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

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

Introduction

Nowadays, more than 40% of patients with a major depressive disorder (MDD) treated for a major depressive episode (MDE) with an adequate dosage and duration of antidepressant drug fail to respond to treatment [1]. Furthermore, approximately half of adults with an MDD do not achieve sustained remission [2]. The poor efficacy of conventional antidepressants in MDD is also shown in patients with bipolar disorder (BD) [3]. Thus, drugs with new mechanisms of action are needed to treat MDEs.

Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) [4] are ligand-dependent transcription factors that form heterodimers with the retinoid X receptors [5], bind to DNA in specific regions (PPAR response elements) [6], and finally regulate the transcription of target genes related to lipid and glucose metabolism, inflammatory processes, and cellular differentiation [5]. PPAR-γ agonists have both anti-inflammatory properties and efficacy in metabolic disorders (type 2 diabetes or polycystic ovary syndrome). Indeed, they can reduce hyperglycemia through enhanced free fatty acid uptake by adipose tissue and can improve beta-cell function and insulin sensitivity in type 2 diabetes mellitus (T2DM) [7]. Decreased free fatty acid plasma levels enhance insulin action in the liver and skeletal muscles [8]. By activating PPAR-γ in adipose tissue, PPAR-γ agonists decrease inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while increasing circulating levels of adiponectin, an insulin-sensitizing adipokine [9].

PPAR-γ agonist drugs such as troglitazone, rosiglitazone, and pioglitazone have been used for the treatment of T2DM [4]. Due to hepatotoxicity, troglitazone was withdrawn from the market by the Food and Drug Administration (FDA) in 2000. Given the potential increased cardiovascular risk, the use of rosiglitazone was strictly limited by the FDA [10] and suspended by the European Medicine Agency in 2010 [11]. Pioglitazone has beneficial effects on cardiovascular diseases [12] [13] [14] [15] [16] [17] [18] and metabolic syndrome in patients with T2DM [19] [20] but can induce weight gain [21] [22] [23], congestive heart failure [4] [24], peripheral edema, macular edema [25], and bone fractures [26].

Preliminary evidence of links between PPAR-γ and mood were drawn from behavioral studies in non-depressed animals. Indeed, the PPAR-γ agonist NP031115 induced an antidepressant-like effect in mice by enhancing PPAR-γ activity [27]. In the tail suspension test and the forced swimming test (2 animal models measuring the effectiveness of antidepressants), rosiglitazone showed an antidepressant-like activity, inducing a significant and dose-dependent decrease in immobility time in mice and rats [28]. Similarly, pioglitazone decreased the immobility time in the forced swimming test in mice [29], an effect that was reversed after administration of the PPAR-γ antagonist GW-9962. Recent data [56] [57] [58] suggest that serotonin could stimulate PPAR-γ activity. Indeed, in fat cells, serotonin leads to the activation of PPAR-γ responsive genes and enhances lipid accumulation [56] [57] [58].

Consequently, some effects of conventional antidepressants that influence the serotonin system functioning (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclics) may involve the activity of the PPAR-γ pathway.

The first use of pioglitazone in MDE was published as a case report in 2009 [30]. A marked improvement of depression was evidenced in a 55-year-old woman treated with pioglitazone (30 mg/d for 12 weeks) for a metabolic syndrome and a resistant MDE. Insulin resistance improved concomitantly with the MDE in this woman. In 2014, a 24-week double-blind RCT in 145 patients with a metabolic syndrome [31] suggested a higher improvement of symptoms of depression and anxiety (assessed with the questionnaire Hospital Anxiety and Depression Scale) with pioglitazone (30 mg/d) than with placebo. However, these patients did not have a diagnosis of MDE.

Hence, we performed a review of the efficacy and safety of PPAR-γ agonists for the treatment of major depression and the association of their antidepressant effects with changes in biomarkers of metabolism and inflammation.

Material and Methods

A search was conducted on PubMed from January 1990 to August 2016 with the following keywords: (pioglitazone) OR (rosiglitazone) OR (thiazolidinedione) OR (troglitazone) [Title/Abstract] AND (depress*) [Title/Abstract] OR (bipolar) [Title/Abstract].

