportionately affected. In addition, young individuals treated with these agents have also been found to be at high risk for glucose dysregulation, including higher rates of prediabetes, with significant associations found between AP use and insulin resistance. Due to the concerning prevalence of these AP metabolic effects, it becomes important to further elucidate the mechanisms underlying AP effects on glucose metabolism, which are still poorly understood. One potential underlying mechanism is insulin which has been found to regulate hepatic (liver) glucose production through insulin receptors in the brain. These insulin receptors also play a role in neuronal growth and memory, or more broadly, cognition. Preliminary data in rat models has demonstrated that the AP olanzapine (OLA) inhibits the ability of a central insulin stimulus (acting at the level of the brain) to decrease endogenous glucose production (EGP), making this mechanism a prime target to translate from rodent models to human research. Furthermore, intranasal insulin (INI) administration (an analogous central insulin stimulus) has been repeatedly associated with improved cognitive performance for verbal memory and visuospatial functions in humans. Given these findings and with the goal of translational research, the present study will investigate OLA's effects in healthy human volunteers including: (a) the ability of INI to reduce EGP during a pancreatic euglycemic clamp (PEC; a glucose metabolism and insulin procedure); and (b) the ability of INI to improve cognitive performance. More specifically, the present study hypothesizes that:

1. INI will be associated with a decrease in EGP relative to intranasal placebo (INP) as measured by the PEC. This effect will be inhibited if OLA is co-administered.
2. OLA administration will be associated with decrements in cognitive measures (i.e., visuospatial, and verbal memory) as compared to placebo (PL). Additionally, OLA co-administration will block the beneficial effects of INI on cognition previously supported by other studies.
3. INI will result in adaptive changes in neurochemical and neurohemodynamic measures as studied using MRI imaging techniques.

Study Overview

• Status: Recruiting
• Conditions: Healthy Controls
• Intervention / Treatment: Drug: OLANZapine 2.5 MG; Drug: Placebo; Drug: Insulin Lispro 100 UNT/ML; Other: Saline

Detailed Description

The primary objective of the study is to examine whether a single dose of OLA given to young healthy volunteers during PECs can inhibit the activity of a central insulin stimulus (i.e, INI) to reduce endogenous glucose production. Secondarily, in an exploratory arm, this study seeks to examine whether a single dose of OLA can inhibit improvements associated with INI administration on specific cognitive domains (visuospatial, and verbal memory). Further, the study will also explore the effects of insulin and OLA on neurochemical and neurohemodynamic measures obtained through MRI imaging techniques.

To accomplish these objectives, this study will have two separate and parallel arms - a metabolic PEC arm to study the primary hypothesis, and an MRI imaging and cognitive testing arm to study the two secondary hypotheses.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Margaret K Hahn, PhD, MD; Phone Number: 34368 416-535-8501; Email: margaret.hahn@camh.ca
• Study Contact Backup: Name: Mahavir Agarwal, MBBS, MD; Phone Number: 30546 416-535-8501; Email: mahavir.agarwal@camh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 1R8
      • Recruiting
      • Center for Addiction and Mental Health
      • Contact: Margaret Hahn, MD, PhD; Phone Number: 34368 416-535-8501; Email: margaret.hahn@camh.ca
      • Contact: Mahavir Agarwal, MD, MBBS; Phone Number: 30546 416-535-8501; Email: mahavir.agarwal@camh.ca
      • Principal Investigator: Margaret Hahn, MD, PhD
      • Sub-Investigator: Mahavir Agarwal, MD, MBBS
    • Toronto, Ontario, Canada, M5G 2C4
      • Active, not recruiting
      • University Health Network - Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 43 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy non-obese volunteers
• Age: 17 to 45 (Cognitive Arm) OR Ages 17-65 (Metabolic Arm)

Exclusion Criteria:

