CompletedNCT02069379Updated Nov 8, 2018Results posted

Endogenous Opioid Activity and Affective State in Insulin Resistant Women

A Phase 4 interventional study of Metformin and Placebo in Depression, Insulin Resistance and Metabolic Syndrome, sponsored by University of Michigan. Completed at 1 site in United States. Open to female participants aged 18 Years to 40 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-11-08.

Sponsored by University of Michigan · Phase 4, Interventional, and Basic science

Phase: Phase 4
Study type: Interventional
Enrollment: 42
Allocation: Randomized
Ages: 18 Years to 40 Years
Sex: Female

Study 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.

Insulin resistant women will have greater μ-opioid receptor availability at baseline, and a larger response to stress challenge than non-insulin resistant women
Insulin resistant women will have greater negative affective state at baseline, and a greater emotional response to stress challenge than non-insulin resistant women.
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.

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.
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.
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.

Read the 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.

Conditions studied

Depression
Insulin Resistance
Metabolic Syndrome

Browse trials for

Keywords

Metabolic syndrome
Insulin resistance
Mu-opioid system
Depression
Emotion regulation

In context

Depression

8,240 studies on the registry are indexed under Depression; 1,641 are open to participants now.

This study's enrollment of 42 is below the median of 84 across 6,869 interventional studies indexed under Depression.

Browse Depression studies →

Lead sponsor

University of Michigan is the lead sponsor of 1,503 studies on the registry; 189 are open to participants now.

Of its 167 completed or terminated interventional studies of FDA-regulated products, 132 (79%) have results posted.

Browse University of Michigan studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 40 Years
Sexes eligible: Female
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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

Study design

Phase: Phase 4
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Triple (Participant, Investigator, Outcomes assessor)
Enrollment: 42 participants (actual)

Study arms

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
Placebo comparator
Placebo
Placebo comparator to metformin treatment
Drug: Placebo

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.
Also known as: Glucophage, Glumetza, Fortamet, Riomet
DrugPlacebo
Placebo capsules prepared identically to Metformin capsules
Also known as: Sugar pills

What researchers measure

Primary outcomes

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
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
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
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

Secondary outcomes

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
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
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
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

Results

Posted Nov 8, 2018

Limitations and caveats

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

Participant flow

Baseline Measurements

Participant flow — Baseline Measurements
Milestone	Controls	Insulin Resistant Participants (Placebo First)	Insulin Resistant Participants (Metformin First)	Insulin Resistant (Not Randomized)
Started	30	4	2	6
Baseline measurements taken	30	4	2	6
Completed	27	4	2	4
Not completed	3	0	0	2
Withdrew: Lost to follow-up	1	0	0	0
Withdrew: Ineligible based on initial assessments	2	0	0	2

First Treatment Arm

Participant flow — First Treatment Arm
Milestone	Insulin Resistant Participants (Placebo First)	Insulin Resistant Participants (Metformin First)
Started	4	2
Completed	3	1
Not completed	1	1
Withdrew: Lost to follow-up	1	1

Washout Period (4 Weeks)

Participant flow — Washout Period (4 Weeks)
Milestone	Insulin Resistant Participants (Placebo First)	Insulin Resistant Participants (Metformin First)
Started	3	1
Completed	1	1
Not completed	2	0
Withdrew: Lost to follow-up	1	0
Withdrew: Unrelated event	1	0

Second Treatment Arm

Participant flow — Second Treatment Arm
Milestone	Insulin Resistant Participants (Placebo First)	Insulin Resistant Participants (Metformin First)
Started	1	1
Completed	1	0
Not completed	0	1
Withdrew: Lost to follow-up	0	1

Outcome measures

PrimaryMu-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

No measurements were reported for this outcome.

PrimaryMu-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

No measurements were reported for this outcome.

PrimaryMu-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

No measurements were reported for this outcome.

PrimaryMu-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

No measurements were reported for this outcome.

SecondaryPositive 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
Reported as:: Mean · units on a scale

Positive and Negative Affect Schedule - Positive Affective State
units on a scale	Controls	Insulin Resistant Participants
Positive and Negative Affect Schedule - Positive Affective State	28.23 ± 8.29	21.83 ± 8.84

SecondaryPositive 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
Reported as:: Mean · units on a scale

Positive and Negative Affect Schedule - Negative Affective State
units on a scale	Controls	Insulin Resistant Participants
Positive and Negative Affect Schedule - Negative Affective State	11.46 ± 1.68	12.83 ± 6.74

SecondaryProfile 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
Reported as:: Mean · units on a scale

Profile of Mood States - Overall Negative Mood
units on a scale	Controls	Insulin Resistant Participants
Profile of Mood States - Overall Negative Mood	3.15 ± 10.60	14.42 ± 20.35

SecondaryBeck 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
Reported as:: Mean · units on a scale