To be included in this review, studies had to fulfill the following criteria:

1. Standardized diagnostic criteria for MDE (DSM-IV)

2. Prospective treatment with PPAR-γ agonists

3. Assessment of depression at baseline and follow-up using standardized depression rating scales

The following data were recorded from each study: sponsor, name of the study, registration trial number, design, number of patients, mean age, percentage of women, diagnosis criteria of MDE, drug, dosage and duration of treatment, concomitant use of psychotropic drugs, and standardized depression rating scale used to assess depression at baseline and follow-up (i. e., Hamilton Depression Rating Scale [HDRS] [32], Inventory for Depressive Symptomatology [IDS] [33], or Quick Inventory for Depressive Symptomatology [QIDS] [33]).

Studies including patients with metabolic comorbidities were not excluded.

Results

8 studies were identified: 4 open-label trials ([Table 1]) and 4 RCT ([Table 2]). Among the 348 patients included, 209 received PPAR-γ agonists. In the 4 open-label trials, patients received either rosiglitazone or pioglitazone. In the 4 double-blind RCT, pioglitazone was compared to a placebo (3 studies) or to metformin (1 study).

Table 1 Open-label studies.

Studies	Rasgon 2010 [34]		Kemp 2012 [35]	Kemp 2014 [36]	Hu 2015 [37]
Trial registration number	No registration		No registration	NCT00835120	No registration
Sponsors	National Institutes of Health		National Institutes of Health, Takeda Pharmaceuticals	Brain and Behavior Research Foundation, National Institutes of Health, Takeda Pharmaceuticals	Chinese State Natural Science Fund
PPAR- ƴ agonist	Rosiglitazone		Pioglitazone	Pioglitazone	Pioglitazone Meformin
Dose (mg/d)	Fixed Starting: 4 After 4 weeks: 8		Flexible Starting: 15 After 4 weeks: 15–45	Flexible Starting: 15 After 4 weeks: 15–30	Pioglitazone: Fixed: 30 Meformin: Fixed: 1 000
Number of patients	12		23	34	118
Concomitant drug use	Add-on with antidepressants (all marketed)		Monotherapy	Add-on with mood stabilizers (all marketed)	Add-on with fluoxetine (20 mg/d)
Diagnosis	MDE-MDD MDE-BD		MDE-MDD	MDE-BD	Post-stroke depression
Age (years [m±sd])	51.9±5.6		44.6±10.2	47.8±10.9	64.6±5.5
Women (%)	91		87	56	56.8
Metabolic status	Insulin resistanceb		Metabolic syndromea or abdominal obesitya	Metabolic syndromea or insulin resistanceb	Type 2 diabetes
Study duration (weeks)	12		12	8	12
Depression scales	HDRS	CGI-S	IDS	IDS	HDRS
Baseline score (m±sd)	19.9±5.0	4.0±0.6	40.3±1.8	38.7±8.2	29.1±12.8
Score change (m±sd)	12.1±na*	2.9±na*	19.2±1.8*	21.9±9.2*	na
Response (n [%])	na	na	15 (65%)	13 (38%)	na
Remission (n [%])	na	na	5 (22%)	8 (24%)	na
Major adverse events	no		no	no	no

MDE: Major Depressive Episode; MDD: Major Depressive Disorder; BD: Bipolar Disorder; ^a: National Cholesterol Education Program’s Adult Treatment Panel III definition; ^b: defined as two or more of the following criteria: body mass index (BMI)≥28, fasting blood glucose (FPG)≥100 mg/dl, triglycerides (TG)≥150 mg/dl, or triglyceride/high-density lipoprotein (HDL)-cholesterol ratio (TG/HDL)≥3.0); HDRS: Hamilton Depression Rating Scale; CGI-S: Clinical Global Impression - Severity; IDS: Inventory for Depressive Symptomatology; na: not available; * p<0.05: comparison of score changes; Response:≥50% reduction in HDRS or IDS total score from baseline to endpoint; Remission: HDRS total score<8 or IDS total score ≤12

Table 2 Double-blind randomized controlled trials.

