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

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.

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.

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