Download PDF
Pharmacopsychiatry 2017; 50(02): 49-55
DOI: 10.1055/s-0042-120120
Review
© Georg Thieme Verlag KG Stuttgart · New York

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

R. Colle   *
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
,
D. de Larminat   *
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
,
S. Rotenberg
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
,
F. Hozer
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
,
P. Hardy
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
,
C. Verstuyft
1   University Paris-Sud, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
5   INSERM UMR_S1184, Centre IMVA
6   Service de Génétique moléculaire, Pharmacogénétique et Hormonologie
,
B. Fève   *
7   Sorbonne Universités, Université Pierre et Marie Curie, Centre de Recherche Saint-Antoine, INSERM UMR_S938, Paris, France
8   Institut Hospitalo-Universitaire ICAN, Paris, France
9   Service d’Endocrinologie, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
,
E. Corruble   *
1   University Paris-Sud, Le Kremlin Bicêtre, France
2   INSERM, UMRS 1178, Le Kremlin Bicêtre, France
3   Hôpital Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
4   Département de Psychiatrie, Le Kremlin Bicêtre, France
› Author Affiliations
Further Information

Publication History

received 08 September 2016
revised 26 September 2016

accepted 25 October 2016

Publication Date:
15 December 2016 (online)

Also available at
   Permissions and Reprints

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.

* These authors contributed equally to this work.


* These authors co-directed this work.


 