Studies	Sepanjnia 2012 [38]		Kashani 2013 [39]		Zeinoddini 2015 [40]		Lin 2015 [41]
Trial registration number	NCT01109030		IRCT201106081556N23		IRCT201211211556N46		NCT01559857
Sponsor	Tehran University of Medical Sciences		Tehran University of Medical Sciences		Tehran University of Medical Sciences		National Institutes of Health
Drugs	Pioglitazone	Placebo	Pioglitazone	Metformin	Pioglitazone	Placebo	Pioglitazone	Placebo
Dose (mg/d)	Fixed: 30	-	Fixed: 1st week: 15 Later: 30	1st week: 500 2nd week: 1 000 Later: 1 500	Fixed: 1st week: 15 Later: 30	–	Fixed: 30	–
Number of patients	40		40		44		37
Diagnosis	MDE-MDD		MDE-MDD		MDE-BD		MDE-MDD or BD
Age (years [m±sd])	32.1±5.4		20.8±4.0		32.7±4.7		46.4±13.8
Women (%)	72.5		100		34.1		na
Metabolic comorbidities	no		Polycystic Ovary Syndrome: 100%		no		Insulin resistancea: 54%
Concomitant drug (Dose [mg/d])	Citalopram (30)		no		Lithium salts (serum: 0.6–0.8 mEq/L)		Marketed antidepressant b
Duration (weeks)	6		6		6		12
Depression scale	HDRS		HDRS		HDRS		HDRS
Baseline score (m±sd)	25.4±3.4		15.1±1.8		23.1±1.7		15.6±5.1
Score change (m±sd)	16.7±3.5*	13.4±3.5*	5.6±2.1*	1.3±0.9*	14.0±3.2*	11.7±2.3*	4.1±na	3.2±na
Response rates (n [%])	19 (95%)*	8 (40%)*	na	na	19 (86%)	16 (73%)	na	na
Remission rates (n [%])	9 (45%)*	3 (15%)*	4 (20%)	0 (0%)	5 (23%)	1 (4%)	na	na
Major Adverse Event	no	no	no	no	no	no	na	na
Adverse Events (difference between groups)	No difference	Increased appetite	Decreased appetite	No difference	na	na

MDE: Major Depressive Episode; MDD: Major Depressive Disorder; BD: Bipolar Disorder; ^a: at least 3 of the following criteria: FPG≥100 mg/dL, Fasting plasma insulin≥15 ml U/ml, Oral Glucose Tolerance Test (OGGT at 120 min≥140 mg/dL); na: not available; ^b: at least 8 weeks of stable antidepressant treatment before inclusion; HDRS: Hamilton Depression Rating Scale; Response:≥50% reduction in HDRS score from baseline to endpoint; Remission: HDRS<8; *p<0.05 for comparison of treatment efficacy rates between pioglitazone and control treatment

Efficacy

Open studies

In the 4 prospective open-label studies [34] [35] [36] [37] ([Table 1]), 118 patients with a current MDE and metabolic disorders were assessed before the beginning and after 8 or 12 weeks of treatment with PPAR-γ agonists (pioglitazone or rosiglitazone) and 59 by metformin. For rosiglitazone [34], the starting dose, 4 mg/d, was increased after 4 weeks at 8 mg/d. For pioglitazone, flexible dose designs were used with a starting dose of 15 mg/d possibly increased depending on response and tolerability at 30 mg/d (mean dose: 27.4±5.8 mg/d) [35] or 45 mg/d (mean dose: 32.7 mg/d ) [36] or was prescribed at fixed dose (30 mg/d) [37]. Concomitant psychotropic treatments were not described in 3 studies [34] [35] [36], but their dose changes were not allowed in 2 studies [35] [36]. Fluoxetine (fixed dose: 20 mg/d) was prescribed in the fourth one [37]. The main outcome was depression severity measured with the HDRS [34] [37] or IDS [35] [36] scales. In 3 studies, score changes from baseline were used to assess antidepressant effect of pioglitazone or rosiglitazone [34] [35] [36]. Of note, the outcome of the fourth study in post-stroke depression (i. e., the final HDRS score) [37] was unusual. Nonetheless, the 4 open studies converge to show that treatment with pioglitazone or rosiglitazone could induce a significant antidepressant effect ([Table 1]).

