Leptin dysregulation is specifically associated with major depression with atypical features: evidence for a mechanism connecting obesity and depression
Open accessAbstract
Background Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features.Methods The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current (n = 1062) or remitted (n = 711) MDD and healthy control subjects (n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed.Results As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted (n = 144, odds ratio = 1.53, 95% confidence interval = 1.16-2.03, p = .003) and current (n = 270, odds ratio = 1.90, 95% confidence interval = 1.51-2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p < .02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis.Conclusions Leptin dysregulation (resistance) may represent an underlying mechanism connecting obesity and MDD with atypical features. Development of treatment effectively targeting leptin resistance may benefit patients with atypical depression characterized by obesity-related metabolic alterations.
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
International physical activity questionnaire: 12-country reliability and validity
CRAIG, C. L., MARSHALL, A. L., SJ??STR??M, M., BAUMAN, A. E., BOOTH, M. L., AINSWORTH, B. E., PRATT, M., EKELUND, U., YNGVE, A., SALLIS, J. F., et al. (2003) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000078924.61453.fb · Cited by 21,619 · see citing works
Overweight, Obesity, and Depression: A Systematic Review and Meta-analysis of Longitudinal Studies
Luppino, F. S., de Wit, L. M., Bouvy, P. F., Stijnen, T., Cuijpers, P., Penninx, B. W. J. H., & Zitman, F. G. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.2 · Cited by 4,322 · see citing works
Self-citationThe Inventory of Depressive Symptomatology (IDS): Psychometric properties
Rush, A. J., Gullion, C. M., Basco, M. R., Jarrett, R. B., & Trivedi, M. H. (1996) · Psychological Medicine · doi:10.1017/s0033291700035558 · Cited by 2,177 · see citing works
Obesity is associated with hypothalamic injury in rodents and humans.
Thaler, J. P., Yi, C.-X., Schur, E. A., Guyenet, S. J., Hwang, B. H., Dietrich, M. O., Zhao, X., Sarruf, D. A., Izgur, V., Maravilla, K. R., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59660 · Cited by 1,857 · see citing works
The cellular and signaling networks linking the immune system and metabolism in disease
Osborn, O., & Olefsky, J. M. (2012) · Nature Medicine · doi:10.1038/nm.2627 · Cited by 1,551 · see citing works
Hypothalamic IKKβ/NF-κB and ER Stress Link Overnutrition to Energy Imbalance and Obesity
Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., & Cai, D. (2008) · Cell · doi:10.1016/j.cell.2008.07.043 · Cited by 1,350 · see citing works
The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods
Penninx, B. W. J. H., Beekman, A. T. F., Smit, J. H., Zitman, F. G., Nolen, W. A., Spinhoven, P., Cuijpers, P. J., de Jong, P. J., van Marwijk, H., Assendelft, W. J., et al. (2008) · International Journal of Methods in Psychiatric Research · doi:10.1002/mpr.256 · Cited by 918 · see citing works
Self-citationPenninx, B. W., Milaneschi, Y., Lamers, F., & Vogelzangs, N. (2013) · BMC Medicine · doi:10.1186/1741-7015-11-129 · Cited by 839 · see citing works
Self-citationNeurobiology of food intake in health and disease
Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3745 · Cited by 748 · see citing works
Lamers, F., Vogelzangs, N., Merikangas, K. R., de Jonge, P., Beekman, A. T. F., & Penninx, B. W. J. H. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.144 · Cited by 691 · see citing works
Self-citationThe organization of the stress system and its dysregulation in depressive illness
Gold, P. W. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.163 · Cited by 654 · see citing works
Linking Molecules to Mood: New Insight Into the Biology of Depression
Krishnan, V., & Nestler, E. J. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.10030434 · Cited by 643 · see citing works
Human Leptin Levels Are Pulsatile and Inversely Related to Pituitary–Ardenal Function
Licinio, J., Mantzoros, C., Negrão, A. B., Cizza, G., Wong, M.-L., Bongiorno, P. B., Chrousos, G. P., Karp, B., Allen, C., Flier, J. S., et al. (1997) · Nature Medicine · doi:10.1038/nm0597-575 · Cited by 632 · see citing works
Molecular and anatomical determinants of central leptin resistance
Münzberg, H., & Myers, M. G. (2005) · Nature Neuroscience · doi:10.1038/nn1454 · Cited by 550 · see citing works
Leptin: A potential novel antidepressant
Lu, X.-Y., Kim, C. S., Frazer, A., & Zhang, W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508901103 · Cited by 446 · see citing works
Latent Class Analysis of Lifetime Depressive Symptoms in the National Comorbidity Survey
Sullivan, P. F., Kessler, R. C., & Kendler, K. S. (1998) · American Journal of Psychiatry · doi:10.1176/ajp.155.10.1398 · Cited by 334 · see citing works
Kendler, K. S. (1996) · Archives of General Psychiatry · doi:10.1001/archpsyc.1996.01830050025004 · Cited by 323 · see citing works
Metabolic disturbances connecting obesity and depression
Hryhorczuk, C., Sharma, S., & Fulton, S. E. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00177 · Cited by 322 · see citing works
The leptin hypothesis of depression: a potential link between mood disorders and obesity?
