DepressionPhase 4NCT02069379
Endogenous Opioid Activity and Affective State in Insulin Resistant Women
A Phase 4 study testing Metformin in people with Depression and Insulin Resistance, run by University of Michigan at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Depression, Insulin Resistance, Metabolic Syndrome
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2014to Sep 2017
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- men
- left handed
- acute medical illness
- uncorrected thyroid disease
- diabetes (fasting glucose ≥126 mg/dL)\
- neurological disease
Show all 20Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Michigan Medical School
Ann Arbor, Michigan, 48103
About this study
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.
Read more
- 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
- Depression, Insulin Resistance, Metabolic Syndrome
- Being tested
- Metformin, Placebo
- Keywords
- Metabolic syndrome, Insulin resistance, Mu-opioid system, Depression, Emotion regulation
- Medical subject headings
- Depression, Insulin Resistance, Metabolic Syndrome, Emotional Regulation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage, Glumetza, Fortamet, Riomet
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.
PlaceboDrug
Also called Sugar pills
Placebo capsules prepared identically to Metformin capsules
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: Drug: Metformin |
| Placebo | Placebo comparator | Placebo comparator to metformin treatment Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 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
Measured: 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
Measured: Baseline, 20 weeks, 40 weeks
Secondary outcomes (4)
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)
Measured: 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)
Measured: 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.
Measured: 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.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Feb 2014 (estimated)
- Study startJul 2014
- Primary completion24 Mar 2017
- Study completionSep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by University of MichiganThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Michigan
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Alison Berent-Spillson, University of Michigan
- Investigators
- Alison Berent-Spillson, PhD, Principal investigator, University of Michigan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02069379
- Sponsor's protocol ID
- HUM00066696
- Other IDs
- K01MH095920
- Status last verified
- Oct 2018
- First submitted
- 6 Nov 2013
- Last updated
- 8 Nov 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Endogenous Opioid Activity and Affective State in Insulin Resistant Women
- ClinicalTrials.gov ID
- NCT02069379
- Acronym / sponsor ID
- HUM00066696
- Conditions
- Depression, Insulin Resistance, Metabolic Syndrome
- Keywords
- Metabolic syndrome, Insulin resistance, Mu-opioid system, Depression, Emotion regulation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- University of MichiganUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- Jul 2014 (actual)
- Primary completion
- 24 Mar 2017 (actual)
- Study completion
- Sep 2017 (actual)
- First posted
- 24 Feb 2014 (estimated)
- Results
- Posted 8 Nov 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: Metformin16 weeks treatment with metformin (insulin sensitizing treatment) |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo comparator to metformin treatment |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (20 listed)
- men
- left handed
- acute medical illness
- uncorrected thyroid disease
- diabetes (fasting glucose ≥126 mg/dL)\
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: Glucophage, Glumetza, Fortamet, RiometWomen 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. | Drug | Metformin |
| PlaceboAlso: Sugar pillsPlacebo capsules prepared identically to Metformin capsules | Drug | Placebo |
Primary outcome
Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State
Time frame: 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
Time frame: 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
Time frame: Baseline, 20 weeks, 40 weeks
Mu-opioid neurotransmission in limbic regions at baseline and change from baseline after metformin treatment
Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State
Time frame: Baseline, 20 weeks, 40 weeks
Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment
4 secondary outcomes
Positive and Negative Affect Schedule - Positive Affective State
Time frame: Baseline
Positive and Negative Affect Schedule - Negative Affective State
Time frame: Baseline
Profile of Mood States - Overall Negative Mood
Time frame: Baseline
Beck Depression Index
Time frame: Baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Nov 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alison Berent-Spillson, PhD principal investigator
University of Michigan
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metformin in people with Depression and Insulin Resistance, run by University of Michigan at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State (time frame: Baseline, 20 weeks, 40 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Nov 2018.