PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression

Abstract

Background: Insulin resistance and other cardio-metabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-γ agonist could reduce bipolar depression symptom severity. A secondary objective was to determine whether levels of highly sensitive C-reactive protein and interleukin (IL)-6 predicted treatment outcome.

Methods: Patients (n = 34) with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms [QIDS] total score ≥11) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR-γ agonist pioglitazone (15-30 mg/day) for 8 weeks. The majority of participants (76 %, n = 26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant.

Results: Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7 ± 8.2 at baseline to 21.2 ± 9.2 at week 8 (p < 0.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p < 0.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p < 0.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (-17.9 ± 3.6; p < 0.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98 ± 0.3; p < 0.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β = -3.89, standard error [SE] = 1.47, p = 0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r = 0.44, p < 0.01).

Conclusions: Open-label administration of the PPAR-γ agonist pioglitazone was associated with improvement in depressive symptoms and reduced cardio-metabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120).

Figures

Figure 1. Disposition of Patients with Bipolar Depression Receiving Pioglitazone

Figure 2. Proposed Pathways by which Insulin Resistance Mediates the Development and Maintenance of Depressive Symptoms

Figure 2 illustrates the pathways by which factors associated with insulin resistance are conceptualized to mediate the development and maintenance of depressive symptoms. A chronic, low-grade inflammatory state within visceral adipose tissue contributes to insulin resistance through activation of inflammatory signaling cascades within immune cells (e.g. macrophages) [58,59]. In addition, reduced secretion of adiponectin by adipocytes directly lowers insulin sensitivity and is inversely correlated with depression severity [48,60]. Although cortisol serves to inhibit the inflammatory response, over-activation of the HPA-axis in response to stress leads to visceral adiposity and further disruption of hepatic glucoregulatory mechanisms. Additionally, insulin resistance leads to alterations in dopamine release and oxidative damage to pancreatic beta-cells and the brain. Insulin resistance is reversed within the central nervous system and periphery through activation of brain PPAR-γ. By attenuating insulin resistance, inducing neuroprotection, and decreasing inflammation, PPAR-γ activation is hypothesized to modulate mood. AKT=Protein kinase B; CRH=Corticotropin-releasing hormone; GL6P=glucose 6-phosphate; HPA=hypothalamic-pituitary-adrenal axis; IL-6=Interleukin-6; IRS=Insulin receptor substrate; NF-κB=Nuclear factor kappa B;NMDA= N-methyl-D-aspartate;PPAR-γ=peroxisome proliferator activated receptor-gamma; ROS=Reactive oxygen species