Antipsychotics for Insulin Resistance in Females

Overseen By Maria Papoulias

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must be taking: Antipsychotics

Must not be taking: Levodopa, Dopamine agonists, Antihypertensives

Disqualifiers: Psychiatric illness, Diabetes, Substance use, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how antipsychotic medications like olanzapine (also known as Zyprexa) might affect insulin action in the brains of females with regular menstrual cycles. Researchers aim to understand whether the brain's response to insulin changes during different phases of the menstrual cycle and how olanzapine might disrupt these changes. The goal is to gain insights into why females taking antipsychotics may face a higher risk of metabolic issues. Young women with regular menstrual cycles, without a history of psychiatric illness or diabetes, and not using hormonal birth control might be suitable candidates for this study. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research on metabolic health in women.

Will I have to stop taking my current medications?

The trial requires that you stop using hormonal birth control and certain other medications like progesterone, estrogen, testosterone, and fertility treatments. Additionally, you cannot use medications that are prohibited with olanzapine, such as Levodopa, dopamine agonists, and antihypertensive agents.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that olanzapine, a medication for mental health conditions, can affect insulin use in the body. It might make cells less responsive to insulin, leading to insulin resistance, even without weight gain. Some studies suggest that olanzapine might also increase certain hormones, complicating the body's management of sugar and fat.

Olanzapine is known for these effects, particularly with long-term use. Clinical trials must monitor participants closely, as some may experience these side effects more than others. Prospective trial participants should be aware of these potential effects and discuss any concerns with the trial team. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the use of olanzapine in addressing insulin resistance in females because it explores a unique intersection of mental health and metabolic health. Unlike typical antidiabetic treatments that focus solely on insulin regulation, olanzapine is an antipsychotic medication that may offer additional benefits in managing insulin resistance, particularly for those who might also experience mental health challenges. This trial also pays special attention to the menstrual cycle's phases, which could lead to more personalized and effective treatment plans for women. This innovative approach could potentially address both psychiatric symptoms and metabolic issues simultaneously, offering a broader therapeutic impact.

What evidence suggests that this trial's treatments could be effective for insulin resistance in females?

Research has shown that olanzapine, a medication for mental health conditions, can impair the body's ability to use insulin properly. Insulin, a hormone, controls blood sugar levels. Olanzapine can disrupt insulin handling, even without weight gain, leading to higher blood sugar and other health issues. This trial will examine these effects during different phases of the menstrual cycle to better manage side effects in women taking this medication. ^{1 2 5 6 7}

Who Is on the Research Team?

Mahavir Agarwal, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for young healthy females who may be experiencing insulin resistance, type 2 diabetes, or menstrual irregularities and are not currently on antipsychotics. Participants should be able to undergo MRI scans and have no history of drug abuse, psychiatric disorders, or significant medical conditions.

Inclusion Criteria

Right-handed

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

My BMI is less than 25.

Exclusion Criteria

A close family member has diabetes.

I have pre-diabetes or diabetes based on my blood sugar levels or I'm taking medication for it.

Evidence of impaired insulin sensitivity, assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) ≥1.8

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Follicular Phase

Participants receive treatment during the follicular phase of their menstrual cycle, including administration of olanzapine and intranasal insulin or placebo, followed by cognitive testing and MRI scanning.

2-6 weeks

2 visits (in-person)

Treatment - Luteal Phase

Participants receive treatment during the luteal phase of their menstrual cycle, including administration of olanzapine and intranasal insulin or placebo, followed by cognitive testing and MRI scanning.

2-6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Insulin Lispro
• Olanzapine

Trial Overview

The study tests how the brain's response to insulin in females is affected by their menstrual cycle phase and the use of an antipsychotic called Olanzapine. It involves giving participants intranasal insulin or a placebo during different phases of their menstrual cycle while monitoring changes with MRI.

How Is the Trial Designed?

Group I: Luteal Phase Visits Experimental Treatment 4 Interventions

Participants will undergo two visits during the luteal phase of the menstrual cycle (they will be scanned between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). 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. MRI assessments will occur 15 minutes after administering 160 International Units (IU) INI/INP.

Group II: Follicular Phase Visits Experimental Treatment 4 Interventions

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). 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. MRI assessments will occur 15 minutes after administering 160 International Units (IU) INI/INP.