Lu, X.-Y. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.10.010 · Cited by 303 · see citing works
Lamers, F., de Jonge, P., Nolen, W. A., Smit, J. H., Zitman, F. G., Beekman, A. T. F., & Penninx, B. W. J. H. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.09m05398blu · Cited by 264 · see citing works
Self-citationImpaired CNS Leptin Action Is Implicated in Depression Associated with Obesity
Yamada, N., Katsuura, G., Ochi, Y., Ebihara, K., Kusakabe, T., Hosoda, K., & Nakao, K. (2011) · Endocrinology · doi:10.1210/en.2011-0004 · Cited by 247 · see citing works
Lasserre, A., Glaus, J., Vandeleur, C., Marques-Vidal, P., Vaucher, J., Bastardot, F., Waeber, G., Vollenweider, P., & Preisig, M. (2014) · JAMA psychiatry · doi:10.1001/jamapsychiatry.2014.411 · Cited by 232 · see citing works
Leptin treatment: Facts and expectations
Paz-Filho, G., Mastronardi, C. A., & Licinio, J. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.014 · Cited by 220 · see citing works
Garza, J. C., Guo, M., Zhang, W., & Lu, X.-Y. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.161 · Cited by 209 · see citing works
Polygenic dissection of major depression clinical heterogeneity
Milaneschi, Y., Lamers, F., Peyrot, W. J., Abdellaoui, A., Willemsen, G. A. H. M., Hottenga, J., Jansen, R., Mbarek, H., Dehghan, A., Lu, C., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.86 · Cited by 183 · see citing works
Self-citationNeurodevelopmental actions of leptin
Bouret, S. G. (2010) · Brain Research · doi:10.1016/j.brainres.2010.04.011 · Cited by 178 · see citing works
The subtypes of major depression in a twin registry
Sullivan, P. F., Prescott, C. A., & Kendler, K. S. (2002) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00364-5 · Cited by 146 · see citing works
Farr, O. M., Tsoukas, M. A., & Mantzoros, C. S. (2014) · Metabolism · doi:10.1016/j.metabol.2014.07.004 · Cited by 146 · see citing works
Adipokines as emerging depression biomarkers: A systematic review and meta-analysis
Carvalho, A. F., Rocha, D. Q. C., McIntyre, R. S., Mesquita, L. M., Köhler, C. A., Hyphantis, T. N., Sales, P. M. G., Machado‐Vieira, R., & Berk, M. (2014) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.08.002 · Cited by 138 · see citing works
Vogelzangs, N., Beekman, A. T., van Reedt Dortland, A. K., Schoevers, R. A., Giltay, E. J., de Jonge, P., & Penninx, B. W. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.9 · Cited by 133 · see citing works
Self-citationRing, L. E., & Zeltser, L. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41985 · Cited by 115 · see citing works
Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours
Guo, M., Huang, T.-Y., Garza, J. C., Chua, S. C., & Lu, X. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712000703 · Cited by 101 · see citing works
Leptin, Abdominal Obesity, and Onset of Depression in Older Men and Women
Milaneschi, Y., Simonsick, E. M., Vogelzangs, N., Strotmeyer, E. S., Yaffe, K. S., Harris, T. B., Tolea, M. I., Ferrucci, L., Penninx, B. W. J. H., & Health, A. (2012) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.11m07552 · Cited by 93 · see citing works
Self-citationStability and transitions of depressive subtypes over a 2-year follow-up
Lamers, F., Rhebergen, D., Merikangas, K. R., de Jonge, P., Beekman, A. T. F., & Penninx, B. W. J. H. (2012) · Psychological Medicine · doi:10.1017/s0033291712000141 · Cited by 88 · see citing works
Self-citationHigh serum leptin levels in depressive disorders with atypical features
Geçici, Ö., Kuloğlu, M., Atmaca, M., Tezcan, A. E., Tunckol, H., Emül, H. M., & Üstündağ, B. (2005) · Psychiatry and Clinical Neurosciences · doi:10.1111/j.1440-1819.2005.01445.x · Cited by 86 · see citing works
The effect of FTO rs9939609 on major depression differs across MDD subtypes
Milaneschi, Y., Lamers, F., Mbarek, H., Hottenga, J.-J., Boomsma, D. I., & Penninx, B. W. J. H. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.4 · Cited by 78 · see citing works
Self-citationKoch, M., & Horváth, T. L. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.30 · Cited by 57 · see citing works
Guo, M., & Lu, X.-Y. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.126 · Cited by 55 · see citing works
The association between leptin and depressive symptoms is modulated by abdominal adiposity
Milaneschi, Y., Sutin, A. R., Terracciano, A., Canepa, M., Gravenstein, K. S., Egan, J. M., Vogelzangs, N., Guralnik, J. M., Bandinelli, S., Penninx, B. W. J. H., et al. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.12.015 · Cited by 50 · see citing works
Self-citationZupancic, M. L., & Mahajan, A. (2011) · Psychosomatic Medicine · doi:10.1097/psy.0b013e31821a196f · Cited by 43 · see citing works
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Milaneschi, Y., Simmons, W. K., van Rossum, E. F. C., & Penninx, B. W. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0017-5 · Cited by 1,073 · see citing works
Self-citationThe menace of obesity to depression and anxiety prevalence
Fulton, S., Décarie-Spain, L., Fioramonti, X., Guiard, B., & Nakajima, S. (2022) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2021.10.005 · Cited by 441 · see citing works
“In a corresponding manner, leptin resistance can elicit depressive-like behaviors in rats [144] and is associated with atypical features of depression (increased appetite and weight) in humans [145].”
BackgroundBeijers, L., Wardenaar, K. J., van Loo, H. M., & Schoevers, R. A. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0385-5 · Cited by 240 · see citing works
Milaneschi, Y., Lamers, F., Peyrot, W. J., Baune, B. T., Breen, G., Dehghan, A., Forstner, A. J., Grabe, H. J., Homuth, G., Kan, C., et al. (2017) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2017.3016 · Cited by 233 · see citing works
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Capuron, L., Lasselin, J., & Castanon, N. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.123 · Cited by 182 · see citing works
The use of latent class analysis for identifying subtypes of depression: a systematic review
Ulbricht, C. M., Chrysanthopoulou, S. A., Levin, L., & Lapane, K. L. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.03.003 · Cited by 138 · see citing works
Circadian depression: A mood disorder phenotype
Carpenter, J. S., Crouse, J. J., Scott, E. M., Naismith, S. L., Wilson, C., Scott, J., Merikangas, K. R., & Hickie, I. B. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.02.045 · Cited by 114 · see citing works
Anhedonia in depression symptomatology: appetite dysregulation and defective brain reward processing
Coccurello, R. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112041 · Cited by 106 · see citing works
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- Authors
- Milaneschi, Y., Lamers, F., Bot, M., Drent, M. L., & Penninx, B. W. J. H.
- Affiliations
- Amsterdam Neuroscience (NL)
- Corresponding author
- Milaneschi, Yuri
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 81
- Issue
- 9
- Pages
- 807-814
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2209055048
- Cited by
- 209
- References
- 41
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 18 · 2023: 17 · 2022: 25 · 2021: 26 · 2020: 26 · 2019: 22 · 2018: 15 · 2017: 15 · 2016: 7
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- green
- research.vu.nl
- Licence
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Geestkracht program of the Netherlands Organization for Health Research and Development (10-000-1002)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Clinical Psychology › Eating Disorders and Behaviors
- Keywords
- leptin, atypical depression, major depressive disorder, leptin resistance, hyperleptinemia, obesity, adiposity, body mass index, waist circumference, hyperphagia, remitted depression, metabolic changes
- MeSH terms
- Adolescent, Adult, Aged, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Netherlands, Obesity, Body Mass Index, Leptin, Adiposity, Young Adult
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