Endogenous Opioid Activity and Affective State in Insulin Resistant Women

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT02069379
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 42
• Location: 1
• Arms: 3
• Actual Duration (Months): 38
• Patients Per Site Per Month: 1.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Depression; Insulin Resistance; Metabolic Syndrome	Drug: Metformin; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Endogenous Opioid Activity and Affective State in Insulin Resistant Women
• Actual Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Mar 24, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Controls metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.
Experimental: Metformin 16 weeks treatment with metformin (insulin sensitizing treatment)	Drug: 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.; Other Names: Glucophage Glumetza Fortamet Riomet
Placebo Comparator: Placebo Placebo comparator to metformin treatment	Drug: Placebo; Placebo capsules prepared identically to Metformin capsules; Other Names: Sugar pills

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

3. 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

4. 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

Secondary Outcome Measures

1. 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)

2. 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)

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Medical School	Ann Arbor	Michigan	United States	48103

Sponsors and Collaborators

• University of Michigan
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Alison Berent-Spillson, PhD, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 19, 2015

More Information

Publications

None provided.

• Responsible Party: Alison Berent-Spillson, Research Investigator, University of Michigan
• ClinicalTrials.gov Identifier: NCT02069379
• Other Study ID Numbers: HUM00066696; K01MH095920
• First Posted: Feb 24, 2014
• Last Update Posted: Nov 8, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Alison Berent-Spillson, Research Investigator, University of Michigan: Metabolic syndrome; Insulin resistance; Mu-opioid system; Depression; Emotion regulation
• Additional relevant MeSH terms: Metabolic Syndrome; Insulin Resistance; Depression; Metformin

Study Results

Participant Flow

Arm/Group Title	Controls	Insulin Resistant Participants (Placebo First)	Insulin Resistant Participants (Metformin First)	Insulin Resistant (Not Randomized)
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Women classified as insulin resistant and randomized to Metformin treatment arm 1st and Placebo treatment arm 2nd	Insulin resistant participants not randomized to treatment arms
Period Title: Baseline Measurements
STARTED	30	4	2	6
Baseline Measurements Taken	30	4	2	6
COMPLETED	27	4	2	4
NOT COMPLETED	3	0	0	2
Period Title: Baseline Measurements
STARTED	0	4	2	0
COMPLETED	0	3	1	0
NOT COMPLETED	0	1	1	0
Period Title: Baseline Measurements
STARTED	0	3	1	0
COMPLETED	0	1	1	0
NOT COMPLETED	0	2	0	0
Period Title: Baseline Measurements
STARTED	0	1	1	0
COMPLETED	0	1	0	0
NOT COMPLETED	0	0	1	0

Baseline Characteristics

Arm/Group Title	Controls	Insulin Resistant Participants	Total
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Total of all reporting groups
Overall Participants	30	12	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	30 100%	12 100%	42 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	30 100%	12 100%	42 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	30 100%	12 100%	42 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3.3%	0 0%	1 2.4%
Asian	6 20%	3 25%	9 21.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 23.3%	2 16.7%	9 21.4%
White	13 43.3%	7 58.3%	20 47.6%
More than one race	1 3.3%	0 0%	1 2.4%
Unknown or Not Reported	2 6.7%	0 0%	2 4.8%
Region of Enrollment (participants) [Number]
United States	30 100%	12 100%	42 100%
Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	80.29 (5.33)	84.67 (9.99)	81.60 (7.21)
Plasma Insulin Levels (mIU/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mIU/L]	10.18 (1.99)	18.61 (3.36)	12.71 (4.61)
HOMA Insulin Resistance (IR) (HOMA IR) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [HOMA IR]	2.01 (0.42)	3.94 (1.11)	2.56 (1.12)

Outcome Measures

1. Primary Outcome

Title	Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State
Description	Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment
Time Frame	Baseline, 20 weeks, 40 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Controls	Metformin	Placebo
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules
Measure Participants	0	0	0

2. Primary Outcome

Title	Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State
Description	Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment
Time Frame	Baseline, 20 weeks, 40 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Controls	Metformin	Placebo
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules
Measure Participants	0	0	0

3. Primary Outcome

Title	Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State
Description	Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment
Time Frame	Baseline, 20 weeks, 40 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Controls	Metformin	Placebo
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules
Measure Participants	0	0	0

4. Primary Outcome

Title	Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State
Description	Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment
Time Frame	Baseline, 20 weeks, 40 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Controls	Metformin	Placebo
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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.	Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules
Measure Participants	0	0	0

5. Secondary Outcome

Title	Positive and Negative Affect Schedule - Positive Affective State
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Controls	Insulin Resistant Participants
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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 Participants	26	12
Mean (Standard Deviation) [units on a scale]	28.23 (8.29)	21.83 (8.84)

6. Secondary Outcome

Title	Positive and Negative Affect Schedule - Negative Affective State
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Controls	Insulin Resistant Participants
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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 Participants	26	12
Mean (Standard Deviation) [units on a scale]	11.46 (1.68)	12.83 (6.74)

7. Secondary Outcome

Title	Profile of Mood States - Overall Negative Mood
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Controls	Insulin Resistant Participants
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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 Participants	26	12
Mean (Standard Deviation) [units on a scale]	3.15 (10.60)	14.42 (20.35)

8. Secondary Outcome

Title	Beck Depression Index
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Controls	Insulin Resistant Participants
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.	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 Participants	26	12
Mean (Standard Deviation) [units on a scale]	2.93 (4.36)	7.00 (9.96)

Adverse Events

Time Frame	Adverse event data were collected for up to 40 weeks of study participation.
Arm/Group Title	Controls		Placebo (First Assignment & Washout or Second Assignment)		Metformin (First Assignment & Washout or Second Assignment)		Insulin-resistant Women Not Randomized
Arm/Group Description	metabolically healthy controls will participate in baseline assessments only, and will not be randomized to the placebo and metformin treatment arms.		Placebo comparator to metformin treatment Placebo: Placebo capsules prepared identically to Metformin capsules		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.		These participants, like controls, did not continue beyond baseline and were not assigned any metformin or placebo.
All Cause Mortality
	Controls		Placebo (First Assignment & Washout or Second Assignment)		Metformin (First Assignment & Washout or Second Assignment)		Insulin-resistant Women Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)
Serious Adverse Events
	Controls		Placebo (First Assignment & Washout or Second Assignment)		Metformin (First Assignment & Washout or Second Assignment)		Insulin-resistant Women Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/5 (0%)		0/3 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Controls		Placebo (First Assignment & Washout or Second Assignment)		Metformin (First Assignment & Washout or Second Assignment)		Insulin-resistant Women Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		2/5 (40%)		0/3 (0%)		0/6 (0%)
Gastrointestinal disorders
Nausea?	1/30 (3.3%)	1	0/5 (0%)	0	0/3 (0%)	0	0/6 (0%)	0
Nervous system disorders
Self-reported seizure	0/30 (0%)	0	1/5 (20%)	1	0/3 (0%)	0	0/6 (0%)	0
Brain lesion detected	0/30 (0%)	0	1/5 (20%)	1	0/3 (0%)	0	0/6 (0%)	0
Renal and urinary disorders
Elevated potassium levels	1/30 (3.3%)	1	0/5 (0%)	0	0/3 (0%)	0	0/6 (0%)	0

Limitations/Caveats

A limitation of this study is the relatively small sample size of the insulin resistant group.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.