Effects of Antipsychotics on Brain Insulin Action in Females

NCT06251635 | Recruiting

• 1 other identifier: 127/2023
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

Females treated with antipsychotics have higher rates of comorbid metabolic syndrome than males. Despite this, females have historically been excluded from many mechanistic studies due to confounding effects of menstrual cycles. Recent evidence suggests that brain insulin resistance may be an underlying mechanism through which antipsychotics may exert their metabolic side effects. This study seeks to investigate how brain insulin action differs in females according to their menstrual cycle phase, and how a high metabolic liability agent such as olanzapine might interrupt these differential insulin effects. Young healthy females will be given olanzapine and intranasal insulin to test how these treatment combinations change brain processes. Participants will be tested during both the first half of their menstrual cycle (follicular phase) and the second half of their cycle (luteal phase). The investigators predict that intranasal insulin will change MRI-based measures in females, in a comparable way to males, in the follicular phase only. Adding olanzapine will block these effects of insulin in females in the follicular phase. This investigation has the potential to generate new knowledge in an area of significant unmet need. Demonstrating that antipsychotics disrupt brain insulin action, evidenced by inhibition of recognized effects of insulin on neuroimaging measures, will provide novel insights into currently poorly understood mechanisms.

Conditions

Insulin Resistance; Menstrual Cycle; Type 2 Diabetes; Antipsychotics

Keywords

Antipsychotics; Brain Insulin Resistance; Magnetic Resonance Imaging (MRI); Metabolic Disturbances; Menstrual Cycle; Hyperinsulinemia; Insulin Lispro; Olanzapine; Physiological Effects of Drugs

Outcome Measures

Primary Outcomes (1)

• Resting State Functional Connectivity (assessed through Functional MRI)

  Participants will complete 4 MRI scans to assess changes in resting state functional connectivity and activity across menstrual cycle phases and randomization conditions.Changes in resting state functional connectivity following intranasal insulin or placebo challenges, compared between the follicular and luteal phases of the menstrual cycle.

  Visits 1-4 (5-6 months); 2 visits during follicular phase, 2 visits during luteal phase. At each visit, either oral olanzapine or placebo is given. MRI #1 occurs after intranasal challenge #1 and MRI #2 occurs after intranasal challenge #2.

Secondary Outcomes (2)

• Visuospatial Memory

  Visits 1-4 (5-6 months) during break between MRI scan #1 and #2.

• Processing Speed

  Visits 1-4 (5-6 months) during break between MRI scan #1 and #2.

Study Arms (2)

Follicular Phase Visits

EXPERIMENTAL

Participants will undergo two visits during the follicular phase of the menstrual cycle (they will be scanned between day 4-10 of their menstrual cycle). Each of the study periods will involve administration of OLA 5 mg HS (or PL) on day 0, OLA 10 mg HS (or PL) on day 1, and cognitive testing and MRI scanning on day 2. MRI assessments will occur 15 minutes after administering 160 International Units (IU) INI/INP.

Drug: Olanzapine 2.5Mg Oral Tablet; Drug: Placebo; Drug: Insulin Lispro 100 UNT/ML; Drug: Saline

Luteal Phase Visits

EXPERIMENTAL

Participants will undergo two visits during the luteal phase of the menstrual cycle (they will be scanned between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). Each of the study periods will involve administration of OLA 5 mg HS (or PL) on day 0, OLA 10 mg HS (or PL) on day 1, and cognitive testing and MRI scanning on day 2. MRI assessments will occur 15 minutes after administering 160 International Units (IU) INI/INP.

Drug: Olanzapine 2.5Mg Oral Tablet; Drug: Placebo; Drug: Insulin Lispro 100 UNT/ML; Drug: Saline

Interventions

Olanzapine 2.5Mg Oral Tablet DRUG

Olanzapine capsules (2.5mg) will be administered during one research visit for each menstrual cycle phase. The dosing schedule is as follows: 1. Day 0- 5mg 2. Day 1- 10mg

Also known as: Apo-Olanzapine

Follicular Phase Visits; Luteal Phase Visits

Placebo DRUG

Placebo capsules visually identical to those containing olanzapine will be administered according to the same dosing schedule during one research visit of each menstrual cycle phase.

