Appetite Hormone Regulation Biotypes of Major Affective Disorders in Proinflammatory Cytokines and Executive Function

Ju-Wei Hsu, MD ; Wei-Chen Lin, MD, PhD ; Ya-Mei Bai, MD, PhD ; Shih-Jen Tsai, MD ; Mu-Hong Chen, MD, PhD

J Clin Psychiatry 2025;86(2):24m15561

Abstract

Backgrounds: Evidence indicates that appetite hormones, namely, insulin, leptin, and adiponectin, play crucial roles in the pathophysiology of major affective disorders. However, whether appetite hormone regulation biotypes differ among patients with major affective disorders remains unclear.

Methods: A total of 501 patients with major affective disorders (278 with bipolar disorder and 223 with major depressive disorder) were enrolled between 2018 and 2022 and clustered into biotype groups on the basis of fasting insulin, leptin, and adiponectin levels. Major affective disorder diagnoses were based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. All participants underwent the Wisconsin Card Sorting Test and proinflammatory cytokine assessment.

Results: A k-means cluster analysis identified 3 biotype groups based on appetite hormone levels: a high insulin/ leptin and low adiponectin group, a low insulin/leptin and high adiponectin group, and an intermediate group. The high insulin/leptin and low adiponectin group exhibited poorer performance on the Wisconsin Card Sorting Test and had higher C-reactive protein and tumor necrosis factor-α levels than did the other biotype groups after adjusting for diagnosis, body mass index, clinical symptoms, and psychotropic medication use.

Discussion: This study identified 3 appetite hormone regulation biotypes among patients with major affective disorders. These biotypes were associated with proinflammatory cytokine profiles and executive function.

J Clin Psychiatry 2025;86(2):24m15561

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References (47)

