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| ID | Type | Description | Link |
|---|---|---|---|
| K01MH095920 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Mental Health (NIMH) | NIH |
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Insulin resistance, a primary component of the metabolic syndrome, is an escalating phenomenon in the United States, and confers an increased risk of depression and mood disorder, particularly in women. The relationship between metabolic and mood disorders may be mediated by endogenous opioid activity in limbic brain regions. We propose to examine affective state and μ- opioid system function in insulin resistant women, and change in response to insulin sensitizing treatment, through the following specific aims and hypotheses:
Establish relationship between insulin resistance, affective state, and μ-opioid receptor function.
Examine effects of insulin regulation on μ-opioid receptor function and affective state.
The expected results would suggest a role for the endogenous μ-opioid system in mediating the relationship between metabolic function and emotional processes.
The objective of this study is to examine the role of the endogenous mu-opioid system in mediating the relationship between metabolic dysfunction and depressive symptoms in reproductive aged women.
PET image data was unable to be analyzed due to PET equipment replacement midway through study, leaving PET images collected at beginning of study incompatible with PET images collected later in study.
Due to insufficient enrollment in treatment arms, the 20 or 40 week data was unusable for analytic goals, so the study was re-framed for what could usefully be learned about baseline characteristics among the study populations and the originally planned outcome measures were amended to only to those that related to understanding the baseline population.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Controls | No Intervention | metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms. | |
| Metformin | Experimental | 16 weeks treatment with metformin (insulin sensitizing treatment) |
|
| Placebo | Placebo Comparator | Placebo comparator to metformin treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin | Drug | Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms. |
| Measure | Description | Time Frame |
|---|---|---|
| Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | Baseline, 20 weeks, 40 weeks |
| Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | Baseline, 20 weeks, 40 weeks |
| Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State | Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment | Baseline, 20 weeks, 40 weeks |
| Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | Baseline, 20 weeks, 40 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Positive and Negative Affect Schedule - Positive Affective State | Compare positive affective state between controls and insulin resistant women. Positive and Negative Affect Schedule - positive affective state. Scores can range from 10-50, with higher scores representing more positive affective state (better outcome) | Baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alison Berent-Spillson, PhD | University of Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Michigan Medical School | Ann Arbor | Michigan | 48103 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Controls | metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms. |
| FG001 | Insulin Resistant Participants (Placebo First) | Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms. |
| FG002 | Insulin Resistant Participants (Metformin First) | Women classified as insulin resistant and randomized to Metformin treatment arm 1st and Placebo treatment arm 2nd |
| FG003 | Insulin Resistant (Not Randomized) | Insulin resistant participants not randomized to treatment arms |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline Measurements |
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| First Treatment Arm |
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| Washout Period (4 Weeks) |
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| Second Treatment Arm |
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All insulin resistant women are grouped together for baseline characteristics, as these measurements were taken prior to treatment arm randomization
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| ID | Title | Description |
|---|---|---|
| BG000 | Controls | metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms. |
| BG001 | Insulin Resistant Participants |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | PET scanners available were replaced for other institutional reasons which resulted in image production so incompatible as to be not comparable. Therefore PET image data files were unable to be analyzed due to inconsistencies with imaging techniques. | Posted | Baseline, 20 weeks, 40 weeks |
|
Adverse event data were collected for up to 40 weeks of study participation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Controls | metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea? | Gastrointestinal disorders | Systematic Assessment |
A limitation of this study is the relatively small sample size of the insulin resistant group.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alison Berent-Spillson | University of Michigan | (734) 936-4400 | berent@umich.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 19, 2015 | Aug 20, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003863 | Depression |
| D007333 | Insulin Resistance |
| D024821 | Metabolic Syndrome |
| D000080103 | Emotional Regulation |
| ID | Term |
|---|---|
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| Placebo | Drug | Placebo capsules prepared identically to Metformin capsules |
|
|
| Positive and Negative Affect Schedule - Negative Affective State |
Measure of overall negative affective state at baseline in controls and insulin resistant women. Positive and Negative Affect Schedule - negative affective state. Scores can range from 10-50, with higher scores representing more negative affective state (worse outcome) |
| Baseline |
| Profile of Mood States - Overall Negative Mood | Measure of overall negative mood at baseline in controls and insulin resistant women; Profile of Mood States are standardized to a relative score where a higher score is a worse mood state. Standardized cores generally ranged from - 11 to 52. | Baseline |
| Beck Depression Index | Measure of depression symptoms at baseline in controls and insulin resistant women. The Beck Depression Index runs on a scale from 0 to 63 where low scores mean less depression and high scores mean greater depression. Clinically, scores of 14 or higher are considered mild depression; 20 is moderate and 29 is severe. | Baseline |
| Ineligible based on initial assessments |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms.
