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

Not Applicable

Not yet recruiting

• Conditions: Brain Insulin Sensitivity; Healthy Controls; Cognition
• Interventions: Drug: Haloperidol; Drug: Placebo; Drug: Insulin Lispro; Other: Saline

• Registration Number: NCT07109245
• Lead Sponsor: Centre for Addiction and Mental Health

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-07
• Study First Submitted: 2025-07-17
• Study First Submitted QC: 2025-07-31
• Last Update Submitted: 2025-07-31
• Study First Posted: 2025-08-07
• Last Update Posted: 2025-08-07
• Study Start: 2025-09-01
• Primary Completion: 2028-08
• Study Completion: 2028-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 35

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Haloperidol	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.
Placebo	Placebo	Placebo capsules, visually identical to those containing haloperidol, will be administered according to the same dosing schedule
Haloperidol	Insulin Lispro	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	Saline	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.
Placebo	Insulin Lispro	Placebo capsules, visually identical to those containing haloperidol, will be administered according to the same dosing schedule
Placebo	Saline	Placebo capsules, visually identical to those containing haloperidol, will be administered according to the same dosing schedule

Primary Outcome Measures

Name	Time	Method
RsFC between the anterior cingulate cortex of the salience network and the lateral parietal cortex of the DMN	From enrollment to the end of study will be up to 5 months	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.
Metabolic Outcome: BMI	From enrollment to the end of study will be up to 5 months	Weight (kg) and Height (cm) will be aggregated to BMI (kg/m\^2) at screening and MRI scanning visits.
Metabolic Outcome: Insulin	From enrollment to the end of study will be up to 5 months	Insulin (uIU/mL), will be measured at screening and at 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.
Metabolic Outcome: C-peptide	From enrollment to the end of study will be up to 5 months	C-peptide (nmol/L), will be measured at screening and 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.
Metabolic Outcome: HbA1c	From enrollment to the end of study will be up to 5 months	HbA1c (mmol/mol), will be measured at screening and 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge
Metabolic Outcome: HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)	From enrollment to the end of study will be up to 5 months	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
Metabolic Outcome: Waist Circumference	From enrollment to the end of study will be up to 5 months	Waist Circumference (cm) collected at screening and MRI scanning visits.
Metabolic Outcome: Glucose	From enrollment to the end of study will be up to 5 months	Glucose (mmol/L), will be measured at 2 time points on each MRI scanning day, pre- and post-intranasal insulin challenge.

Secondary Outcome Measures

Name	Time	Method
Antipsychotic Related Outcome: Plasma antipsychotic (haloperidol) level	From enrollment to the end of study will be up to 5 months	Plasma antipsychotic (haloperidol) levels will be measured with concentrations expressed in nanograms per millilitre (ng/mL). Collected on each MRI scanning day.
Antipsychotic Related Outcome: Stanford Sleepiness Scale	From enrollment to the end of study will be up to 5 months	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.
Antipsychotic Related Outcome: Digit Symbol Substitution Test	From enrollment to the end of study will be up to 5 months	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.
Antipsychotic Related Outcome: Barnes Akathisia Scale	From enrollment to the end of study will be up to 5 months	The Barnes Akathisia Scale (BAS) (scale of 0-14), with higher scores indicating more severe akathisia. Administered on each MRI scanning day.
Antipsychotic Related Outcome: Simpson-Angus Scale	From enrollment to the end of study will be up to 5 months	The Simpson-Angus Scale (SAS) (scale of 0-40), where higher values indicate more pronounced parkinsonian symptoms. Administered on each MRI scanning day.
Antipsychotic Related Outcome: Abnormal Involuntary Movement Scale	From enrollment to the end of study will be up to 5 months	Abnormal Involuntary Movement Scale (AIMS) (scale of 0-42), with higher scores corresponding to more severe involuntary movements. Administered on each MRI scanning day.
Antipsychotic Related Outcome: UKU Side Effect Rating Scale	From enrollment to the end of study will be up to 5 months	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.

Trial Locations

Locations (1)

Centre for Addiction and Mental Health; 🇨🇦 Toronto, Ontario, Canada