Beck Depression Index
units on a scale	Controls	Insulin Resistant Participants
Beck Depression Index	2.93 ± 4.36	7.00 ± 9.96

Adverse events

Collected over Adverse event data were collected for up to 40 weeks of study participation.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Controls	0/30 (0%)	0/30 (0%)	2/30 (6.7%)
Placebo (First Assignment & Washout or Second Assignment)	0/5 (0%)	0/5 (0%)	2/5 (40%)
Metformin (First Assignment & Washout or Second Assignment)	0/3 (0%)	0/3 (0%)	0/3 (0%)
Insulin-resistant Women Not Randomized	0/6 (0%)	0/6 (0%)	0/6 (0%)

Most frequent other events

Most frequent other events
Event	Controls	Placebo (First Assignment & Washout or Second Assignment)	Metformin (First Assignment & Washout or Second Assignment)	Insulin-resistant Women Not Randomized
Self-reported seizureNervous system disorders	0/30	1/5	0/3	0/6
Brain lesion detectedNervous system disorders	0/30	1/5	0/3	0/6
Nausea?Gastrointestinal disorders	1/30	0/5	0/3	0/6
Elevated potassium levelsRenal and urinary disorders	1/30	0/5	0/3	0/6

Baseline characteristics

All insulin resistant women are grouped together for baseline characteristics, as these measurements were taken prior to treatment arm randomization

Age, Categorical
Age, Categorical(Participants)	Controls	Insulin Resistant Participants	Total
<=18 years	0	0	0
Between 18 and 65 years	30	12	42
>=65 years	0	0	0

Sex: Female, Male
Sex: Female, Male(Participants)	Controls	Insulin Resistant Participants	Total
Female	30	12	42
Male	0	0	0

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Controls	Insulin Resistant Participants	Total
Hispanic or Latino	0	0	0
Not Hispanic or Latino	0	0	0
Unknown or Not Reported	30	12	42

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Controls	Insulin Resistant Participants	Total
American Indian or Alaska Native	1	0	1
Asian	6	3	9
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	7	2	9
White	13	7	20
More than one race	1	0	1
Unknown or Not Reported	2	0	2

Region of Enrollment
Region of Enrollment(participants)	Controls	Insulin Resistant Participants	Total
United States	30	12	42

Glucose
Glucose(mg/dL)	Controls	Insulin Resistant Participants	Total
Mean	80.29 ± 5.33	84.67 ± 9.99	81.60 ± 7.21

Plasma Insulin Levels
Plasma Insulin Levels(mIU/L)	Controls	Insulin Resistant Participants	Total
Mean	10.18 ± 1.99	18.61 ± 3.36	12.71 ± 4.61

HOMA Insulin Resistance (IR)
HOMA Insulin Resistance (IR)(HOMA IR)	Controls	Insulin Resistant Participants	Total
Mean	2.01 ± 0.42	3.94 ± 1.11	2.56 ± 1.12

Study locations

1 site

University of Michigan Medical School
Ann Arbor, Michigan 48103, United States

References and documents

Study documents

Protocol and statistical analysis plan · Nov 19, 2015

Documents are hosted by the registry — open the source record to download them.

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Jul 2014 to primary completion in Mar 2017, 32 months.

Results were first posted in Nov 2018, 1 year 7 months after primary completion.

Of 131 non-industry phase 4 interventional studies under Depression, half reached primary completion within 34 months of starting (the median), counting those still running; a quarter within 17 and three quarters within 59. This study's 32 months is close to that.

Counting every sponsor, half of 150 studies reached it within 32 months; a quarter within 17 and three quarters within 58.

How these figures are worked out, and which studies are left out of them.

Registered: Nov 6, 2013
First posted: Feb 24, 2014
StartActual: Jul 2014
Primary completionActual: Mar 24, 2017
CompletionActual: Sep 2017
Results first posted: Nov 8, 2018
Last update: Nov 8, 2018

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Nov 8, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02069379
Lead sponsor: University of Michigan
Collaborators: National Institute of Mental Health (NIMH)
Responsible party: Alison Berent-Spillson (Research Investigator, University of Michigan) — Principal investigator
First posted: Feb 24, 2014
Start date: Jul 2014
Primary completion: Mar 24, 2017
Completion: Sep 2017
Results posted: Nov 8, 2018
Last update: Nov 8, 2018

Study contacts

Alison Berent-Spillson, PhD

principal investigator · University of Michigan

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Oct 2018. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Studies of the drug tested here: Metformin

Other studies in this condition

Depression →

Other studies from this sponsor

University of Michigan →

Start the discussion

Endogenous Opioid Activity and Affective State in Insulin Resistant Women

Study summary

Conditions studied

Browse trials for

Keywords

In context

Depression

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Study documents

Timeline

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria