Leptin Dysregulation Is Specifically Associated With Major Depression With Atypical Features: Evidence for a Mechanism Connecting Obesity and Depression

  • Yuri Milaneschi
    Address correspondence to: Yuri Milaneschi, Ph.D., VU University Medical Center/GGZ inGeest, Department of Psychiatry, A.J. Ernststraat 1187, 1081 HL Amsterdam, Amsterdam, The Netherlands.
    Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
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  • Femke Lamers
    Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
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  • Mariska Bot
    Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
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  • Madeleine L. Drent
    Department of Internal Medicine, Endocrine Section, VU University Medical Center, Department of Clinical Neuropsychology, Faculty of Psychology and Education, VU University, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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  • Brenda W.J.H. Penninx
    Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ ingest, Amsterdam, The Netherlands
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Published:November 17, 2015DOI:


      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.


      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.


      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.


      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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