Endogenous Opioid Activity and Affective State in Insulin Resistant Women

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified February 2014 by University of Michigan
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Alison Berent-Spillson, University of Michigan
ClinicalTrials.gov Identifier:
NCT02069379
First received: November 6, 2013
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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 Intervention Phase
Depression
Insulin Resistance
Metabolic Syndrome
Drug: Metformin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Endogenous Opioid Activity and Affective State in Insulin Resistant Women

Resource links provided by NLM:


Further study details as provided by University of Michigan:

Primary Outcome Measures:
  • Mu-opioid receptor binding potential in left nucleus accumbens, resting state [ Time Frame: Baseline, 20 weeks, 40 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Mu-opioid neurotransmission in limbic brain regions at baseline and change from baseline after metformin treatment


Secondary Outcome Measures:
  • Positive and Negative Affect Schedule - positive affective state [ Time Frame: Baseline, 20 weeks, 40 weeks ] [ Designated as safety issue: No ]
    Measure of overall positive affective state at baseline and change from baseline after metformin treatment

  • Positive and Negative Affect Schedule - negative affective state [ Time Frame: Baseline, 20 weeks, 40 weeks ] [ Designated as safety issue: No ]
    Measure of overall negative affective state at baseline and change from baseline after metformin treatment

  • Profile of Mood States - overall negative mood [ Time Frame: Baseline, 20 weeks, 40 weeks ] [ Designated as safety issue: No ]
    Measure of overall negative mood at baseline and change from baseline after metformin treatment

  • Beck Depression Index [ Time Frame: Baseline, 20 weeks, 40 weeks ] [ Designated as safety issue: No ]
    Measure of depression symptoms at baseline and change from baseline after metformin treatment


Estimated Enrollment: 38
Study Start Date: July 2014
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02069379

Contacts
Contact: Alison Berent-Spillson, PhD 734-615-4252 MoodMetabolism@umich.edu

Locations
United States, Michigan
University of Michigan Medical School Not yet recruiting
Ann Arbor, Michigan, United States, 48103
Contact: Alison Berent-Spillson, PhD       MoodMetabolism@umich.edu   
Principal Investigator: Alison Berent-Spillson, PhD         
Sub-Investigator: Jon-Kar Zubieta, MD, PhD         
Sub-Investigator: Charles Burant, MD, PhD         
Sub-Investigator: Yolanda R Smith, MD, MS         
Sponsors and Collaborators
University of Michigan
Investigators
Principal Investigator: Alison Berent-Spillson, PhD University of Michigan
  More Information

No publications provided

Responsible Party: Alison Berent-Spillson, Research Investigator, University of Michigan
ClinicalTrials.gov Identifier: NCT02069379     History of Changes
Other Study ID Numbers: HUM00066696, K01MH095920
Study First Received: November 6, 2013
Last Updated: February 24, 2014
Health Authority: United States: Federal Government

Keywords provided by University of Michigan:
Metabolic syndrome
Insulin resistance
Mu-opioid system
Depression
Emotion regulation

Additional relevant MeSH terms:
Insulin Resistance
Metabolic Syndrome X
Glucose Metabolism Disorders
Metabolic Diseases
Insulin, Globin Zinc
Insulin
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Hyperinsulinism
Metformin
Endorphins
Analgesics, Opioid
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Narcotics
Central Nervous System Depressants
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 18, 2014