Endogenous Opioid Activity and Affective State in Insulin Resistant Women

NCT02069379 | Completed Phase 4 Results

• 2 other identifiers: HUM00066696K01MH095920
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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. 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. 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. 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.
4. 4.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.
5. 5.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.
6. 6.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.

Conditions

Depression; Insulin Resistance; Metabolic Syndrome

Keywords

Metabolic syndrome; Insulin resistance; Mu-opioid system; Depression; Emotion regulation

Outcome Measures

Primary Outcomes (4)

• 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

  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

  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

  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

  Baseline, 20 weeks, 40 weeks

Secondary Outcomes (4)

• Positive and Negative Affect Schedule - Positive Affective State

  Baseline

• Positive and Negative Affect Schedule - Negative Affective State

  Baseline

• Profile of Mood States - Overall Negative Mood

  Baseline

• Beck Depression Index

  Baseline

Study Arms (3)

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)

Drug: Metformin

Placebo

PLACEBO COMPARATOR

Placebo comparator to metformin treatment

Drug: Placebo

Interventions

Metformin DRUG

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

Metformin

Placebo DRUG

Placebo capsules prepared identically to Metformin capsules

Also known as: Sugar pills

Placebo

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Women
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Michigan: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of Michigan Medical School

Ann Arbor, Michigan, 48103, United States

Location

MeSH Terms

Conditions

Depression; Insulin Resistance; Metabolic Syndrome; Emotional Regulation

Interventions

Metformin

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Self-Control; Social Behavior

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

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

Results Point of Contact

• Title: Alison Berent-Spillson
• Organization: University of Michigan

berent@umich.edu

(734) 936-4400

Study Officials

• Alison Berent-Spillson, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Investigator

Study Record Dates

• First Submitted: November 6, 2013
• First Posted: February 24, 2014
• Study Start: July 1, 2014
• Primary Completion: March 24, 2017
• Study Completion: September 1, 2017
• Last Updated: November 8, 2018
• Results First Posted: November 8, 2018

Record last verified: 2018-10

Locations

US (1)