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.

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.

Inclusion Criteria:

• Age between 20 and 65 years
• BMI between 25 and 35
• Diagnosis of unipolar, non-psychotic, non-melancholic major depressive disorder (MDD) or depressive episode of bipolar disorder (Bipolar I, II or NOS)
• Depression severity as defined by score of < 12 on the 21-item Hamilton Rating Scale for Depression and no psychiatric admission within 6 months from study entry and no suicide attempt within the last 12 months
• Willingness to sign human subjects consent form

Exclusion Criteria:

• Diagnosis of possible or probable cognitive impairment
• For women only: pregnancy, breastfeeding
• Personal history of Type I or Type II diabetes
• Unstable cardiovascular disease or other major medical condition, or history of myocardial infarction within the previous year
• Significant cerebrovascular disease, as evidenced by neurological examination, uncontrolled hypertension (systolic blood pressure > 170 or diastolic blood pressures > 100)
• Current drug or alcohol abuse
• History of neurological disorder, e.g. multiple sclerosis, stroke etc
• Use of any drug that may significantly affect psychometric testing or the insulin testing

The study period was 12 weeks.