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
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| Glucose | Mean | Standard Deviation | mg/dL |
|
| Plasma Insulin Levels | Mean | Standard Deviation | mIU/L |
|
| HOMA Insulin Resistance (IR) | Mean | Standard Deviation | HOMA IR |
|
16 weeks treatment with metformin (insulin sensitizing treatment)
Metformin: Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms.
| OG002 | Placebo | Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules |
|
| Primary | Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | PET scanners available were replaced for other institutional reasons which resulted in image production so incompatible as to be not comparable. Therefore PET image data files were unable to be analyzed due to inconsistencies with imaging techniques. | Posted | Baseline, 20 weeks, 40 weeks |
|
|
| Primary | Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State | Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment | PET scanners available were replaced for other institutional reasons which resulted in image production so incompatible as to be not comparable. Therefore PET image data files were unable to be analyzed due to inconsistencies with imaging techniques. | Posted | Baseline, 20 weeks, 40 weeks |
|
|
| Primary | Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment | PET scanners available were replaced for other institutional reasons which resulted in image production so incompatible as to be not comparable. Therefore PET image data files were unable to be analyzed due to inconsistencies with imaging techniques. | Posted | Baseline, 20 weeks, 40 weeks |
|
|
| Secondary | Positive and Negative Affect Schedule - Positive Affective State | Compare positive affective state between controls and insulin resistant women. Positive and Negative Affect Schedule - positive affective state. Scores can range from 10-50, with higher scores representing more positive affective state (better outcome) | All women assessed at baseline, prior to treatment arm randomization, so all insulin resistant women are analyzed as a single group. On the Control side, one woman's data for affective state is unavailable. | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
| Secondary | Positive and Negative Affect Schedule - Negative Affective State | Measure of overall negative affective state at baseline in controls and insulin resistant women. Positive and Negative Affect Schedule - negative affective state. Scores can range from 10-50, with higher scores representing more negative affective state (worse outcome) | All women assessed at baseline, prior to treatment arm randomization, so all insulin resistant women analyzed as a single group. One woman's baseline affective score is not available. | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
| Secondary | Profile of Mood States - Overall Negative Mood | Measure of overall negative mood at baseline in controls and insulin resistant women; Profile of Mood States are standardized to a relative score where a higher score is a worse mood state. Standardized cores generally ranged from - 11 to 52. | All women assessed at baseline, prior to treatment arm randomization, so all insulin resistant women analyzed as a single group; one woman on the control side's data is not available | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
| Secondary | Beck Depression Index | Measure of depression symptoms at baseline in controls and insulin resistant women. The Beck Depression Index runs on a scale from 0 to 63 where low scores mean less depression and high scores mean greater depression. Clinically, scores of 14 or higher are considered mild depression; 20 is moderate and 29 is severe. | All women assessed at baseline, prior to treatment arm randomization, so all insulin resistant women analyzed as a single group. The data for one woman in the control group is unavailable. Note: women with BDI scores of greater than 20 were excluded from the study by definition and therefore could not be in either arm. | Posted | Mean | Standard Deviation | units on a scale | Baseline |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 2 |
| 30 |
| EG001 | Placebo (First Assignment & Washout or Second Assignment) | Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules | 0 | 5 | 0 | 5 | 2 | 5 |
| EG002 | Metformin (First Assignment & Washout or Second Assignment) | 16 weeks treatment with metformin (insulin sensitizing treatment) Metformin: Women classified as insulin resistant will participate in both a placebo and a metformin treatment arm, each lasting about 16 weeks. Women will be randomized to order of treatment arms. | 0 | 3 | 0 | 3 | 0 | 3 |
| EG003 | Insulin-resistant Women Not Randomized | These participants, like controls, did not continue beyond baseline and were not assigned any metformin or placebo. | 0 | 6 | 0 | 6 | 0 | 6 |
| Elevated potassium levels | Renal and urinary disorders | Systematic Assessment |
|
| Self-reported seizure | Nervous system disorders | Systematic Assessment | Participant reported undiagnosed seizure during placebo treatment; study participation was halted |
|
| Brain lesion detected | Nervous system disorders | Systematic Assessment | Brain lesion was detected during study MRI scan. Participant notified and spoke with study radiologist, and referred to diagnostic radiologist care. |
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| D008659 |
| Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000068356 | Self-Control |
| D012919 | Social Behavior |