Effect of Antipsychotics on Central Insulin Action in Relation to Glucose Metabolism and Cognition in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 64
- 试验地点
- 4
- 主要终点
- Endogenous Glucose Production: Pancreatic Euglycemic Clamp Experiments
研究概览
简要总结
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:
- 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.
- 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.
- INI will result in adaptive changes in neurochemical and neurohemodynamic measures as studied using MRI imaging techniques.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
Participants will be masked to:
- Knowing whether they were assigned to the olanzapine or placebo conditions
- Knowing whether they were assigned to the intranasal insulin or intranasal placebo conditions.
Investigators will only be masked to the randomization of placebo or olanzapine for the participants, but will know whether the participant receives intranasal insulin or intranasal placebo. In the Cognitive Arm, a separate staff member who is unaware of drug condition will administer cognitive assessments.
入排标准
- 年龄范围
- 17 Years 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy non-obese volunteers
- •Age: 17 to 45 (Cognitive Arm) OR Ages 17-65 (Metabolic Arm)
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Placebo (Drug)
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.
干预措施: OLANZapine 2.5 MG (Drug)
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.
干预措施: Insulin Lispro 100 UNT/ML (Drug)
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.
干预措施: Saline (Other)
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.
干预措施: Placebo (Drug)
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.
干预措施: Insulin Lispro 100 UNT/ML (Drug)
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.
干预措施: Saline (Other)
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.
干预措施: OLANZapine 2.5 MG (Drug)
结局指标
主要结局
Endogenous Glucose Production: Pancreatic Euglycemic Clamp Experiments
时间窗: Visits 1-3 (12-16 weeks) for the metabolic arm
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.
次要结局
- Changes in Cognitive Functioning: MRI scans across the 4 visit conditions(Visits 1-4 (9-18 weeks) for the cognitive arm)
- Oral Glucose Tolerance Test(Screening Visit 2 (1-2 weeks) for both arms)
研究者
Margaret Hahn
Clinician Scientist
Centre for Addiction and Mental Health