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

NCT07109245 | Recruiting Phase 4

• 1 other identifier: 2025/010
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Brain Insulin Sensitivity; Healthy Controls; Cognition

Keywords

Brain Insulin Sensitivity; Healthy Control Study; Haloperidol; Cognition; MRI

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (7)

• Antipsychotic Related Outcome: Plasma antipsychotic (haloperidol) level

  From enrollment to the end of study will be up to 5 months

• Antipsychotic Related Outcome: Stanford Sleepiness Scale

  From enrollment to the end of study will be up to 5 months

• Antipsychotic Related Outcome: Digit Symbol Substitution Test

  From enrollment to the end of study will be up to 5 months

• Antipsychotic Related Outcome: Barnes Akathisia Scale

  From enrollment to the end of study will be up to 5 months

• Antipsychotic Related Outcome: Simpson-Angus Scale

  From enrollment to the end of study will be up to 5 months

Study Arms (2)

Haloperidol

EXPERIMENTAL

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; Drug: Insulin Lispro; Other: Saline

Placebo

PLACEBO COMPARATOR

Placebo capsules, visually identical to those containing haloperidol, will be administered according to the same dosing schedule

Drug: Placebo; Drug: Insulin Lispro; Other: Saline

Interventions

Placebo DRUG

Oral placebo, encapsulated and to be taken at an equivalent titration schedule to Haloperidol.

Placebo

Insulin Lispro DRUG

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

Haloperidol; Placebo

Saline OTHER

A total of 1.6 mL of intranasal saline will be administered on each MRI scanning visit (0.8 mL delivered per nostril).

Haloperidol; Placebo

Haloperidol DRUG

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.

Haloperidol

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• History of psychiatric illness, including any substance use (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
• History of cell blood disorders
• 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 \[50\]
• Current use of progesterone, estrogen, testosterone, or fertility treatment.
• Pregnant, gave birth in the last year, or breastfeeding. Participants must have at least 3 regular menstrual cycles post-breastfeeding before beginning the study.
• Major medical or surgical event within the last 6 months
• Contraindications for MRI, including metal implants, pacemakers, cochlear implants, claustrophobia, weight \>250 lbs
• Any medications that increases risk of hypoglycemia or could contribute to hyperglycemia
• Any medical conditions that constitute as a warning/precaution for haloperidol, lorazepam, benztropine, or insulin.

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead
• The Physicians' Services Incorporated Foundation: collaborator

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M6J 1H3, Canada

RECRUITING

MeSH Terms

Interventions

Haloperidol; Insulin Lispro; Sodium Chloride

Intervention Hierarchy (Ancestors)

Butyrophenones; Ketones; Organic Chemicals; Insulin, Short-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Mahavir Agarwal, MBBS, MD, PhD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mahavir Agarwal, MBBS, MD, PhD

CONTACT

416-535-8501; mahavir.agarwal@camh.ca

Maria Papoulias, MSc

CONTACT

416-535-8501; maria.papoulias@camh.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2025
• First Posted: August 7, 2025
• Study Start: December 11, 2025
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 2, 2026

Record last verified: 2026-03

Locations

CA (1)