Depression, Insulin Resistance, Metabolic Syndrome
Conditions
Keywords
Metabolic syndrome, Insulin resistance, Mu-opioid system, Depression, Emotion regulation
Brief summary
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. 1. Insulin resistant women will have greater μ-opioid receptor availability at baseline, and a larger response to stress challenge than non-insulin resistant women 2. Insulin resistant women will have greater negative affective state at baseline, and a greater emotional response to stress challenge than non-insulin resistant women. 3. Mediational analyses will reveal that the relationship between insulin resistance and negative affect is mediated by μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens affect-regulating regions. Examine effects of insulin regulation on μ-opioid receptor function and affective state. 1. Improved insulin sensitivity will be accompanied by decreased μ-opioid receptor availability at baseline and a reduced response to stress challenge. Degree of change in baseline receptor availability and response to stress challenge after treatment will correlate with degree of insulin regulation. 2. Improved insulin sensitivity will be associated with improved affective state at baseline, and with a reduced emotional response to stress challenge. Degree of change in affective state and emotional response to stress challenge after treatment will correlate with degree of insulin regulation. 3. Mediational analyses will reveal that the change in affective state after insulin regulation is mediated by change in μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens. The expected results would suggest a role for the endogenous μ-opioid system in mediating the relationship between metabolic function and emotional processes.
Detailed description
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.
Interventions
DRUGMetformin
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.
DRUGPlacebo
Placebo capsules prepared identically to Metformin capsules
Sponsors
National Institute of Mental Health (NIMH)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Women * 18-40 years old * metabolically healthy or insulin resistant (insulin sensitivity \> 1.89x10-4 (min-1 x µU-1 x mL-1; calculated by minimal model assessment of glucose tolerance test) * body mass index (BMI = weight (kg) / height2 (m2)) between 18 kg/m2 and 35 kg/m2. * Women with mild or moderate depressive symptoms not meeting the criteria for Major Depressive Disorder will be included.
Exclusion criteria
* men * left handed * acute medical illness * uncorrected thyroid disease * diabetes (fasting glucose ≥126 mg/dL)\\ * neurological disease * major depression * substance abuse * MRI contraindications (claustrophobia, pacemakers, pumps, metallic agents or devices) * severe calorie restriction * intense physical exercise ≥1 hour/day * smoking within 6 months * hormonal, insulin sensitizing, or centrally acting medications within 2 months * pregnancy within 6 months * lactation * cardiac or pulmonary insufficiency * liver or renal insufficiency (\>2.5 x normal transaminases levels, plasma creatinine ≥1.4 mg/dL) * history of lactic acidosis * BMI ≥35 kg/m2 * opioid allergy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State | Baseline, 20 weeks, 40 weeks | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment |
| Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State | Baseline, 20 weeks, 40 weeks | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment |
| Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State | Baseline, 20 weeks, 40 weeks | Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment |
| Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State | Baseline, 20 weeks, 40 weeks | Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Affect Schedule - Positive Affective State | Baseline | 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) |
| Positive and Negative Affect Schedule - Negative Affective State | Baseline | 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) |
| Profile of Mood States - Overall Negative Mood | Baseline | 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. |
| Beck Depression Index | Baseline | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Controls metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms. | 30 |
| Insulin Resistant Participants 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. | 12 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Baseline Measurements | Ineligible based on initial assessments | 2 | 0 | 0 | 2 |
| Baseline Measurements | Lost to Follow-up | 1 | 0 | 0 | 0 |
| First Treatment Arm | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Second Treatment Arm | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Washout Period (4 Weeks) | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Washout Period (4 Weeks) | Unrelated event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Controls | Total | Insulin Resistant Participants |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 42 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 30 Participants | 42 Participants | 12 Participants |
| Glucose | 80.29 mg/dL STANDARD_DEVIATION 5.33 | 81.60 mg/dL STANDARD_DEVIATION 7.21 | 84.67 mg/dL STANDARD_DEVIATION 9.99 |
| HOMA Insulin Resistance (IR) | 2.01 HOMA IR STANDARD_DEVIATION 0.42 | 2.56 HOMA IR STANDARD_DEVIATION 1.12 | 3.94 HOMA IR STANDARD_DEVIATION 1.11 |
| Plasma Insulin Levels | 10.18 mIU/L STANDARD_DEVIATION 1.99 | 12.71 mIU/L STANDARD_DEVIATION 4.61 | 18.61 mIU/L STANDARD_DEVIATION 3.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 20 Participants | 7 Participants |
| Region of Enrollment United States | 30 participants | 42 participants | 12 participants |
| Sex: Female, Male Female | 30 Participants | 42 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 5 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 2 / 30 | 2 / 5 | 0 / 3 | 0 / 6 |
| serious Total, serious adverse events | 0 / 30 | 0 / 5 | 0 / 3 | 0 / 6 |
Outcome results
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
Time frame: Baseline, 20 weeks, 40 weeks
Population: 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.
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
Time frame: Baseline, 20 weeks, 40 weeks
Population: 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.
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
Time frame: Baseline, 20 weeks, 40 weeks
Population: 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.
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
Time frame: Baseline, 20 weeks, 40 weeks
Population: 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.
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.
Time frame: Baseline
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Controls | Beck Depression Index | 2.93 units on a scale | Standard Deviation 4.36 |
| Metformin | Beck Depression Index | 7.00 units on a scale | Standard Deviation 9.96 |
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)
Time frame: Baseline
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Controls | Positive and Negative Affect Schedule - Negative Affective State | 11.46 units on a scale | Standard Deviation 1.68 |
| Metformin | Positive and Negative Affect Schedule - Negative Affective State | 12.83 units on a scale | Standard Deviation 6.74 |
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)
Time frame: Baseline
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Controls | Positive and Negative Affect Schedule - Positive Affective State | 28.23 units on a scale | Standard Deviation 8.29 |
| Metformin | Positive and Negative Affect Schedule - Positive Affective State | 21.83 units on a scale | Standard Deviation 8.84 |
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.
Time frame: Baseline
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Controls | Profile of Mood States - Overall Negative Mood | 3.15 units on a scale | Standard Deviation 10.6 |
| Metformin | Profile of Mood States - Overall Negative Mood | 14.42 units on a scale | Standard Deviation 20.35 |