Do Antipsychotics Block Insulin Action in the Brain: is it a Class Effect?

This study aimed at helping researchers understand how a medication called haloperidol can affect insulin action in the brain. Insulin is a hormone in the body that controls sugar levels in part by lowering the amount of glucose produced by the liver. After eating a meal, insulin levels go up in both the blood and the brain. Insulin in the brain has also been shown to affect the way the brain works and processes information (also known as "cognition"). Haloperidol, is an antipsychotic medication used to treat a variety of disorders such as schizophrenia spectrum disorders, bipolar disorder, and major depressive disorder, but long-term use can have metabolic side effects, like weight gain, type 2 diabetes, and cardiovascular disease. The purpose of this study is to investigate how antipsychotic medications, such as haloperidol, which carries the risk of metabolic changes, might interrupt the effect of insulin action in the brain. This will help researchers learn how to potentially reduce metabolic risk for people who take these kinds of medications in the future.

Study Overview

• Status: Recruiting
• Conditions: Cognition; Healthy Controls; Brain Insulin Sensitivity
• Intervention / Treatment: Drug: Haloperidol; Drug: Insulin Lispro; Other: Saline; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mahavir Agarwal, MBBS, MD, PhD; Phone Number: 30546 416-535-8501; Email: mahavir.agarwal@camh.ca
• Study Contact Backup: Name: Maria Papoulias, MSc; Phone Number: 39365 416-535-8501; Email: maria.papoulias@camh.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J 1H3
      • Recruiting
      • Centre for Addiction and Mental Health
      • Contact: Mahavir Agarwal, MBBS, MD, PhD; Phone Number: 30546 416-535-8501; Email: mahavir.agarwal@camh.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Must be deemed to have the capacity to provide informed consent
2. Must sign and date the informed consent form
3. Stated willingness to comply with all study procedures;
4. Age: 18-35
5. Body Mass Index (BMI) 18.5-24.9 kg/m2
6. Both sexes

Exclusion Criteria:

1. History of psychiatric illness, including any substance use (screened using the Mini International Neuropsychiatric Interview (MINI))
2. Pre-diabetes or diabetes (fasting glucose ≥6.0 mmol/L, HbA1c>6% or use of anti-diabetic drug),
3. Evidence of impaired insulin sensitivity, assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥2.5
4. Family history of diabetes in a first degree relative (parent or sibling)
5. Use of weight reducing agents
6. History of kidney or liver disease
7. History of cell blood disorders
8. 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)
9. 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 [50]
10. Current use of progesterone, estrogen, testosterone, or fertility treatment.
11. Pregnant, gave birth in the last year, or breastfeeding. Participants must have at least 3 regular menstrual cycles post-breastfeeding before beginning the study.
12. Major medical or surgical event within the last 6 months
13. Contraindications for MRI, including metal implants, pacemakers, cochlear implants, claustrophobia, weight >250 lbs
14. Any contraindications to the investigational products as listed in the product monographs including known hypersensitivity to the drug or the excipients of the product (note: enzymatic lactose intolerance is NOT exclusionary),
15. Any medications that increases risk of hypoglycemia or could contribute to hyperglycemia
16. Any medical conditions that constitute as a warning/precaution for haloperidol, lorazepam, benztropine, or insulin.
17. Use of any of the prohibited medications listed in the product monograph of haloperidol, lorazepam, benztropine, or insulin (Pheochromocytoma, barbiturates, and narcotics are exclusionary, any use of painkillers and antihistamines must be reviewed by PI but are not exclusionary