• History of current or past psychiatric illness (according to the Mini International Neuropsychiatric Interview [MINI]).[As an exception for the Metabolic Arm only, anxiety disorders will not be exclusionary (including, but not limited to: agoraphobia, social anxiety disorder, generalized anxiety disorder, and panic disorder)].
• Left-handedness (only for the cognitive and MRI arm)
• Pre-diabetes or diabetes (fasting glucose ≥6.0mmol/L or use of anti-diabetic drug);
• Evidence of impaired glucose tolerance on screening OGTT
• Family history of diabetes
• Use of weight reducing agents or other medications based on the discretion of the PI
• History of liver disease or AST> 2 times upper limit of normal
• History of kidney disease
• Major medical or surgical event within the last 6 months
• Any condition that interferes with safe acquisition of MRI data such as metal implants, pacemakers, cochlear implants, claustrophobia, etc. (only for the cognitive and MRI component)
• Pregnancy and/or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cognitive and MRI Arm; This arm includes a screening visit 1 and screening visit 2 to assess eligibility. This arm includes an MRI scan and cognitive testing at visits 1 to 4. Visits 1 to 4 each consist of 3 days (day 0, day 1, and day 2). Olanzapine 2.5mg (or placebo) will be administered in doses of 5mg on day 0, and 10mg on day 1. Cognitive testing and MRI scanning then occur on day 2. On day 2, the participant is also randomized to and administered either intranasal insulin/Insulin Lispro 100 UNT/ML (or saline placebo) prior to conducting the MRI imaging and cognitive testing.	Drug: OLANZapine 2.5 MG; Olanzapine capsules (2.5mg) will be administered with the following dosing schedules for each arm: Metabolic arm - 5mg on Day 0, 7.5mg on Day 1, and 10mg on Day 2; Cognitive arm - 5mg on Day 0, 10mg on Day 1; Other Names: Mylan-Olanzapine; Drug: Placebo; Placebo capsules visually identical to those containing olanzapine will be administered according to the same dosing schedule for each arm.; Other Names: Olanzapine Placebo; Drug: Insulin Lispro 100 UNT/ML; Intranasal insulin spray (or placebo) will be administered on day 2 for each arm. For the metabolic arm: 40 IU of intranasal insulin lispro will be administered at timepoint 0 during the pancreatic euglycemic clamp procedure. For the cognitive arm: 160 IU of intranasal insulin lispro will be administered at about 11 am on day 2 prior to the MRI imaging and cognitive testing procedures.; Other Names: Intranasal Insulin; Other: Saline; Placebo saline spray visually identical to the intranasal insulin spray will be administered on day 2 for each arm according the same dosing schedules.
Experimental: Metabolic Arm; This arm includes a screening visit 1 and screening visit 2 to assess eligibility. This arm then includes the pancreatic euglycemic clamp procedure at visits 1 to 3. Visits 1 to 3 each consist of 3 days (day 0, day 1, and day 2). Olanzapine 2.5mg (or placebo) will be administered in doses of 5mg on day 0, 7.5mg on day 1, and 10mg on day 2. Day 2 consists of the final dose of olanzapine (or placebo) and the pancreatic euglycemic clamp procedure and other assessment procedures. On day 2, the participant is also randomized to and administered either intranasal insulin/Insulin Lispro 100 UNT/ML (or saline placebo) during the pancreatic euglycemic clamp procedure.	Drug: OLANZapine 2.5 MG; Olanzapine capsules (2.5mg) will be administered with the following dosing schedules for each arm: Metabolic arm - 5mg on Day 0, 7.5mg on Day 1, and 10mg on Day 2; Cognitive arm - 5mg on Day 0, 10mg on Day 1; Other Names: Mylan-Olanzapine; Drug: Placebo; Placebo capsules visually identical to those containing olanzapine will be administered according to the same dosing schedule for each arm.; Other Names: Olanzapine Placebo; Drug: Insulin Lispro 100 UNT/ML; Intranasal insulin spray (or placebo) will be administered on day 2 for each arm. For the metabolic arm: 40 IU of intranasal insulin lispro will be administered at timepoint 0 during the pancreatic euglycemic clamp procedure. For the cognitive arm: 160 IU of intranasal insulin lispro will be administered at about 11 am on day 2 prior to the MRI imaging and cognitive testing procedures.; Other Names: Intranasal Insulin; Other: Saline; Placebo saline spray visually identical to the intranasal insulin spray will be administered on day 2 for each arm according the same dosing schedules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous Glucose Production: Pancreatic Euglycemic Clamp Experiments	Participants in the metabolic arm will complete four pancreatic euglycemic clamp (PEC) procedures. The PEC will measure changes in the ability of INI to reduce endogenous glucose production (EGP; the primary outcome measure) relative to INP and the presence of OLA (or PL). EGP will be reflected in dextrose infusion rates (InFR) measured during the PEC across treatment conditions.	Visits 1-3 (12-16 weeks) for the metabolic arm

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Cognitive Functioning: MRI scans across the 4 visit conditions	Participants in the cognitive arm will complete 4 MRI scans that will include intra-scanner testing to assess changes in cognitive functioning across randomization conditions.	Visits 1-4 (9-18 weeks) for the cognitive arm
Oral Glucose Tolerance Test	Following collection of baseline samples, a standard glucose drink (75mg) is given orally, and a blood sample of insulin and glucose is obtained 2 hours after the glucose drink is administered. Serums which will be collected during this procedure include fasting glucose and fasting insulin related to weight gain and glucose metabolism.	Screening Visit 2 (1-2 weeks) for both arms

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: University Health Network, Toronto
• Investigators: Principal Investigator: Margaret K Hahn, PhD, MD, Centre for Addiction and Mental Health; Principal Investigator: Satya Dash, MD, PhD, University Health Network, Toronto General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2019
• Primary Completion (Estimated): July 30, 2024
• Study Completion (Estimated): July 30, 2024

Study Registration Dates

• First Submitted: November 3, 2018
• First Submitted That Met QC Criteria: November 9, 2018
• First Posted (Actual): November 15, 2018

Study Record Updates

• Last Update Posted (Actual): July 17, 2023
• Last Update Submitted That Met QC Criteria: July 13, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Insulin; Insulin, Globin Zinc; Olanzapine; Insulin Lispro
• Other Study ID Numbers: 075/2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No