Double-blind RCT

4 double-blind RCT of pioglitazone [38] [39] [40] [41] are available for a total number of 161 patients with a diagnosis of MDE (MDD or BD) ([Table 2]). Eighty-one patients received pioglitazone and 80 received a placebo (n=60) [38] [40] [41] or metformin (n=20) [37] [39]. The pioglitazone dose was 30 mg/d in 2 studies [38] [41] or began at 15 mg/d for the first week and 30 mg/d thereafter in fixed designs in the 2 others [39] [40]. The main statistical analysis was performed in intent-to-treat in only 2 studies [38] [39] and in per-protocol in the others [40] [41]. The main outcome measure was the mean HDRS score change (from baseline to follow-up), which was compared between pioglitazone and control groups. The HDRS score changes were higher in the pioglitazone group than in the control group in 3 double-blind RCTs [38] [39] [40] but were not different in 1 study [41]. However, in this study [41] with pioglitazone (30 mg/d), participants could benefit from their concomitant individualized treatment for depression. That could explain the absence of difference between pioglitazone and placebo. The HDRS score change differences between pioglitazone and controls that were reported in 3 double-blind RCT [38] [39] [40] [41] were comprised between 2.3 and 4.2 HDRS points. In 1 study [38] but not the others, higher rates of remitters were shown with pioglitazone than with placebo.

Safety

In the 8 studies, there were no deaths, no major adverse events, no clinically significant weight gain (≥7% increase in basal weight), and no significant difference in weight change.

The common side effects reported with pioglitazone were the following: increased appetite (15–25%), headache (5–26%), nausea (8.7–25%), sexual dysfunction (20%), abdominal pain (20%), muscular pains (10–17.4%), blurred vision (13–15%), irritability (11.7%), insomnia (8.7–10%), decreased appetite (5%), and edema (11.7%). In 1 RCT with pioglitazone (30 mg/d) [41], 1 patient (4.7%) discontinued because of an edema. In another RCT with pioglitazone (30 mg/d) [37], 3 (5.1%) patients discontinued because of mild adverse events (not described) [37]. The 2 studies in which patients discontinued because of adverse events were the 2 longer (12 weeks). Of note, these studies did not stratify on the presence or absence of metabolic comorbidities. Thus, the safety of these drugs in patients with major depression without comorbidities remains poorly known.

Association of improvement of depression and improvement of biomarkers of metabolism/inflammation

Several markers of metabolism were studied in 5 different studies [35] [36] [37] [39] [41] but detailed in only 2 studies [35] [36]. Some of them were clinical: weight, waist circumference, body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Others were biological: total-cholesterolemia (TC), triglyceridemia (TG), low-density lipoprotein cholesterolemia (LDL-C), high-density lipoprotein cholesterolemia (HDL-C), TG/HDL-C ratio, fasting plasma glucose (FPG), fasting plasma insulinemia (FPI), Homeostatic Model Assessment (HOMA-IR) (fasting insulin [μU/mL]) × ((fasting glucose [mg/dL]) ÷ 22.5), insulin sensitivity index (ISI), oral glucose tolerance test (OGTT), and adiponectin.

Some inflammatory biomarkers were studied in 2 studies [35] [36]: high-sensitivity C-reactive protein (hsCRP); IL-1, IL-6, and IL-10; and TNF-α.

For metabolism, an association between depression score improvement and HOMA-IR score decrease was observed with pioglitazone (30 mg/d) in 2 studies [35] [39]. HDRS score decreases were associated with FPG and OGTT decreases [41]. No significant difference was observed for the other 15 biomarkers studied in all the studies.

For inflammation, a significant association was observed between decrease in IL-6 and the improvement of depression score in 1 study [36] but not in the other one [35]. No significant association was found with the other 5 inflammatory biomarkers studied in all the studies.

Thus, there are positive results with 4 biomarkers out of the 21 studied. They may suggest a link between the antidepressant response to PPAR-γ agonists and metabolism (insulin resistance) and inflammation (IL-6 serum levels).