  • References

  • 1 Thomas SJ, Shin M, McInnis MG et al. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression. Pharmacotherapy 2015; 35: 433-449
    CrossrefPubMedSearch in Google Scholar
  • 2 McIntyre RS, Filteau MJ, Martin L et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014; 156: 1-7
    CrossrefPubMedSearch in Google Scholar
  • 3 Perlis RH, Ostacher MJ, Patel JK et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006; 163: 217-224
    CrossrefPubMedSearch in Google Scholar
  • 4 Consoli A, Formoso G. Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?. Diabetes Obes Metab 2013; 15: 967-977
    CrossrefPubMedSearch in Google Scholar
  • 5 Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci. 2008; 13: 1813-1826
    CrossrefPubMedSearch in Google Scholar
  • 6 Garcia-Bueno B, Perez-Nievas BG, Leza JC. Is there a role for the nuclear receptor PPARgamma in neuropsychiatric diseases?. Int J Neuropsychopharmacol 2010; 13: 1411-1429
    CrossrefPubMedSearch in Google Scholar
  • 7 Lincoff AM, Tardif JC, Schwartz GG et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014; 311: 1515-1525
    CrossrefPubMedSearch in Google Scholar
  • 8 Kovacs P, Stumvoll M. Fatty acids and insulin resistance in muscle and liver. Best Pract Res Clin Endocrinol Metab 2005; 19: 625-635
    CrossrefPubMedSearch in Google Scholar
  • 9 Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008; 77: 289-312
    CrossrefPubMedSearch in Google Scholar
  • 10 Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 2011; 342: d1309
    CrossrefPubMedSearch in Google Scholar
  • 11 Rosen CJ. Revisiting the rosiglitazone story–lessons learned. N Engl J Med. 2010; 363: 803-806
    CrossrefPubMedSearch in Google Scholar
  • 12 Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-1289
    CrossrefPubMedSearch in Google Scholar
  • 13 Dormandy JA, Betteridge DJ, Schernthaner G et al. Impact of peripheral arterial disease in patients with diabetes–results from PROactive (PROactive 11). Atherosclerosis 2009; 202: 272-281
    CrossrefPubMedSearch in Google Scholar
  • 14 Erdmann E, Dormandy JA, Charbonnel B et al. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007; 49: 1772-1780
    CrossrefPubMedSearch in Google Scholar
  • 15 Erdmann E, Charbonnel B, Wilcox RG et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007; 30: 2773-2778
    CrossrefPubMedSearch in Google Scholar
  • 16 Mazzone T, Meyer PM, Feinstein SB et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006; 296: 2572-2581
    CrossrefPubMedSearch in Google Scholar
  • 17 Nissen SE, Nicholls SJ, Wolski K et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008; 299: 1561-1573
    CrossrefPubMedSearch in Google Scholar
  • 18 Wilcox R, Bousser MG, Betteridge DJ et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007; 38: 865-873
    CrossrefPubMedSearch in Google Scholar
  • 19 Schernthaner G, Currie CJ, Schernthaner GH. Do we still need pioglitazone for the treatment of type 2 diabetes? A risk-benefit critique in 2013. Diabetes Care 2013; 36 Suppl 2: S155-S161
    CrossrefPubMedSearch in Google Scholar
  • 20 van Wijk JP, de Koning EJ, Martens EP et al. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2003; 23: 1744-1749
    CrossrefPubMedSearch in Google Scholar
  • 21 Doehner W, Erdmann E, Cairns R et al. Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. Int J Cardiol. 2012; 162: 20-26
    CrossrefPubMedSearch in Google Scholar
  • 22 Domecq JP, Prutsky G, Leppin A et al. Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015; 100: 363-370
    CrossrefPubMedSearch in Google Scholar
  • 23 Jacob AN, Salinas K, Adams-Huet B et al. Weight gain in type 2 diabetes mellitus. Diabetes Obes Metab. 2007; 9: 386-393
    CrossrefPubMedSearch in Google Scholar
  • 24 Lincoff AM, Wolski K, Nicholls SJ et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298: 1180-1188
    CrossrefPubMedSearch in Google Scholar
  • 25 Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med. 2012; 172: 1005-1011
    PubMedSearch in Google Scholar
  • 26 Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials. Bone 2014; 68: 115-123
    CrossrefPubMedSearch in Google Scholar
  • 27 Rosa AO, Kaster MP, Binfare RW et al. Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1549-1556
    CrossrefPubMedSearch in Google Scholar
  • 28 Eissa Ahmed AA, Al-Rasheed NM, Al-Rasheed NM. Antidepressant-like effects of rosiglitazone, a PPARgamma agonist, in the rat forced swim and mouse tail suspension tests. Behav Pharmacol. 2009; 20: 635-642
    CrossrefPubMedSearch in Google Scholar
  • 29 Sadaghiani MS, Javadi-Paydar M, Gharedaghi MH et al. Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. Behav Brain Res. 2011; 224: 336-343
    CrossrefPubMedSearch in Google Scholar
  • 30 Kemp DE, Ismail-Beigi F, Calabrese JR. Antidepressant response associated with pioglitazone: support for an overlapping pathophysiology between major depression and metabolic syndrome. Am J Psychiatry. 2009; 166: 619
    PubMedSearch in Google Scholar
  • 31 Roohafza H, Shokouh P, Sadeghi M et al. A Possible Role for Pioglitazone in the Management of Depressive Symptoms in Metabolic Syndrome Patients (EPICAMP Study): A Double Blind, Randomized Clinical Trial. Int Sch Res Notices 2014; 2014: 697617
    PubMedSearch in Google Scholar
  • 32 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
    CrossrefPubMedSearch in Google Scholar
  • 33 Trivedi MH, Rush AJ, Ibrahim HM et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. 2004; 34: 73-82
    CrossrefPubMedSearch in Google Scholar
  • 34 Rasgon NL, Kenna HA, Williams KE et al. Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study. ScientificWorldJournal 2010; 10: 321-328
    CrossrefPubMedSearch in Google Scholar
  • 35 Kemp DE, Ismail-Beigi F, Ganocy SJ et al. Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity. J Affect Disord. 2012; 136: 1164-1173
