Pioglitazone 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.