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Haloperidol; The oral investigational agent haloperidol (Generic Brand: TEVA-HALOPERIDOL) will be self-administered, at night, over 7 days. Haloperidol will be titrated up to 2 mg.	Drug: Haloperidol; The oral investigational agent haloperidol (Generic Brand: TEVA-HALOPERIDOL) will be self-administered, at night, over 7 days. Haloperidol will be titrated up to 2 mg.; Drug: Insulin Lispro; A total of 160 IU of intransal insulin (=1.6 mL) will be administered on MRI scanning visits (80 IU = 0.8 mL delivered per nostril). Humalog; Eli Lilly Canada; Other: Saline; A total of 1.6 mL of intranasal saline will be administered on each MRI scanning visit (0.8 mL delivered per nostril).
Placebo Comparator: Placebo; Placebo capsules, visually identical to those containing haloperidol, will be administered according to the same dosing schedule	Drug: Insulin Lispro; A total of 160 IU of intransal insulin (=1.6 mL) will be administered on MRI scanning visits (80 IU = 0.8 mL delivered per nostril). Humalog; Eli Lilly Canada; Other: Saline; A total of 1.6 mL of intranasal saline will be administered on each MRI scanning visit (0.8 mL delivered per nostril).; Drug: Placebo; Oral placebo, encapsulated and to be taken at an equivalent titration schedule to Haloperidol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RsFC between the anterior cingulate cortex of the salience network and the lateral parietal cortex of the DMN	Resting state functional connectivity (rsFC) between the anterior cingulate cortex of the salience network and the lateral parietal cortex of the default mode network (DMN) will be assessed through a MRI-based assay. Calculated using the correlation between two brain regions' blood-oxygen-level-dependent (BOLD) signal times.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: BMI	Weight (kg) and Height (cm) will be aggregated to BMI (kg/m^2) at screening and MRI scanning visits.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: Waist Circumference	Waist Circumference (cm) collected at screening and MRI scanning visits.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: Glucose	Glucose (mmol/L), will be measured at 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: Insulin	Insulin (uIU/mL), will be measured at screening and at 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: C-peptide	C-peptide (nmol/L), will be measured at screening and 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: HbA1c	HbA1c (mmol/mol), will be measured at screening and 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge	From enrollment to the end of study will be up to 5 months
Metabolic Outcome: HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)	HOMA-IR, will be measured at 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge. HOMA-IR = (Fasting Insulin (uIU/mL) * Fasting Glucose (mmol/L)) / 22.5	From enrollment to the end of study will be up to 5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antipsychotic Related Outcome: Plasma antipsychotic (haloperidol) level	Plasma antipsychotic (haloperidol) levels will be measured with concentrations expressed in nanograms per millilitre (ng/mL). Collected on each MRI scanning day.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: Stanford Sleepiness Scale	The Stanford Sleepiness Scale (SSS), which is a self-reported scale (scale of 1-7), where higher scores indicate greater sedation. Administered on each MRI scanning visit.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: Digit Symbol Substitution Test	The Digit Symbol Substitution Test (DSST), which will be reported as the number of correct responses (count per 90 seconds), where lower scores reflect greater sedation or cognitive slowing. Administered on each MRI scanning day.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: Barnes Akathisia Scale	The Barnes Akathisia Scale (BAS) (scale of 0-14), with higher scores indicating more severe akathisia. Administered on each MRI scanning day.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: Simpson-Angus Scale	The Simpson-Angus Scale (SAS) (scale of 0-40), where higher values indicate more pronounced parkinsonian symptoms. Administered on each MRI scanning day.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: Abnormal Involuntary Movement Scale	Abnormal Involuntary Movement Scale (AIMS) (scale of 0-42), with higher scores corresponding to more severe involuntary movements. Administered on each MRI scanning day.	From enrollment to the end of study will be up to 5 months
Antipsychotic Related Outcome: UKU Side Effect Rating Scale	Side effects will be assessed using the UKU Side Effect Rating Scale, which will be reported as a scale score (scale of 0-144), where higher scores indicate a greater burden of side effects. Administered on each MRI scanning day.	From enrollment to the end of study will be up to 5 months

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: The Physicians' Services Incorporated Foundation
• Investigators: Principal Investigator: Mahavir Agarwal, MBBS, MD, PhD, Centre for Addiction and Mental Health

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2025
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: July 17, 2025
• First Submitted That Met QC Criteria: July 31, 2025
• First Posted (Actual): August 7, 2025

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: MRI; Cognition; Haloperidol; Brain Insulin Sensitivity; Healthy Control Study
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Glucose Metabolism Disorders; Hyperinsulinism; Hypersensitivity; Insulin Resistance; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Inorganic Chemicals; Chlorine Compounds; Insulins; Pancreatic Hormones; Butyrophenones; Ketones; Sodium Compounds; Insulin, Short-Acting; Chlorides; Hydrochloric Acid; Insulin Lispro; Haloperidol; Sodium Chloride
• Other Study ID Numbers: 2025/010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No