Olanzapine is already approved in United States, European Union for the following indications:

Approved in United States as Zyprexa for:

• Schizophrenia
• Bipolar disorder
• Depression
• Nausea and vomiting associated with chemotherapy
• Off-label use for cancer cachexia and anorexia

Approved in European Union as Zyprexa for:

• Schizophrenia
• Bipolar disorder
• Depression
• Nausea and vomiting associated with chemotherapy

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

In a study of 24 non-obese schizophrenia patients treated with either quetiapine or olanzapine, olanzapine was associated with significant insulin resistance and higher fasting plasma glucose levels compared to normal controls.

Quetiapine did not show significant differences in insulin resistance or glucose metabolism when compared to olanzapine or normal controls, suggesting it may have a more favorable metabolic profile in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Henderson, DC., Copeland, PM., Borba, CP., et al.[2019]

A systematic review of 40 studies involving 3725 participants found that olanzapine significantly increases insulin resistance compared to other second-generation antipsychotics like aripiprazole, ziprasidone, and risperidone.

Patients treated with olanzapine had higher levels of insulin resistance index (IRI), fasting blood glucose (FBG), and fasting insulin (FINS), indicating a greater metabolic risk associated with olanzapine in patients with schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin resistance induced by olanzapine and other second-generation antipsychotics in Chinese patients with schizophrenia: a comparative review and meta-analysis. Yu, L., Wu, S., Deng, Y., et al.[2020]

In a study of 30 patients with schizophrenia on olanzapine, the addition of angiotensin II receptor blockers (valsartan and telmisartan) significantly improved insulin sensitivity and reduced insulin resistance, as measured by HOMA-IR.

Both valsartan and telmisartan were effective in lowering fasting insulin levels without any observed adverse effects, suggesting they are safe adjunct treatments for managing metabolic disturbances in patients taking olanzapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II type 1 receptor blockers improve insulin sensitivity in patients with schizophrenia being treated with olanzapine. Yamashita, H., Yoda, H., Kuroki, N., et al.[2021]

Certain atypical antipsychotics, particularly clozapine and olanzapine, are associated with a higher risk of developing diabetes mellitus, while others show only a slight increase in risk.

The mechanism behind this increased risk may involve disruptions in glucose and fatty acid metabolism, potentially leading to insulin resistance and diabetes, highlighting the need for careful consideration in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Diabetes mellitus as a complication of treatment with atypical neuroleptics. Possible pathomechanisms and treatment recommendations]. Jahn, H., Schneider, T.[2019]

Olanzapine, an atypical antipsychotic used to treat schizophrenia, can cause serious side effects such as increased appetite and weight gain, which are common.

This report highlights a rare case of diabetic ketoacidosis occurring in a 16-year-old girl during olanzapine treatment, indicating that this severe adverse effect can also manifest in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetic ketoacidosis associated with olanzapine in an adolescent patient. Selva, KA., Scott, SM.[2018]

Clozapine and olanzapine, two atypical antipsychotics, may increase the risk of developing glucose dysregulation or new onset diabetes, as evidenced by the management of six patients who developed diabetes after starting olanzapine.

Switching from olanzapine to quetiapine led to improved glycemic control in two out of six patients, highlighting the importance of monitoring and managing blood sugar levels in patients treated with antipsychotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of diabetes mellitus occurring during treatment with olanzapine: report of six cases and clinical implications. Ashim, S., Warrington, S., Anderson, IM.[2018]

In a study of 54 patients treated with second-generation antipsychotics (SGAs), it was found that body mass index (BMI) contributes similarly to insulin resistance in patients on SGAs as in a reference population not on these medications.

Patients taking olanzapine exhibited significantly higher insulin resistance compared to those on aripiprazole and risperidone, indicating that olanzapine may have an independent effect on insulin resistance beyond what is caused by weight gain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents. Kim, SH., Nikolics, L., Abbasi, F., et al.[2021]

A 27-year-old man developed severe hyperglycemia and acidosis two years after starting olanzapine, highlighting the drug's association with insulin resistance and new-onset diabetes, even without weight gain.

Switching from insulin to pioglitazone successfully stabilized the patient's glucose levels while allowing continued use of olanzapine, suggesting that alternative diabetes management strategies may be necessary for patients on this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature. Seaburg, HL., McLendon, BM., Doraiswamy, PM.[2019]

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