Insulin-sensitizing medications were originally used in psychiatric practice to treat weight gain and other metabolic side effects that accompany the use of mood stabilizers, antipsychotics, and some antidepressants. However, in recent studies these medications have been shown to cause improvement in depressive symptoms, creating a potential new indication outside of metabolic regulation. However, it is still unclear whether the antidepressant properties of these medications are associated with improvements in metabolic markers. We performed a systematic search of the literature following PRISMA guidelines of studies investigating antidepressant effects of insulin-sensitizing medications. We specifically focused on whether any improvements in depressive symptoms were connected to the improvement of metabolic dysfunction. Majority of the studies included in this review reported significant improvement in depressive symptoms following treatment with insulin-sensitizing medications. Nine out of the fifteen included studies assessed for a correlation between improvement in symptoms and changes in metabolic markers and only two of the nine studies found such association, with effect sizes ranging from R2 = 0.26-0.38. The metabolic variables, which correlated with improvements in depressive symptoms included oral glucose tolerance test, fasting plasma glucose and glycosylated hemoglobin following treatment with pioglitazone or metformin. The use of insulin-sensitizing medications has a clear positive impact on depressive symptoms. However, it seems that the symptom improvement may be unrelated to improvement in metabolic markers or weight. It is unclear which additional mechanisms play a role in the observed clinical improvement. Some alternative options include inflammatory, neuroinflammatory changes, improvements in cognitive functioning or brain structure. Future studies of insulin-sensitizing medications should measure metabolic markers and study the links between changes in metabolic markers and changes in depression. Additionally, it is important to use novel outcomes in these studies, such as changes in cognitive functioning and to investigate not only acute, but also prophylactic treatment effects.

Charles University 3rd Faculty of Medicine Prague Czech Republic

Department of Psychiatry Dalhousie University Halifax NS Canada

National Institute of Mental Health Klecany Czech Republic

Zobrazit více v PubMed

Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis. World Psychiatry J World Psychiatr Assoc WPA. 2015;14:339–47. doi: 10.1002/wps.20252. PubMed DOI PMC

Afzal M, Siddiqi N, Ahmad B, Afsheen N, Aslam F, Ali A, et al. Prevalence of overweight and obesity in people with severe mental illness: systematic review and meta-analysis. Front Endocrinol. 2021;12:769309. doi: 10.3389/fendo.2021.769309. PubMed DOI PMC

Calkin CV, Gardner DM, Ransom T, Alda M. The relationship between bipolar disorder and type 2 diabetes: more than just co-morbid disorders. Ann Med. 2013;45:171–81. doi: 10.3109/07853890.2012.687835. PubMed DOI

Calkin CV, Ruzickova M, Uher R, Hajek T, Slaney CM, Garnham JS, et al. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry. 2015;206:52–57. doi: 10.1192/bjp.bp.114.152850. PubMed DOI

Pan A, Lucas M, Sun Q, Van Dam RM, Franco OH, Manson JE, et al. Bidirectional association between depression and type 2 diabetes mellitus in women. Arch Intern Med. 2010;170:1884–91. doi: 10.1001/archinternmed.2010.356. PubMed DOI PMC

Silarova B, Giltay EJ, Dortland AVR, Van Rossum EFC, Hoencamp E, Penninx BWJH, et al. Metabolic syndrome in patients with bipolar disorder: comparison with major depressive disorder and non-psychiatric controls. J Psychosom Res. 2015;78:391–8. doi: 10.1016/j.jpsychores.2015.02.010. PubMed DOI

Cassidy F, Ahearn E, Carroll BJ. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry. 1999;156:1417–20. doi: 10.1176/ajp.156.9.1417. PubMed DOI

Fagiolini A, Kupfer DJ, Houck PR, Novick DM, Frank E. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry. 2003;160:112–7. doi: 10.1176/appi.ajp.160.1.112. PubMed DOI

Fagiolini A, Kupfer DJ, Rucci P, Scott JA, Novick DM, Frank E. Suicide attempts and ideation in patients with bipolar I disorder. J Clin Psychiatry. 2004;65:509–14. doi: 10.4088/jcp.v65n0409. PubMed DOI

Fagiolini A, Kupfer DJ, Masalehdan A, Scott JA, Houck PR, Frank E. Functional impairment in the remission phase of bipolar disorder. Bipolar Disord. 2005;7:281–5. doi: 10.1111/j.1399-5618.2005.00207.x. PubMed DOI

Salvi V, Di Salvo G, Korčáková J, Torriero S, Aragno E, Kolenič M, et al. Insulin resistance is associated with verbal memory impairment in bipolar disorders. J Affect Disord. 2020;266:610–4. doi: 10.1016/j.jad.2020.01.145. PubMed DOI

Mora E, Portella MJ, Martinez-Alonso M, Teres M, Forcada I, Vieta E, et al. The impact of obesity on cognitive functioning in euthymic bipolar patients: a cross-sectional and longitudinal study. J Clin Psychiatry. 2017;78:e924–e932. doi: 10.4088/JCP.16m10968. PubMed DOI

Kemp DE, Gao K, Chan PK, Ganocy SJ, Findling RL, Calabrese JR. Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome. Bipolar Disord. 2010;12:404–13. doi: 10.1111/j.1399-5618.2010.00823.x. PubMed DOI PMC

McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry. 2001;46:273–81. doi: 10.1177/070674370104600308. PubMed DOI

Newall H, Myles N, Ward PB, Samaras K, Shiers D, Curtis J. Efficacy of metformin for prevention of weight gain in psychiatric populations: a review. Int Clin Psychopharmacol. 2012;27:69–75. doi: 10.1007/s10578-022-01424-6. PubMed DOI

Baptista T, Rangel N, Fernández V, Carrizo E, El Fakih Y, Uzcáteguiet E, et al. Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial. Schizophr Res. 2007;93:99–108. doi: 10.1016/j.schres.2007.03.029. PubMed DOI

Praharaj SK. Metformin for lithium-induced weight gain: a case report. Clin Psychopharmacol Neurosci. 2016;14:101–3. doi: 10.9758/cpn.2016.14.1.101. PubMed DOI PMC

Zheng W, Li XB, Tang YL, Xiang YQ, Wang CY, de Leon J. Metformin for weight gain and metabolic abnormalities associated with antipsychotic treatment: meta-analysis of randomized placebo-controlled trials. J Clin Psychopharmacol. 2015;35:499–509. doi: 10.1097/JCP.0000000000000392. PubMed DOI

Colle R, De Larminat D, Rotenberg S, Hozer F, Hardy P, Verstuyft C, et al. PPAR-γ agonists for the treatment of major depression: a review. Pharmacopsychiatry. 2017;50:49–55. doi: 10.1055/s-0042-120120. PubMed DOI

Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists. Front Biosci J Virtual Libr. 2008;13:1813. doi: 10.2741/2802. PubMed DOI PMC

Yasmin S, Jayaprakash V. Thiazolidinediones and PPAR orchestra as antidiabetic agents: from past to present. Eur J Med Chem. 2017;126:879–93. doi: 10.1016/j.ejmech.2016.12.020. PubMed DOI

Rasgon NL, Kenna HA, Williams KE, Powers B, Wroolie T, Schatzberg AF. Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study. ScientificWorldJournal. 2010;10:321–8. doi: 10.1100/tsw.2010.32. PubMed DOI PMC

Zeinoddini A, Sorayani M, Hassanzadeh E, Arbabi M, Farokhnia M, Salimi S, et al. Pioglitazone adjunctive therapy for depressive episode of bipolar disorder: a randomized, double‐blind, placebo‐controlled trial. Depress Anxiety. 2015;32:167–73. doi: 10.1002/da.22340. PubMed DOI

Jones BDM, Farooqui S, Kloiber S, Husain MO, Mulsant BH, Husain MI. Targeting metabolic dysfunction for the treatment of mood disorders: review of the evidence. Life Basel Switz. 2021;11:819. doi: 10.3390/life11080819. PubMed DOI PMC

Abdallah MS, Mosalam EM, Zidan AAA, Elattar KS, Zaki SA, Ramadan AN, et al. The antidiabetic metformin as an adjunct to antidepressants in patients with major depressive disorder: a proof-of-concept, randomized, double-blind, placebo-controlled trial. Neurotherapeutics. 2020;17:1897–906. doi: 10.1007/s13311-020-00878-7. PubMed DOI PMC

Aftab A, Kemp DE, Ganocy SJ, Schinagle M, Conroy C, Brownrigg B, et al. Double-blind, placebo-controlled trial of pioglitazone for bipolar depression. J Affect Disord. 2019;245:957–64. doi: 10.1016/j.jad.2018.11.090. PubMed DOI

AlHussain F, AlRuthia Y, Al-Mandeel H, Bellahwal A, Alharbi F, Almogbel Y, et al. Metformin improves the depression symptoms of women with polycystic ovary syndrome in a lifestyle modification program. Patient Prefer Adherence. 2020;14:737–46. doi: 10.2147/PPA.S244273. PubMed DOI PMC

Erensoy H, Niafar M, Ghafarzadeh S, Aghamohammadzadeh N, Nader ND. A pilot trial of metformin for insulin resistance and mood disturbances in adolescent and adult women with polycystic ovary syndrome. Gynecol Endocrinol J Int Soc Gynecol Endocrinol. 2019;35:72–75. doi: 10.1080/09513590.2018.1498476. PubMed DOI

Guo M, Mi J, Jiang QM, Xu JM, Tang YY, Tian G, et al. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin Exp Pharm Physiol. 2014;41:650–6. doi: 10.1111/1440-1681.12265. PubMed DOI

Hu Y, Xing H, Dong X, Lu W, Xiao X, Gao L, et al. Pioglitazone is an effective treatment for patients with post-stroke depression combined with type 2 diabetes mellitus. Exp Ther Med. 2015;10:1109–14. doi: 10.3892/etm.2015.2593. PubMed DOI PMC

Kashani L, Omidvar T, Farazmand B, Modabbernia A, Ramzanzaeh F, Tehraninejad ES, 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;38:767–76. doi: 10.1016/j.psyneuen.2012.08.010. PubMed DOI

Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, 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;136:1164–73. doi: 10.1016/j.jad.2011.06.033. PubMed DOI PMC

Kemp DE, Schinagle M, Gao K, Conroy C, Ganocy SJ, Ismail-Beigi F, et al. PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression. CNS Drugs. 2014;28:571–81. doi: 10.1007/s40263-014-0158-2. PubMed DOI PMC

Lin KW, Wroolie TE, Robakis T, Rasgon NL. Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response. Psychiatry Res. 2015;230:846–52. doi: 10.1016/j.psychres.2015.10.013. PubMed DOI PMC

Moulton CD, Rokakis AS, Pickup JC, Young AH, Stahl D, Ismail K. SITAgliptin for depressive symptoms in type 2 diabetes: a feasibility randomized controlled trial. Psychosom Med. 2021;83:913–23. doi: 10.1097/PSY.0000000000000985. PubMed DOI

Roohafza H, Shokouh P, Sadeghi M, Alikhassy Z, Sarrafzadegan N. 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 Not. 2014;2014:697617. doi: 10.1155/2014/697617. PubMed DOI PMC

Sepanjnia K, Modabbernia A, Ashrafi M, Modabbernia MJ, Akhondzadeh S. Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. Neuropsychopharmacology. 2012;37:2093–2100. doi: 10.1038/npp.2012.58. PubMed DOI PMC

Mansur RB, Ahmed J, Cha DS, Woldeyoannes HO, Subramaniapillai M, Lovshin J, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord. 2017;207:114–20. doi: 10.1016/j.jad.2016.09.056. PubMed DOI

Mansur RB, Zugman A, Ahmed J, Cha DS, Subramaniapillai M, Lee Y, et al. Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2017;27:1153–62. doi: 10.1016/j.euroneuro.2017.08.433. PubMed DOI

Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuroinflammation and psychiatric illness. J Neuroinflammation. 2013;10:816. doi: 10.1186/1742-2094-10-43. PubMed DOI PMC

Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, et al. Neuroinflammation and depression: a review. Eur J Neurosci. 2021;53:151–71. doi: 10.1111/ejn.14720. PubMed DOI

Dantzer R, O’connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. doi: 10.1038/nrn2297. PubMed DOI PMC

García-Bueno B, Pérez-Nievas BG, Leza JC. Is there a role for the nuclear receptor PPARγ in neuropsychiatric diseases? Int J Neuropsychopharmacol. 2010;13:1411–29. doi: 10.2174/0929867321666140303143455. PubMed DOI

Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011;4:1110–8. doi: 10.1016/j.jcmg.2011.08.007. PubMed DOI

Schöndorf T, Musholt PB, Hohberg C, Forst T, Lehmann U, Fuchs W, et al. The fixed combination of pioglitazone and metformin improves biomarkers of platelet function and chronic inflammation in type 2 diabetes patients: results from the PIOfix study. J Diabetes Sci Technol. 2011;5:426–32. doi: 10.1177/193229681100500233. PubMed DOI PMC

Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashzaki Y, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharm. 2013;715:246–55. doi: 10.1016/j.ejphar.2013.05.014. PubMed DOI

