Phase 4 N=42 Randomized Triple-blind Basic Science

Endogenous Opioid Activity and Affective State in Insulin Resistant Women

Depression · Insulin Resistance · Metabolic Syndrome

Bottom Line

View on ClinicalTrials.gov: NCT02069379 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Nov 2018

Primary outcome: Primary: Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State

Study Design & Population

Study type: Interventional
Phase: Phase 4
Interventions: Metformin (Drug); Placebo (Drug)
Age: Adult · 18+ yrs
Sex: Female
Sponsor: University of Michigan
Primary completion: Mar 2017

Outcome Measures

Outcome	Result	p-value
PRIMARY Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State	—	—
PRIMARY Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State	—	—
PRIMARY Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State	—	—
PRIMARY Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State	—	—
SECONDARY Positive and Negative Affect Schedule - Positive Affective State	28.23; 21.83	—
SECONDARY Positive and Negative Affect Schedule - Negative Affective State	11.46; 12.83	—
SECONDARY Profile of Mood States - Overall Negative Mood	3.15; 14.42	—
SECONDARY Beck Depression Index	2.93; 7.00	—

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.

Eligibility 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

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Data sourced from ClinicalTrials.gov (NCT02069379). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.