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

Trial Summary

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.

What data supports the effectiveness of the drug Insulin Lispro in treating insulin resistance in females taking antipsychotics?

The research indicates that olanzapine, an antipsychotic, is linked to insulin resistance and diabetes, suggesting that managing blood sugar with insulin, like Insulin Lispro, could be beneficial for patients experiencing these side effects. ^{1 2 3 4 5}

Is the treatment with olanzapine and insulin safe for humans?

Olanzapine, a medication used for mental health conditions, has been linked to insulin resistance and diabetes, which means it can affect how the body processes sugar. Some people taking olanzapine have developed high blood sugar levels and diabetes, so it's important for healthcare providers to monitor these side effects. ^{2 3 4 6 7}

How does the drug Olanzapine differ from other treatments for insulin resistance in females?

Olanzapine is unique because it is primarily an antipsychotic medication used for schizophrenia, but it has been associated with causing insulin resistance and diabetes, which is unusual for a treatment being studied for insulin resistance itself. This dual role highlights the need for careful monitoring of blood sugar levels when using Olanzapine. ^{2 3 4 7 8}

What is the purpose of this trial?

Females treated with antipsychotics have higher rates of comorbid metabolic syndrome than males. Despite this, females have historically been excluded from many mechanistic studies due to confounding effects of menstrual cycles. Recent evidence suggests that brain insulin resistance may be an underlying mechanism through which antipsychotics may exert their metabolic side effects. This study seeks to investigate how brain insulin action differs in females according to their menstrual cycle phase, and how a high metabolic liability agent such as olanzapine might interrupt these differential insulin effects. Young healthy females will be given olanzapine and intranasal insulin to test how these treatment combinations change brain processes. Participants will be tested during both the first half of their menstrual cycle (follicular phase) and the second half of their cycle (luteal phase). The investigators predict that intranasal insulin will change MRI-based measures in females, in a comparable way to males, in the follicular phase only. Adding olanzapine will block these effects of insulin in females in the follicular phase. This investigation has the potential to generate new knowledge in an area of significant unmet need. Demonstrating that antipsychotics disrupt brain insulin action, evidenced by inhibition of recognized effects of insulin on neuroimaging measures, will provide novel insights into currently poorly understood mechanisms.

Research Team

Mahavir Agarwal, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

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

My BMI is less than 25.

Right-handed

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

Exclusion Criteria

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

A close family member has diabetes.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents. [2021]

2. Germany 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. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Olanzapine-associated severe hyperglycemia, ketonuria, and acidosis: case report and review of literature. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Management of diabetes mellitus occurring during treatment with olanzapine: report of six cases and clinical implications. [2018]

5. Germany pubmed.ncbi.nlm.nih.gov

[Diabetes mellitus as a complication of treatment with atypical neuroleptics. Possible pathomechanisms and treatment recommendations]. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Angiotensin II type 1 receptor blockers improve insulin sensitivity in patients with schizophrenia being treated with olanzapine. [2021]

7. United States 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. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Diabetic ketoacidosis associated with olanzapine in an adolescent patient. [2018]