Effects of Antipsychotics on Brain Insulin Action in Females

Type 2 Diabetes Clinical Trial

Official title:

Effects of Antipsychotics on Brain Insulin Action in Females: A Randomised Placebo-Controlled, Crossover Multi-Modal Neuroimaging Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06251635
• Other study ID #: 127/2023
• Status: Recruiting
• Phase: N/A
• Start date: February 28, 2024
• Est. completion date: March 1, 2026

Study information

• Verified date: January 2024
• Source: Centre for Addiction and Mental Health
• Contact: Mahavir Agarwal, MBBS, PhD
• Phone: 4165358501
• Email: mahavir.agarwal[@]camh.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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). We 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.

Description:

BACKGROUND: Antipsychotics (APs) cause serious metabolic adverse effects, including weight gain and type 2 diabetes. Females are disproportionally more affected by this problem than males. While the pathophysiology of these effects remain unclear, brain insulin resistance (IR) is posited to be an important determinant. Currently there are no direct methods to investigate brain IR, but physiological response to intranasal insulin (INI) can be used as a surrogate marker. INI reliably suppresses endogenous glucose production, modulates brain activity, and improves cognition. In a proof-of-concept neuroimaging study at CAMH, we investigated AP-induced brain IR using an INI challenge. As expected, preliminary data show acute olanzapine (OLA) administration attenuates INI-induced changes in cerebral blood flow and resting state activity; however, the findings are only observed in males. It was recently suggested that brain insulin action differs between sexes, and this may relate to menstrual phases. Specifically, IR is physiologically induced in the luteal, but not follicular phase of the menstrual cycle. Hence, this study seeks to explore if the effects of APs on brain insulin action in females is modulated by menstrual stages.

HYPOTHESES: 1) INI, but not intranasal placebo (INP) will modulate resting state activity in the brain in females during the follicular phase of their menstrual cycle but not the luteal phase; 2) oral OLA will inhibit all INI-induced effects, relative to oral PL, during the follicular phase. OLA will have no apparent effect on females in the luteal phase given pre-existing brain IR.

APPROACH AND METHODOLOGY: Fifteen healthy normal weight (BMI <25 kg/m2), normal cycling female volunteers between the ages of 18-35 years will be recruited to participate in the study. In a single blind, crossover design, each participant will receive 4 treatment conditions (INP/PL, INI/PL, INP/OLA or INI-OLA) twice on 4 separate occasions (two visits per cycle phase). 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. On Day 2, fasting blood work (glucose, insulin, c-peptide, olanzapine measures) will be followed by an MRI-based protocol of brain insulin action. This includes two MRI scans; one with intranasal insulin challenge (160 IU) and one with intranasal placebo. Study visits will take place 2-6 weeks apart to ensure specific menstrual phase across the four visits. 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), and another two visits during the luteal phase of their menstrual cycle (between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). Menstrual cycles will be tracked by self-report of the last three menstruation onset dates. Average cycle duration will be calculated to determine cycle phases. Based on this, participants will be invited to complete the visits during the specific windows of their follicular and luteal phase; measurement of sex hormones (progesterone, estrogen, luteinizing hormone (LH) and follicular stimulating hormone (FSH)) will be done at each visit to confirm cycle phase.

SIGNIFICANCE: Females suffer the most from AP-related metabolic adverse effects. Brain insulin action is increasingly being recognized as a potential mediator of these side effects. Disappointingly, females are an underrepresented population in the field because of the complex confounding effects of monthly hormonal variations. This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of APs. Thus, this investigation has the potential to generate new knowledge in an area of significant unmet need. Demonstrating that APs disrupt brain insulin action, evidenced by inhibition of recognized effects of INI on neuroimaging measures, will provide novel insights into currently poorly understood mechanisms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: March 1, 2026
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

• Age: 18-35 years

• Body Mass Index (BMI) <25 kg/m2

• Right-handed

• Normal menstrual cycle (defined as cycle length ranging from 21 to 35 days over the past 6 months).

Exclusion Criteria:

• 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) =1.8;

• Family history of diabetes in a first degree relative;

• 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.

Related Conditions & MeSH terms

• Antipsychotics
• Insulin Resistance
• Menstrual Cycle
• Type 2 Diabetes

Intervention

Drug:
• Olanzapine 2.5Mg Oral Tablet
Olanzapine capsules (2.5mg) will be administered during one research visit for each menstrual cycle phase. The dosing schedule is as follows: Day 0- 5mg Day 1- 10mg
• Placebo
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.
• Insulin Lispro 100 UNT/ML
At each visit, participants will be given an intranasal insulin challenge (160 IU) to assess brain insulin signalling via MRI based assay.
• Saline
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.

Locations

Country	Name	City	State
Canada	Centre for Addiction and Mental Health (CAMH)	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Centre for Addiction and Mental Health

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Visuospatial Memory	Participants will complete the Brief Visuospatial Memory Test (BVMT) to assess visuospatial memory outcomes across the randomization conditions.; BVMT Scoring: 0-36 (minimum 0, maximum 36)	Visits 1-4 (5-6 months) during break between MRI scan #1 and #2.
Secondary	Processing Speed	Participants will complete the Digit-Symbol Substitution Test (DSST) to assess processing speed across the randomization conditions.; DSST Scoring: 0-110 (minimum 0, maximum 110)	Visits 1-4 (5-6 months) during break between MRI scan #1 and #2.