NCT03741478

Intranasal Insulin and Olanzapine Study in Healthy Volunteers

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

• Status: Unknown
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 64 (estimated)
• Sponsor: Centre for Addiction and Mental Health · Academic / Other
• Sex: All
• Age: 17 Years – 45 Years
• Healthy volunteers: Accepted

Summary

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.

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.

Conditions

• Healthy Controls

Interventions

Type	Name	Description
DRUG	OLANZapine 2.5 MG	Olanzapine capsules (2.5mg) will be administered with the following dosing schedules for each arm: 1. Metabolic arm - 5mg on Day 0, 7.5mg on Day 1, and 10mg on Day 2 2. Cognitive arm - 5mg on Day 0, 10mg on Day 1
DRUG	Placebo	Placebo capsules visually identical to those containing olanzapine will be administered according to the same dosing schedule for each arm.
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	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.

Timeline

• Start date: 2019-10-22
• Primary completion: 2024-07-30
• Completion: 2024-07-30
• First posted: 2018-11-15
• Last updated: 2023-07-17

Locations

2 sites across 1 country: Canada