Endogenous Opioid Activity and Affective State in Insulin Resistant Women
Condition: Depression; Insulin Resistance; Metabolic Syndrome
MeSH terms: Metabolic Syndrome; Insulin Resistance; Depression
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Placebo capsules prepared identically to Metformin capsules
Other intervention name(s): Glucophage; Glumetza; Fortamet; Riomet; Sugar pills
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Metabolic syndrome; Insulin resistance; Mu-opioid system; Depression; Emotion regulation