O’Rourke RW. Inflammation in obesity-related diseases. Surgery. 2009;145:255–9. doi: 10.1016/j.surg.2008.08.038. PubMed DOI PMC

Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016;21:71–9. doi: 10.1038/mp.2015.22. PubMed DOI PMC

McIntyre RS, Subramaniapillai M, Lee Y, Pan Z, Carmona NE, Shekotikhina M, et al. Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. JAMA Psychiatry. 2019;76:783–90. doi: 10.1001/jamapsychiatry.2019.0779. PubMed DOI PMC

Allison DB, Newcomer JW, Dunn AL, Blumenthal JA, Fabricatore AN, Daumit GL, et al. Obesity among those with mental disorders: a National Institute of Mental Health meeting report. Am J Prev Med. 2009;36:341–50. doi: 10.1016/j.amepre.2008.11.020. PubMed DOI

Faith MS, Butryn M, Wadden TA, Fabricatore A, Nguyen AM, Heymsfield SB. Evidence for prospective associations among depression and obesity in population-based studies. Obes Rev J Int Assoc Study Obes. 2011;12:e438–453. doi: 10.1111/j.1467-789X.2010.00843.x. PubMed DOI

McIntyre RS, Konarski JZ, Wilkins K, Soczynska JK, Kennedy SH. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being. Can J Psychiatry Rev Can Psychiatr. 2006;51:274–80. doi: 10.1177/070674370605100502. PubMed DOI

Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB. Lower cognitive function in the presence of obesity and hypertension: the Framingham heart study. Int J Obes Relat Metab Disord J Int Assoc Study Obes. 2003;27:260–8. doi: 10.1038/sj.ijo.802225. PubMed DOI

McWhinney SR, Brosch K, Calhoun VD, Crespo- Facorro B, Crossley NA, Dannlowski U, et al. Obesity and brain structure in schizophrenia—ENIGMA study in 3021 individuals. Mol Psychiatry. 2022. 10.1038/s41380-022-01616-5. PubMed PMC

McWhinney SR, Abé C, Alda M, Benedetti F, Bøen E, Del Mar Bonnin C, et al. Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness-ENIGMA study in 2436 individuals. Bipolar Disord. 2021. 10.1111/bdi.13172. PubMed PMC

McWhinney S, Kolenic M, Franke K, Fialova M, Knytl P, Matejka M, et al. Obesity as a risk factor for accelerated brain ageing in first-episode psychosis—a longitudinal study. Schizophr Bull. 2021;47:1772–81. doi: 10.1093/schbul/sbab064. PubMed DOI PMC

McWhinney SR, Abé C, Alda M, Benedetti F, Bøen E, Del Mar Bonnin C, et al. Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals. Mol Psychiatry. 2021;26:6806–19. doi: 10.1038/s41380-021-01098-x. PubMed DOI PMC

Nota MHC, Vreeken D, Wiesmann M, Aarts EO, Hazebroek EJ, Kiliaan AJ. Obesity affects brain structure and function- rescue by bariatric surgery. Neurosci Biobehav Rev. 2020;108:646–57. doi: 10.1016/j.neubiorev.2019.11.025. PubMed DOI

Veronese N, Facchini S, Stubbs B, Luchini C, Solmi M, Manzato E, et al. Weight loss is associated with improvements in cognitive function among overweight and obese people: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2017;72:87–94. doi: 10.1016/j.neubiorev.2016.11.017. PubMed DOI

Ma J, Rosas LG, Lv N, Xiao L, Snowden MB, Venditti EM, et al. Effect of integrated behavioral weight loss treatment and problem-solving therapy on body mass index and depressive symptoms among patients with obesity and depression: the RAINBOW randomized clinical trial. JAMA. 2019;321:869–79. doi: 10.1001/jama.2019.0557. PubMed DOI PMC

McIntyre RS, McCann SM, Kennedy SH. Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities. Can J Psychiatry Rev Can Psychiatr. 2001;46:273–81. doi: 10.1177/070674370104600308. PubMed DOI

Hajek T, Hahn M, Slaney C, Garnham J, Green J, Růzicková M, et al. Rapid cycling bipolar disorders in primary and tertiary care treated patients. Bipolar Disord. 2008;10:495–502. doi: 10.1111/j.1399-5618.2008.00587.x. PubMed DOI PMC

Ruzickova M, Slaney C, Garnham J, Alda M. Clinical features of bipolar disorder with and without comorbid diabetes mellitus. Can J Psychiatry Rev Can Psychiatr. 2003;48:458–61. doi: 10.1177/070674370304800705. PubMed DOI