Grant: Project Grant

Patients with schizophrenia die 20 years earlier than the general population due to cardiovascular disease. Antipsychotic (AP) medications, a prototype of which is olanzapine (OLA), are the mainstay treatment for schizophrenia. They are widely prescribed in other psychiatric disorders, especially in young individuals. These medications are however linked with serious metabolic side-effects, including blood sugar (glucose) problems, linked to impaired sensitivity to the main hormone which regulates glucose levels, called insulin. In turn, patients with schizophrenia have rates of type 2 diabetes that are 3-5 times higher than the general population. However, how APs cause problems in glucose metabolism is largely unknown. The brain is now recognized as having an important role in energy and glucose balance, and also brain function (cognition). It has been shown that insulin receptors in the brain have a key role in regulating glucose production by the liver, and improving cognition. We have shown in rats that OLA can block the effects of insulin in the brain leading to increased production of glucose by the liver (which is also a main feature of diabetes). In healthy humans, others have provided insulin to the brain through a nasal spray, and shown decreases in glucose production, and improvements in cognition. Here we want to see if OLA can block these effects of intranasal insulin, which would tell us more about how APs cause diabetes, and why AP medications don't treat cognitive symptoms that are seen in schizophrenia. To test this, we will give OLA and intranasal insulin to young volunteers, as their young age makes them similar to youth with psychosis receiving APs for the first time. Glucose metabolism will be measured by a procedure called "pancreatic clamp". Cognition will be measured by standard tests. We predict that OLA will block the beneficial effects of intranasal insulin on glucose metabolism and cognition.