Pioglitazone in Patients With Mood Disorders
Condition: Major Depressive Disorder; Insulin Resistance
MeSH terms: Insulin Resistance; Depressive Disorder; Depressive Disorder, Major; Mood Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to see how an insulin sensitizing medication, Pioglitazone, can
      cause changes in mood in some depressed patients. Study participants receive assessment of
      their cognitive and metabolic functioning.

      If they meet criteria, they will be asked to take either Pioglitazone or a placebo for a
      90-day trial. Participants will undergo an Oral Glucose Tolerance Test to measure fasting
      insulin and glucose levels, as well as routine blood testing.

      The investigators hope to quantify the role of Pioglitazone in patients with mood disorders
      and compare the values to those previously obtained in a healthy age-matched control
      population. The investigators also hope to examine the association between IR and cognitive
      performance and clinical course of depression in patients with mood disorders.
    

Detailed description: 
      While the association between insulin resistance (IR) and depressive symptoms is well
      documented (Gold et al., 2005), causal aspects of the relationship are incompletely
      documented and likely bidirectional. As the current prevalence rates of DM2 and related
      diseases grow worldwide and its associated metabolic consequences become more salient, it is
      increasingly critical to understand the role of IR in depressive disorders.

      Insulin has been shown to alter central nervous system (CNS) concentrations of
      neurotransmitters such as dopamine (Lozovsky et al., 1981) and norepinephrine (Boyd et al.,
      1985), by a variety of mechanisms, as well as to have direct electrophysiological effects on
      neuronal activity (Boyd et al., 1985). Additionally, induced IR in the CNS has been shown to
      result in cognitive and behavioral alterations in animal models (Kovacs and Hajnal, 2009).

      Accordingly, when depression manifests as a sequela of metabolic disorders such as obesity
      and DM2, it is hypothesized to be associated with resistance of CNS structures to the effects
      of insulin, which may derive from genetic polymorphisms, as well as from long-term exposure
      to excess amounts of circulating insulin due to peripheral IR (Okamura et al., 2000b). Thus,
      "overcoming" central IR," for example by pharmacological interventions, could be an
      attractive strategy in the treatment and prevention of these disorders.

      This study aimed to assess mood effects in a 12-week double-blind, randomized-controlled
      trial of adjuvant treatment with the PPARγ-agonist pioglitazone, an insulin-sensitizing
      agent, compared with treatment with placebo, in participants with non-psychotic,
      non-remitting depression receiving standard psychiatric regimens for unipolar or bipolar
      depression. Pioglitazone is an FDA-approved, insulin-sensitizing treatment for DM2 and has
      particularly beneficial effects on lipid profile (Goldberg et al., 2005) and rate of
      cardiovascular events (Lincoff et al., 2007) in this population. Furthermore, in assessing
      the utility of an additive insulin-sensitizing agent on mood outcomes in both insulin
      sensitive and insulin resistant patients, this study attempted to disentangle the role of
      insulin-sensitizing and anti-inflammatory mechanisms.

      In an a prior manner, this study's aims were twofold: (1) to assess whether treatment with
      pioglitazone would result in significantly greater mood improvement compared to treatment
      with placebo among patients with unremitted depression despite treatment as usual (TAU) and
      (2) to examine mechanisms of proposed effects of a PPARγ-agonist on mood outcomes by
      comparing treatment outcomes based on surrogate markers of glucose metabolic status
      (hereafter referred to IR and IS) between IR and insulin sensitive (IS) participants.
    

Intervention name(s): Pioglitazone; Sugar Pill
Intervention type(s): Drug; Drug
Intervention description(s): 30mg once daily for 12 weeks; Placebo
Other intervention name(s): Actos; Placebo
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; Insulin resistance; Mood disorder