Ignite Creation Date:
2024-05-06 @ 8:06 PM
Last Modification Date:
2025-12-16 @ 6:38 PM
Study NCT ID:
NCT06251635
Status:
None
Last Update Posted:
2024-08-01 00:00:00
First Post:
2024-02-01 00:00:00
Brief Title:
Effects of Antipsychotics on Brain Insulin Action in Females
Sponsor:
Centre for Addiction and Mental Health
Organization:
Centre for Addiction and Mental Health
Study Overview
Official Title:
Effects of Antipsychotics on Brain Insulin Action in Females: A Randomised Placebo-Controlled, Crossover Multi-Modal Neuroimaging Study
Status:
None
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
BACKGROUND: Antipsychotics (APs) cause serious metabolic adverse effects, including weight gain and type 2 diabetes. Females are disproportionally more affected by this problem than males. While the pathophysiology of these effects remain unclear, brain insulin resistance (IR) is posited to be an important determinant. Currently there are no direct methods to investigate brain IR, but physiological response to intranasal insulin (INI) can be used as a surrogate marker. INI reliably suppresses endogenous glucose production, modulates brain activity, and improves cognition. In a proof-of-concept neuroimaging study at CAMH, the investigators investigated AP-induced brain IR using an INI challenge. As expected, preliminary data show acute olanzapine (OLA) administration attenuates INI-induced changes in cerebral blood flow and resting state activity; however, the findings are only observed in males. It was recently suggested that brain insulin action differs between sexes, and this may relate to menstrual phases. Specifically, IR is physiologically induced in the luteal, but not follicular phase of the menstrual cycle. Hence, this study seeks to explore if the effects of APs on brain insulin action in females is modulated by menstrual stages.
HYPOTHESES: 1) INI, but not intranasal placebo (INP) will modulate resting state activity in the brain in females during the follicular phase of their menstrual cycle but not the luteal phase; 2) oral OLA will inhibit all INI-induced effects, relative to oral PL, during the follicular phase. OLA will have no apparent effect on females in the luteal phase given pre-existing brain IR.
APPROACH AND METHODOLOGY: Fifteen healthy normal weight (BMI \<25 kg/m2), normal cycling female volunteers between the ages of 18-35 years will be recruited to participate in the study. In a single blind, crossover design, each participant will receive 4 treatment conditions (INP/PL, INI/PL, INP/OLA or INI-OLA) twice on 4 separate occasions (two visits per cycle phase). 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. On Day 2, fasting blood work (glucose, insulin, c-peptide, olanzapine measures) will be followed by an MRI-based protocol of brain insulin action. This includes two MRI scans; one with intranasal insulin challenge (160 IU) and one with intranasal placebo. Study visits will take place 2-6 weeks apart to ensure specific menstrual phase across the four visits. 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), and another two visits during the luteal phase of their menstrual cycle (between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). Menstrual cycles will be tracked by self-report of the last three menstruation onset dates. Average cycle duration will be calculated to determine cycle phases. Based on this, participants will be invited to complete the visits during the specific windows of their follicular and luteal phase; measurement of sex hormones (progesterone, estrogen, luteinizing hormone (LH) and follicular stimulating hormone (FSH)) will be done at each visit to confirm cycle phase.
SIGNIFICANCE: Females suffer the most from AP-related metabolic adverse effects. Brain insulin action is increasingly being recognized as a potential mediator of these side effects. Disappointingly, females are an underrepresented population in the field because of the complex confounding effects of monthly hormonal variations. This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of APs. Thus, this investigation has the potential to generate new knowledge in an area of significant unmet need. Demonstrating that APs disrupt brain insulin action, evidenced by inhibition of recognized effects of INI on neuroimaging measures, will provide novel insights into currently poorly understood mechanisms.
HYPOTHESES: 1) INI, but not intranasal placebo (INP) will modulate resting state activity in the brain in females during the follicular phase of their menstrual cycle but not the luteal phase; 2) oral OLA will inhibit all INI-induced effects, relative to oral PL, during the follicular phase. OLA will have no apparent effect on females in the luteal phase given pre-existing brain IR.
APPROACH AND METHODOLOGY: Fifteen healthy normal weight (BMI \<25 kg/m2), normal cycling female volunteers between the ages of 18-35 years will be recruited to participate in the study. In a single blind, crossover design, each participant will receive 4 treatment conditions (INP/PL, INI/PL, INP/OLA or INI-OLA) twice on 4 separate occasions (two visits per cycle phase). 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. On Day 2, fasting blood work (glucose, insulin, c-peptide, olanzapine measures) will be followed by an MRI-based protocol of brain insulin action. This includes two MRI scans; one with intranasal insulin challenge (160 IU) and one with intranasal placebo. Study visits will take place 2-6 weeks apart to ensure specific menstrual phase across the four visits. 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), and another two visits during the luteal phase of their menstrual cycle (between day 16-22, or within 5 days of next expected menses depending on individual cycle duration). Menstrual cycles will be tracked by self-report of the last three menstruation onset dates. Average cycle duration will be calculated to determine cycle phases. Based on this, participants will be invited to complete the visits during the specific windows of their follicular and luteal phase; measurement of sex hormones (progesterone, estrogen, luteinizing hormone (LH) and follicular stimulating hormone (FSH)) will be done at each visit to confirm cycle phase.