Ongoing registered double-blind RCT

2 other double-blind RCT of pioglitazone are currently ongoing for the treatment of BD. The first ongoing study (NCT01717040, Calabrese, clinicaltrials.gov) compares pioglitazone (first week at 15 mg/d then flexible 15–45 mg/d) vs. placebo for 8 weeks in 36 patients with bipolar depression (inclusion completed). The first objective of this study is to assess the efficacy of pioglitazone in bipolar depression, and its second objective is to assess changes in insulin resistance (HOMA-IR and fasting lipid profile). The second ongoing study (2014-003803-31, clinicaltrialsregisters.ue) compares pioglitazone to placebo for 3 months in 60 patients with bipolar depression. The first objective of this study is to assess the efficacy and safety of pioglitazone in bipolar depression. Its second aims are to determine the effects of pioglitazone on remission rates and to assess the association of antidepressant effects with the pro/anti-inflammatory status, BDNF levels, and cognitive functioning.

Discussion

This work highlights the potential relevance of PPAR-γ agonists for the treatment of MDE. From the 8 available studies, 4 open-label trials and 3 out of the 4 double-blind RCT, PPAR-γ agonists, either alone or in add-on therapy, may have significant antidepressant properties with no significant adverse events in patients with MDE. These effects may be associated with improvement of insulin resistance (HOMA-IR, OGTT, and FPG) and inflammation (IL-6), but this point should be further studied because only 4 biomarkers out of 21 were positively associated with depression improvement.

Some limits have to be emphasized for this review. First, the efficacy and safety of pioglitazone are assessed in short-term (6–12 weeks) but not in long-term studies. This point should be further studied because antidepressant treatments are usually needed for several months or years. Second, the effects of the inclusion criteria in terms of diagnoses of mood disorder (MDD, BD, or post-stroke depression) and concomitant psychotropic treatments were not studied here. This heterogeneity may also influence the results. Third, the number of studies available is low and the number of patients treated with PPAR-γ is relatively low (n=209). Fourth, the current review is vulnerable to publication bias. Hence, these findings should be considered as preliminary. Fifth, association is not causation; thus, it cannot be stated that clinical and biomarkers changes are due to PPAR-γ agonists effects. They could be independent from the PPAR-γ mechanism of action. Indeed, rosiglitazone and pioglitazone have been reported to have off-target effects such as partial glucocorticoid receptor agonism leading to anti-steroid properties [42] or retinoic acid receptor agonism [43] [44], which may contribute to their potential antidiabetic and antidepressant effects. Of note, anti-steroid drugs with PPAR-γ properties (such as aminoglutethimide, for example [45] [46]) could be considered for the treatment of T2DM and major depression.

The 2 registered ongoing studies in larger samples will enable to confirm or not the effects of pioglitazone in MDE and to explore the mechanisms of action of PPAR-γ agonists in MDE. Furthermore, further research is warranted to validate the benefits of pioglitazone in the specific diabetic subpopulation to treat major depression. In line with recent data showing a high comorbidity between MDD and metabolic syndrome [47] [48] [49] and that conventional antidepressant medication could induce or worsen metabolic syndromes [50], PPAR-γ agonists could combine beneficial effects on mood and metabolic disorders. The insulin-sensitizing and anti-inflammatory effects of PPAR-γ agonists could act in interaction and convergence to improve major depression. In this context, anti-inflammatory approaches may be promising approaches to treat both diabetes [51] and major depression [52] [53].

Furthermore, the neuroprotective effects of PPAR-γ agonists, shown in a variety of pre-clinical models of neurological disorders [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64], could be useful for the treatment of mood disorders.

Conclusion

The present review argues for significant antidepressant properties of PPAR-γ agonists, especially pioglitazone, in the treatment of MDE in patients with MDD or BD, with or without concomitant metabolic comorbidities. It should be further studied whether these antidepressant effects are associated with improvement of insulin resistance and inflammation.

Conflicts of Interest

Romain Colle, Delphine de Larminat, Samuel Rotenberg, Franz Hozer, Patrick Hardy, Céline Verstuyft, and Emmanuelle Corruble declare no potential conflict of interest. Bruno Fève has received conference fees for Astra-Zeneca, Sanofi, NovoNordisk, and MSD and consulting fees from Sanofi.

^* These authors contributed equally to this work.

^* These authors co-directed this work.

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