Hsu JW, Chen LC, Bai YM, et al. Appetite hormone dysregulation, body mass index, and emotional dysregulation in nonobese adolescents with first-episode schizophrenia, bipolar disorder, and major depressive disorder: a cross-sectional association study. CNS Spectr. 2023;28(5):629–636. CrossRef
Chen MH, Hsu JW, Huang KL, et al. Role of appetite hormone dysregulation in the cognitive function among patients with bipolar disorder and major depressive disorder. World J Biol Psychiatry. 2021;22(6):428–434. CrossRef
Misiak B, Kowalski K, Stanczykiewicz B, et al. Appetite-regulating hormones in bipolar disorder: a systematic review and meta-analysis. Front Neuroendocrinol. 2022;67:101013.
Amare AT, Schubert KO, Klingler-Hoffmann M, et al. The genetic overlap between mood disorders and cardiometabolic diseases: a systematic review of genome wide and candidate gene studies. Transl Psychiatry. 2017;7(1):e1007. PubMed CrossRef
Erichsen JM, Fadel JR, Reagan LP. Peripheral versus central insulin and leptin resistance: role in metabolic disorders, cognition, and neuropsychiatric diseases. Neuropharmacology. 2022;203:108877. CrossRef
Forny-Germano L, De Felice FG, Vieira M. The role of leptin and adiponectin in obesity-associated cognitive decline and Alzheimer’s disease. Front Neurosci. 2018;12:1027.
Geroldi C, Frisoni GB, Paolisso G, et al. Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol. 2005;62(7):1067–1072. PubMed CrossRef
Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13(2):84–89. PubMed CrossRef
Tasnim N, Khan N, Gupta A, et al. Exploring the effects of adiponectin and leptin in correlating obesity with cognitive decline: a systematic review. Ann Med Surg. 2023;85(6):2906–2915. CrossRef
Bove RM, Brick DJ, Healy BC, et al. Metabolic and endocrine correlates of cognitive function in healthy young women. Obesity (Silver Spring). 2013;21(7):1343–1349. PubMed CrossRef
Smith PJ, Mabe S, Sherwood A, et al. Association between insulin resistance, plasma leptin, and neurocognition in vascular cognitive impairment. J Alzheimers Dis. 2019;71(3):921–929. CrossRef
Mac Giollabhui N, Swistun D, Murray S, et al. Executive dysfunction in depression in adolescence: the role of inflammation and higher body mass. Psychol Med. 2020;50(4):683–691. PubMed CrossRef
Simmons WK, Burrows K, Avery JA, et al. Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry. 2020;25(7):1457–1468. PubMed CrossRef
Lamers F, Vogelzangs N, Merikangas KR, et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013;18(6):692–699. PubMed CrossRef
Everson-Rose SA, Clark CJ, Wang Q, et al. Depressive symptoms and adipokines in women: study of women’s health across the nation. Psychoneuroendocrinology. 2018;97:20–27. PubMed CrossRef
Badini I, Coleman JRI, Hagenaars SP, et al. Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption. Psychol Med. 2022;52(4):726–736. CrossRef
Campbell IH, Campbell H. The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania. Mol Psychiatry. 2024;29(5):1521–1527. CrossRef
Calkin CV, Ruzickova M, Uher R, et al. Insulin resistance and outcome in bipolar disorder. Br J Psychiatry. 2015;206(1):52–57. PubMed CrossRef
Tsai SY, Lee HC, Chen CC. Hyperinsulinaemia associated with beta-adrenoceptor antagonist in medicated bipolar patients during manic episode. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(5):1038–1043. PubMed CrossRef
Montgomery SA, Rani SJ, McAuley R, et al. The antidepressant efficacy of zimelidine and maprotiline. Acta Psychiatr Scand Suppl. 1981;290:219–224. PubMed CrossRef
Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. PubMed CrossRef
Suzuki A, Aoshima T, Fukasawa T, et al. A three-factor model of the MADRS in major depressive disorder. Depress Anxiety. 2005;21(2):95–97. PubMed CrossRef
Quilty LC, Robinson JJ, Rolland JP, et al. The structure of the Montgomery Asberg depression rating scale over the course of treatment for depression. Int J Methods Psychiatr Res. 2013;22(3):175–184. PubMed CrossRef
Fey ET. The performance of young schizophrenics and young normals on the Wisconsin Card Sorting Test. J Consult Psychol. 1951;15(4):311–319. PubMed CrossRef
Chen MH, Hsu JW, Huang KL, et al. Role of obesity in systemic low-grade inflammation and cognitive function in patients with bipolar I disorder or major depressive disorder. CNS Spectr. 2021;26(5):521–527. CrossRef
Chen MH, Kao ZK, Chang WC, et al. Increased proinflammatory cytokines, executive dysfunction, and reduced gray matter volumes in first-episode bipolar disorder and major depressive disorder. J Affect Disord. 2020;274:825–831. CrossRef
Mineo L, Rodolico A, Spedicato GA, et al. Exploration of mood spectrum symptoms during a major depressive episode: the impact of contrapolarity-results from a transdiagnostic cluster analysis on an Italian sample of unipolar and bipolar patients. Eur Psychiatry. 2022;65(1):e30. CrossRef
Steinley D. K-means clustering: a half-century synthesis. Br J Math Stat Psychol. 2006;59(Pt 1):1–34. PubMed CrossRef
Miles S, Howlett CA, Berryman C, et al. Considerations for using the Wisconsin Card Sorting Test to assess cognitive flexibility. Behav Res Methods. 2021;53(5):2083–2091. CrossRef
Uddin LQ. Cognitive and behavioural flexibility: neural mechanisms and clinical considerations. Nat Rev Neurosci. 2021;22(3):167–179. CrossRef
Tong K, Fu X, Hoo NP, et al. The development of cognitive flexibility and its implications for mental health disorders. Psychol Med. 2024;54(12):1–7.
Yang Y, Shields GS, Guo C, et al. Executive function performance in obesity and overweight individuals: a meta-analysis and review. Neurosci Biobehav Rev. 2018;84:225–244. PubMed CrossRef
Cserjesi R, Luminet O, Poncelet AS, et al. Altered executive function in obesity. Exploration of the role of affective states on cognitive abilities. Appetite. 2009;52(2):535–539. PubMed CrossRef
Shapiro ALB, Wilkening G, Aalborg J, et al. Childhood metabolic biomarkers are associated with performance on cognitive tasks in young children. J Pediatr. 2019;211:92–97. CrossRef
Wroolie TE, Kenna HA, Singh MK, et al. Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age specific effects. J Psychiatr Res. 2015;60:65–72. PubMed CrossRef
Labad J, Price JF, Strachan MW, et al. Edinburgh Type 2 Diabetes Study I. Serum leptin and cognitive function in people with type 2 diabetes. Neurobiol Aging. 2012;33:2938–2941 e2.
Schuur M, Henneman P, van Swieten JC, et al. Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study. Eur J Epidemiol. 2010;25(8):561–568. PubMed CrossRef
Bai YM, Chen MH, Hsu JW, et al. A comparison study of metabolic profiles, immunity, and brain gray matter volumes between patients with bipolar disorder and depressive disorder. J Neuroinflammation. 2020;17(1):42. PubMed CrossRef
de Melo LGP, Nunes SOV, Anderson G, et al. Shared metabolic and immune inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:34–50. PubMed CrossRef
Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21(10):1358–1365. PubMed CrossRef
Goldsmith DR, Bekhbat M, Le NA, et al. Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression. Brain Behav Immun. 2020;88:193–202. PubMed CrossRef
Zhao S, Lin Q, Xiong W, et al. Hyperleptinemia contributes to antipsychotic drug associated obesity and metabolic disorders. Sci Transl Med. 2023;15(723):eade8460.
Chen J, Huang XF, Shao R, et al. Molecular mechanisms of antipsychotic drug induced diabetes. Front Neurosci. 2017;11:643.
McIntyre RS, Kwan ATH, Rosenblat JD, et al. Psychotropic drug-related weight gain and its treatment. Am J Psychiatry. 2024;181(1):26–38. CrossRef
Miller GD. Appetite regulation: hormones, peptides, and neurotransmitters and their role in obesity. Am J Lifestyle Med. 2019;13(6):586–601. CrossRef
Correll CU, Sikich L, Reeves G, et al. Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry. 2020;19(1):69–80. PubMed CrossRef
Calkin CV, Chengappa KNR, Cairns K, et al. Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD study): a randomized, quadruple masked, placebo-controlled clinical trial. J Clin Psychiatry. 2022;83(2):21m14022.