SIGNIFICANCE: Females suffer the most from AP-related metabolic adverse effects. Brain insulin action is increasingly being recognized as a potential mediator of these side effects. Disappointingly, females are an underrepresented population in the field because of the complex confounding effects of monthly hormonal variations. This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of APs. Thus, this investigation has the potential to generate new knowledge in an area of significant unmet need. Demonstrating that APs disrupt brain insulin action, evidenced by inhibition of recognized effects of INI on neuroimaging measures, will provide novel insights into currently poorly understood mechanisms.
Detailed Description:
BACKGROUND Antipsychotics APs cause serious metabolic adverse effects including weight gain and type 2 diabetes Females are disproportionally more affected by this problem than males While the pathophysiology of these effects remain unclear brain insulin resistance IR is posited to be an important determinant Currently there are no direct methods to investigate brain IR but physiological response to intranasal insulin INI can be used as a surrogate marker INI reliably suppresses endogenous glucose production modulates brain activity and improves cognition In a proof-of-concept neuroimaging study at CAMH the investigators investigated AP-induced brain IR using an INI challenge As expected preliminary data show acute olanzapine OLA administration attenuates INI-induced changes in cerebral blood flow and resting state activity however the findings are only observed in males It was recently suggested that brain insulin action differs between sexes and this may relate to menstrual phases Specifically IR is physiologically induced in the luteal but not follicular phase of the menstrual cycle Hence this study seeks to explore if the effects of APs on brain insulin action in females is modulated by menstrual stages
HYPOTHESES 1 INI but not intranasal placebo INP will modulate resting state activity in the brain in females during the follicular phase of their menstrual cycle but not the luteal phase 2 oral OLA will inhibit all INI-induced effects relative to oral PL during the follicular phase OLA will have no apparent effect on females in the luteal phase given pre-existing brain IR
APPROACH AND METHODOLOGY Fifteen healthy normal weight BMI 25 kgm2 normal cycling female volunteers between the ages of 18-35 years will be recruited to participate in the study In a single blind crossover design each participant will receive 4 treatment conditions INPPL INIPL INPOLA or INI-OLA twice on 4 separate occasions two visits per cycle phase 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 On Day 2 fasting blood work glucose insulin c-peptide olanzapine measures will be followed by an MRI-based protocol of brain insulin action This includes two MRI scans one with intranasal insulin challenge 160 IU and one with intranasal placebo Study visits will take place 2-6 weeks apart to ensure specific menstrual phase across the four visits 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 and another two visits during the luteal phase of their menstrual cycle between day 16-22 or within 5 days of next expected menses depending on individual cycle duration Menstrual cycles will be tracked by self-report of the last three menstruation onset dates Average cycle duration will be calculated to determine cycle phases Based on this participants will be invited to complete the visits during the specific windows of their follicular and luteal phase measurement of sex hormones progesterone estrogen luteinizing hormone LH and follicular stimulating hormone FSH will be done at each visit to confirm cycle phase
SIGNIFICANCE Females suffer the most from AP-related metabolic adverse effects Brain insulin action is increasingly being recognized as a potential mediator of these side effects Disappointingly females are an underrepresented population in the field because of the complex confounding effects of monthly hormonal variations This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of APs Thus this investigation has the potential to generate new knowledge in an area of significant unmet need Demonstrating that APs disrupt brain insulin action evidenced by inhibition of recognized effects of INI on neuroimaging measures will provide novel insights into currently poorly understood mechanisms
HYPOTHESES 1 INI but not intranasal placebo INP will modulate resting state activity in the brain in females during the follicular phase of their menstrual cycle but not the luteal phase 2 oral OLA will inhibit all INI-induced effects relative to oral PL during the follicular phase OLA will have no apparent effect on females in the luteal phase given pre-existing brain IR
APPROACH AND METHODOLOGY Fifteen healthy normal weight BMI 25 kgm2 normal cycling female volunteers between the ages of 18-35 years will be recruited to participate in the study In a single blind crossover design each participant will receive 4 treatment conditions INPPL INIPL INPOLA or INI-OLA twice on 4 separate occasions two visits per cycle phase 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 On Day 2 fasting blood work glucose insulin c-peptide olanzapine measures will be followed by an MRI-based protocol of brain insulin action This includes two MRI scans one with intranasal insulin challenge 160 IU and one with intranasal placebo Study visits will take place 2-6 weeks apart to ensure specific menstrual phase across the four visits 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 and another two visits during the luteal phase of their menstrual cycle between day 16-22 or within 5 days of next expected menses depending on individual cycle duration Menstrual cycles will be tracked by self-report of the last three menstruation onset dates Average cycle duration will be calculated to determine cycle phases Based on this participants will be invited to complete the visits during the specific windows of their follicular and luteal phase measurement of sex hormones progesterone estrogen luteinizing hormone LH and follicular stimulating hormone FSH will be done at each visit to confirm cycle phase
SIGNIFICANCE Females suffer the most from AP-related metabolic adverse effects Brain insulin action is increasingly being recognized as a potential mediator of these side effects Disappointingly females are an underrepresented population in the field because of the complex confounding effects of monthly hormonal variations This is the first study to explore the effect of menstrual cycle phases on the anti-insulin action of APs Thus this investigation has the potential to generate new knowledge in an area of significant unmet need Demonstrating that APs disrupt brain insulin action evidenced by inhibition of recognized effects of INI on neuroimaging measures will provide novel insights into currently poorly understood mechanisms
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None