Also known as: Olanzapine Placebo

Follicular Phase Visits; Luteal Phase Visits

Insulin Lispro 100 UNT/ML DRUG

At each visit, participants will be given an intranasal insulin challenge (160 IU) to assess brain insulin signalling via MRI based assay.

Also known as: Intranasal Insulin

Follicular Phase Visits; Luteal Phase Visits

Saline DRUG

At each visit, participants will be given an intranasal saline placebo (1.6 mL) in order to establish baseline brain insulin signalling via MRI based assay.

Also known as: Intranasal Saline

Follicular Phase Visits; Luteal Phase Visits

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age: 18-35 years
• Body Mass Index (BMI) between 18.5 - 24.9 kg/m2
• Normal menstrual cycle (defined as cycle length ranging from 21 to 35 days over the past 6 months).

You may not qualify if:

• History of psychiatric illness (screened using the Mini International Neuropsychiatric Interview (MINI));
• Pre-diabetes or diabetes (fasting glucose ≥6.0 mmol/L, HbA1c\>6% or use of anti-diabetic drug);
• Evidence of impaired insulin sensitivity, assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥2.5;
• Family history of diabetes in a first degree relative (parent or sibling)
• Use of weight reducing agents;
• History of kidney or liver disease;
• Moderate-to-severe substance use;
• Irregular menstrual cycles (e.g., menstruation occurs less than 21 days or more than 35 days apart, or not having menstruated for three months (or 90 days), or conditions such as endometriosis or polycystic ovary syndrome (PCOS) or prior surgical interventions such as a hysterectomy or oophorectomy);
• Current use of hormonal birth control (e.g., pill, patch, hormonal intrauterine device \[IUD\], ring). Participants must have had at least 2 regular menstrual cycles following the discontinuation of hormonal birth control;
• Pregnant, gave birth in the last year, or breastfeeding. Participants must have at least 3 regular menstrual cycles post-breastfeeding before beginning the study;
• Current use of progesterone, estrogen, testosterone, or fertility treatment;
• 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.
• Use of any of the prohibited medications listed in the product monograph of olanzapine (e.g., Levodopa and dopamine agonists and antihypertensive agents).

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead

Study Sites (1)

Centre for Addiction and Mental Health (CAMH)

Toronto, Ontario, M6J 1H3, Canada

RECRUITING

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus, Type 2; Hyperinsulinism

Interventions

Olanzapine; Tablets; Sodium Chloride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dosage Forms; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Mahavir Agarwal, MBBS, PhD, MD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mahavir Agarwal, MBBS, PhD

CONTACT

4165358501; mahavir.agarwal@camh.ca

Maria Papoulias

CONTACT

4165358501; maria.papoulias@camh.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Participants will be masked to: 1. Knowing whether they were assigned to the olanzapine or placebo conditions 2. Knowing the order of the intranasal spray condition (insulin or placebo). Investigators will know when participants receive oral olanzapine or placebo and intranasal insulin or saline (required in order to schedule study assessments, and given the order of assessments on the MRI day). A separate staff member who is unaware of drug condition will administer cognitive assessments to mitigate bias of these outcomes.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will follow a single-blind, crossover design wherein each participant will complete an MRI based protocol of brain insulin action. Participants will take part in two research visits during the follicular phase of their menstrual cycle (i.e., between day 4-10 of their menstrual cycle) and two visits during the luteal phase (between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). In each cycle phase, participants will be given two doses of either oral olanzapine or oral placebo. After an overnight fast, fasting bloodwork will be obtained, followed by two MRI scans: one with intranasal placebo and one with intranasal insulin challenge (160 IU; 80 IU per nostril). Between scans they will have a short break and be asked to complete cognitive assessments/questionnaires.

Study Record Dates

• First Submitted: February 1, 2024
• First Posted: February 9, 2024
• Study Start: June 3, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)