    CrossrefPubMedSearch in Google Scholar
  • 36 Kemp DE, Schinagle M, Gao K et al. PPAR-gamma agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression. CNS Drugs 2014; 28: 571-581
    CrossrefPubMedSearch in Google Scholar
  • 37 Hu Y, Xing H, Dong X et al. Pioglitazone is an effective treatment for patients with post-stroke depression combined with type 2 diabetes mellitus. Exp Ther Med 2015; 10: 1109-1114
    CrossrefPubMedSearch in Google Scholar
  • 38 Sepanjnia K, Modabbernia A, Ashrafi M et al. Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology 2012; 37: 2093-2100
    CrossrefPubMedSearch in Google Scholar
  • 39 Kashani L, Omidvar T, Farazmand B et al. Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology 2013; 38: 767-776
    CrossrefPubMedSearch in Google Scholar
  • 40 Zeinoddini A, Sorayani M, Hassanzadeh E et al. Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double-blind, placebo-controlled trial. Depress Anxiety. 2015; 32: 167-173
    CrossrefPubMedSearch in Google Scholar
  • 41 Lin KW, Wroolie TE, Robakis T et al. Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry Res. 2015; 230: 846-852
    CrossrefPubMedSearch in Google Scholar
  • 42 Matthews L, Berry A, Tersigni M et al. Thiazolidinediones are partial agonists for the glucocorticoid receptor. Endocrinology 2009; 150: 75-86
    CrossrefPubMedSearch in Google Scholar
  • 43 Kotake D, Hirasawa N. Activation of a retinoic acid receptor pathway by thiazolidinediones induces production of vascular endothelial growth factor/vascular permeability factor in OP9 adipocytes. Eur J Pharmacol. 2013; 707: 95-103
    CrossrefPubMedSearch in Google Scholar
  • 44 Iqbal S, Naseem I. Role of vitamin A in type 2 diabetes mellitus biology: effects of intervention therapy in a deficient state. Nutrition 2015; 31: 901-907
    CrossrefPubMedSearch in Google Scholar
  • 45 Lu JM, Li JY, Pan CY et al. Changes in pituitary-adrenal function in diabetics and their response to aminoglutethimide. Chin Med J (Engl) 1988; 101: 587-590
    PubMedSearch in Google Scholar
  • 46 Sonino N, Fava GA. Erratum to “CNS drugs in Cushing’s disease: pathophysiological and therapeutic implications for mood disorders” [Prog. Neuro-Psycol. Biol. Psychiatry, 26, 763 (2002)]. Prog Neuropsychopharmacol Biol Psychiatry. 2002; 26: 1011-1018
    CrossrefPubMedSearch in Google Scholar
  • 47 Pan A, Keum N, Okereke OI et al. Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care. 2012; 35: 1171-1180
    CrossrefPubMedSearch in Google Scholar
  • 48 Vancampfort D, Correll CU, Wampers M et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables. Psychol Med. 2014; 44: 2017-2028
    CrossrefPubMedSearch in Google Scholar
  • 49 Rhee SJ, Kim EY, Kim SH et al. Subjective depressive symptoms and metabolic syndrome among the general population. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 54: 223-230
    CrossrefPubMedSearch in Google Scholar
  • 50 Corruble E, El Asmar K, Trabado S et al. Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohort. World Psychiatry. 2015; 14: 366-367
    CrossrefPubMedSearch in Google Scholar
  • 51 Bellucci PN, Gonzalez Bagnes MF, Di Girolamo G et al. Potential effects of nonsteroidal anti-inflammatory drugs in the prevention and treatment of type 2 diabetes mellitus. J Pharm Pract 2016 [Epub ahead of print]
    PubMed
  • 52 Kohler O, Benros ME, Nordentoft M et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 2014; 71: 1381-1391
    CrossrefPubMedSearch in Google Scholar
  • 53 Kohler O, Krogh J, Mors O et al. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr Neuropharmacol. 2016; 14: 732-742
    CrossrefPubMedSearch in Google Scholar
  • 54 Chen YC, Wu JS, Tsai HD et al. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and neurodegenerative disorders. Mol Neurobiol. 2012; 46: 114-124
    CrossrefPubMedSearch in Google Scholar
  • 55 Moreno S, Farioli-Vecchioli S, Ceru MP. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 2004; 123: 131-145
    CrossrefPubMedSearch in Google Scholar
  • 56 Skerrett R, Pellegrino MP, Casali BT et al. Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor gamma Agonist Treatment Reduces Amyloid beta Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. J Biol Chem. 2015; 290: 21591-21602
    CrossrefPubMedSearch in Google Scholar
  • 57 Carta AR. PPAR-gamma: therapeutic prospects in Parkinson’s disease. Curr Drug Targets. 2013; 14: 743-751
    CrossrefPubMedSearch in Google Scholar
  • 58 Lecca D, Nevin DK, Mulas G et al. Neuroprotective and anti-inflammatory properties of a novel non-thiazolidinedione PPARgamma agonist in vitro and in MPTP-treated mice. Neuroscience 2015; 302: 23-35
    CrossrefPubMedSearch in Google Scholar
  • 59 Gold PW, Licinio J, Pavlatou MG. Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-gamma systems. Mol Psychiatry. 2013; 18: 154-165
    CrossrefPubMedSearch in Google Scholar
  • 60 Wu JS, Tsai HD, Cheung WM et al. PPAR-gamma Ameliorates Neuronal Apoptosis and Ischemic Brain Injury via Suppressing NF-kappaB-Driven p22phox Transcription. Mol Neurobiol. 2016; 53: 3626-3645
    CrossrefPubMedSearch in Google Scholar
  • 61 Cimini A, Ceru MP. Emerging roles of peroxisome proliferator-activated receptors (PPARs) in the regulation of neural stem cells proliferation and differentiation. Stem Cell Rev. 2008; 4: 293-303
    CrossrefPubMedSearch in Google Scholar
  • 62 Sato T, Hanyu H, Hirao K et al. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011; 32: 1626-1633
    CrossrefPubMedSearch in Google Scholar
  • 63 Brundin P, Wyse R. Parkinson disease: laying the foundations for disease-modifying therapies in PD. Nat Rev Neurol 2015; 11: 553-555
    CrossrefPubMedSearch in Google Scholar
  • 64 Pershadsingh HA, Heneka MT, Saini R et al. Effect of pioglitazone treatment in a patient with secondary multiple sclerosis. J Neuroinflammation 2004; 1: 3
    CrossrefPubMedSearch in Google Scholar