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NCT Number: NCT07109245

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.

Recruiting

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Key information

Age range

18 year–35 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Centre for Addiction and Mental Health

Toronto, Ontario, M6J 1H3, Canada

Location status: Recruiting

Location contact

Mahavir Agarwal, MBBS, MD, PhD

CONTACT

[email protected]

416-535-8501 ext. 30546

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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 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),
  • 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.
  • 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

Treatment and study plan

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.

Placebo

Drug

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

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

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).

Primary outcomes

  1. RsFC between the anterior cingulate cortex of the salience network and the lateral parietal cortex of the DMN

    Time frame: 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.

  2. Metabolic Outcome: BMI

    Time frame: 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.

  3. Metabolic Outcome: Waist Circumference

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

    Waist Circumference (cm) collected at screening and MRI scanning visits.

  4. Metabolic Outcome: Glucose

    Time frame: 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.

  5. Metabolic Outcome: Insulin

    Time frame: 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.

  6. Metabolic Outcome: C-peptide

    Time frame: 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.

  7. Metabolic Outcome: HbA1c

    Time frame: 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

  8. Metabolic Outcome: HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)

    Time frame: 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

Secondary outcomes

  1. Antipsychotic Related Outcome: Plasma antipsychotic (haloperidol) level

    Time frame: 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.

  2. Antipsychotic Related Outcome: Stanford Sleepiness Scale

    Time frame: 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.

  3. Antipsychotic Related Outcome: Digit Symbol Substitution Test

    Time frame: 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.

  4. Antipsychotic Related Outcome: Barnes Akathisia Scale

    Time frame: 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.

  5. Antipsychotic Related Outcome: Simpson-Angus Scale

    Time frame: 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.

  6. Antipsychotic Related Outcome: Abnormal Involuntary Movement Scale

    Time frame: 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.

  7. Antipsychotic Related Outcome: UKU Side Effect Rating Scale

    Time frame: 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.

Study contacts

Contact information is provided by the study sponsor or research team.

Mahavir Agarwal, MBBS, MD, PhD

CONTACT

[email protected]

416-535-8501 ext. 30546

Maria Papoulias, MSc

CONTACT

[email protected]

416-535-8501 ext. 39365

Sponsors and collaborators

Lead sponsor

Centre for Addiction and Mental Health

Other

Collaborators

  • The Physicians' Services Incorporated Foundation

Registry information

Important dates

Study start
2025
Primary completion
2028
Study completion
2028
First posted
Aug 7, 2025
Registry last updated
Apr 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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