PPAR-γ Agonists for the Treatment of Major Depression: A Review

Abstract

Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

Vortioxetine exerts anti‐inflammatory and immunomodulatory effects on human monocytes/macrophages

“…Nonetheless, it is also possible that vortioxetine activates PPARγ directly in a 5‐HT‐independent fashion. This alternative hypothesis would be consistent with reports suggesting that PPARγ agonists may have antidepressant activity via their ability to reduce the levels of inflammatory cytokines such as IL‐6 and TNFα both in depressed patients and murine models of depression (Kemp et al ., 2014; Colle et al, ; ; Liao et al, ).…”

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…For example, thiazolidinediones, including pioglitazone and rosiglitazone, are synthetic ligands that selectively bind at PPAR-γ and are used clinically for the treatment of diabetes [15]. However, given their side effects on weight gain, congestive heart failure, bone fractures, and macular and peripheral edema, the Food and Drug Administration (FDA) has limited their use [16]. PPAR-α synthetic ligands, including the fibrates (fenofibrate, clofibrate) (depicted in Figure 2) are characterized by a much safer pharmacological profile and are widely prescribed to lower high cholesterol blood levels and triglycerides [17].…”

Drug repurposing may generate novel approaches to treating depression

“…In particular, metformin, a widely prescribed oral antidiabetic and slimming agent, has demonstrated little promise in this regard, and therefore, large‐scale studies are required before a decision concerning its repurposing could be made . In contrast, clinical trials showed that insulin sensitizer antidiabetic drugs activating peroxisome proliferator‐activated receptor gamma substantially reduced depressive symptoms in patients . For example, pioglitazone was found to enhance remission in patients with MDD or bipolar disorders .…”

“…[98] In contrast, clinical trials showed that insulin sensitizer antidiabetic drugs activating peroxisome proliferator-activated receptor gamma substantially reduced depressive symptoms in patients. [99] For example, pioglitazone was found to enhance remission in patients with MDD or bipolar disorders. [100] It was reported that pioglitazone mediated improvement in depressed patients probably through suppressing proinflammatory cytokines such as IL-6.…”