Pioglitazone could induce remission in major depression: a meta-analysis

Abstract

BackgroundPioglitazone, a selective agonist of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ), prescribed for the treatment of type 2 diabetes, could have antidepressant properties. However, its potential to induce remission of major depressive episodes, the optimal clinical target for an antidepressant drug, is a matter of concern. Indeed, only one out of four double-blind randomized controlled trials show higher remission rates with pioglitazone than with control treatments. Hence, the main aim of this study was to perform a meta-analysis of the efficacy of pioglitazone for the treatment of MDE, focusing on remission rates.MethodsFour double-blind randomized controlled trials, comprising 161 patients with an MDE, were included in this meta-analysis. Pioglitazone was studied either alone (one study) or as add-on therapy to conventional treatments (antidepressant drugs or lithium salts). It was compared either to placebo (three studies) or to metformin (one study). Remission was defined by a Hamilton Depression Rating Scale score <8 after treatment.ResultsPioglitazone could induce higher remission rates than control treatments (27% versus 10%, I2=17.3%, fixed-effect model: odds ratio [OR] =3.3, 95% confidence interval [95% CI; 1.4; 7.8], P=0.008). The OR was even higher in the subgroup of patients with major depressive disorder (n=80; 23% versus 8%, I2=0.0%; fixed-effect model: OR =5.9, 95% CI [1.6; 22.4], P=0.009) and in the subgroup of patients without metabolic comorbidities (n=84; 33% versus 10%, I2=0.0%; fixed-effect model: OR =5.1, 95% CI [1.5; 17.9], P=0.01). As compared to control treatments, results suggest six patients would need to be treated with pioglitazone in order to achieve the possibility of one more remission.ConclusionPioglitazone, either alone or as add-on therapy to conventional treatments, could induce remission of MDE, suggesting that drugs with PPAR-γ agonist properties may be true and clinically relevant antidepressants, even in patients without metabolic comorbidities.

Differential associations of depression‐related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways

“…Some interesting genes listed included FTO, which is a wellknown gene in controlling weight and energy balance (Speakman, 2015); TCF7L2, a transcription factor of key role of Wnt signaling pathway that is strongly associated with diabetes (Jin & Liu, 2008); PPARG, a target for anti-diabetic agents (notably the PPAR-gamma agonist pioglitazone was shown to be efficacious in depression (Colle et al, 2017)) and others. Some interesting genes listed included FTO, which is a wellknown gene in controlling weight and energy balance (Speakman, 2015); TCF7L2, a transcription factor of key role of Wnt signaling pathway that is strongly associated with diabetes (Jin & Liu, 2008); PPARG, a target for anti-diabetic agents (notably the PPAR-gamma agonist pioglitazone was shown to be efficacious in depression (Colle et al, 2017)) and others.…”

“…An example in this field is pioglitazone, an insulin sensitizer which was shown in a meta-analyses of four RCTs to be a safe and effective adjunctive medication in nondiabetic patients with MDD (Colle et al, 2017). Nevertheless, due to the computational nature and limitations as will be discussed later, the drug enrichment or repositioning analysis should be regarded as an exploratory proof-of-concept example rather than a confirmatory study.…”

Drug repurposing may generate novel approaches to treating depression

“…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 . It was reported that pioglitazone mediated improvement in depressed patients probably through suppressing pro‐inflammatory cytokines such as IL‐6 .…”

“…[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. [101] Moreover, neuroprotective effects have been suggested for these antidiabetic drugs.…”

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited

“…In a recent metaanalyses resulting from 4 open-label trials and 4 randomized controlled trials in 448 patients peroxisome proliferator-activated receptor-gamma agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT [73]. Pioglitazone, either alone or as addon therapy to conventional treatments, could induce remission of depression, suggesting that drugs with peroxisome proliferator-activated receptor-gamma agonist properties may be true and clinically relevant antidepressants, even in patients without metabolic comorbidities, improving depression with mechanisms largely unrelated to its insulin-sensitizing action [72, 74].…”