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Leptin Plasma Concentrations Increase During Antidepressant Treatment With Amitriptyline and Mirtazapine, But Not Paroxetine and Venlafaxine: Leptin Resistance Mediated by Antihistaminergic Activity?

∥Peptide Hormone Research Laboratory, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen
Journal of clinical psychopharmacology (Impact Factor: 3.76). 12/2012; 33(1). DOI: 10.1097/JCP.0b013e31827cb179
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ABSTRACT Treatment with several psychopharmacological agents has been associated with increased leptin plasma concentrations. We measured leptin plasma concentrations in 76 adult depressed patients after a 6-day washout phase and again after 35 days of treatment with amitriptyline or paroxetine, as well as in 73 depressed patients after 28 days of treatment with either mirtazapine or venlafaxine. Leptin plasma concentrations increased during treatment with amitriptyline and mirtazapine, even after controlling for increased body mass index and irrespective of response to treatment [14.5 (13.8) vs 20.3 (18.7) ng/mL, and 12.2 (15.8) vs 14.4 (16.5) ng/mL in the 2 cohorts, respectively]. In contrast, paroxetine and venlafaxine treatment was not associated with changes in leptin plasma concentrations [14.8 (12.0) vs 13.6 (10.6); 15.9 (17.3) vs 13.5 (14.6) ng/mL] nor with weight gain. We conclude that treatment with amitriptyline or mirtazapine is associated with an increase in leptin secretion beyond change in weight. Thus, high leptin levels apparently are ineffective in the control of weight gain, indicating leptin resistance. Leptin resistance may be mediated by an antihistaminergic effect on hypothalamic nuclei integrating signals relevant for energy balance.

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    • "For example, Shilling and colleagues had demonstrated that leptin serum levels increased during mirtazapine and amitriptyline treatment, but not following treatment with either paroxetine or venlafaxine (Schilling et al., 2013). Furthermore, for mirtazapine-treated patients the increase in leptin levels was higher for remitters compared to non-remitters (Schilling et al., 2013). This finding suggests that leptin may be also a marker for metabolic abnormalities associated with antidepressant treatment. "
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    ABSTRACT: Adiponectin, leptin and resistin may play a role in the pathophysiology of major depressive disorder (MDD). However, differences in peripheral levels of these hormones are inconsistent across diagnostic and intervention studies. Therefore, we performed meta-analyses of diagnostic studies (i.e., MDD subjects versus healthy controls) and intervention investigations (i.e., pre-vs. post-antidepressant treatment) in MDD. Adiponectin (N = 1278; Hedge's g = -0.35; P = 0.16) and leptin (N = 893; Hedge's g = -0.018; P = 0.93) did not differ across diagnostic studies. Meta-regression analyses revealed that gender and depression severity explained the heterogeneity observed in adiponectin diagnostic studies, while BMI and the difference in BMI between MDD individuals and controls explained the heterogeneity of leptin diagnostic studies. Subgroup analyses revealed that adiponectin peripheral levels were significantly lower in MDD participants compared to controls when assayed with RIA, but not ELISA. Leptin levels were significantly higher in individuals with mild/moderate depression versus controls. Resistin serum levels were lower in MDD individuals compared to healthy controls (N = 298; Hedge's g = -0.25; P = 0.03). Leptin serum levels did not change after antidepressant treatment. However, heterogeneity was significant and sample size was low (N = 108); consequently meta-regression analysis could not be performed. Intervention meta-analyses could not be performed for adiponectin and resistin (i.e., few studies met inclusion criteria). In conclusion, this systematic review and meta-analysis underscored that relevant moderators/confounders (e.g., BMI, depression severity and type of assay) should be controlled for when considering the role of leptin and adiponectin as putative MDD diagnostic biomarkers.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.08.002 · 4.09 Impact Factor
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    • "In contrast, an increase in plasma leptin levels has also been observed in women with depressive disorder compared with controls (Rubin et al., 2002; Esel et al., 2005; Zeman et al., 2009). However, leptin levels were either increased (Kraus et al., 2002; Esel et al., 2005; Schilling et al., 2013) or unchanged (Kraus et al., 2002; Schilling et al., 2013) by antidepressant treatment. "
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    ABSTRACT: Stress is defined as a state that can threaten homeostasis in an organism to initiate the adaptive process. Stress mediators, which include the classic neuroendocrine hormones and a number of neurotransmitters, cytokines, and growth factors, regulate both basal and threatened homeostasis to help control the stress. Severity of stress, as well as malfunctioning of stress pathways, may impair its controllability, leading to the pathogenesis of psychiatric illnesses including depression. Leptin was initially identified as an antiobesity hormone, acting as a negative feedback adiposity signal to control energy homeostasis by binding to its receptors in the hypothalamus. Accumulating evidence has expanded the function of leptin from the control of energy balance to the regulation of other physiological and psychological processes. The aim of this paper is to evaluate the potential role of leptin in stress controllability. To this end, studies on the role of leptin in stress-induced activation of the hypothalamus-pituitary-adrenocortical axis, feeding behavior, learned helplessness, and other depression models have been accumulated. The knowledge accumulated in this article may facilitate the development of alternative treatment strategies, beyond serotonin and noradrenaline reuptake inhibition, for psychiatric care and stress-related disorders.
    Behavioural Pharmacology 07/2014; 25(5-6). DOI:10.1097/FBP.0000000000000050 · 2.19 Impact Factor
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    • "The effect of treatment on leptin levels Moosa et al. 2003 11 No change with fluoxetine, imipramine Schilling et al. 2013 12 Increase with amitriptyline and mirtazapine, but not paroxetine and venlafaxine Kraus et al. 2002 13 Increase with mirtazapine, no change with venlafaxine Kurt et al. 2007 14 No change with ect in patients with mood disorders Ghrelin levels in depressive patients Barim et al. 2009 20 Low Schanze et al. 2008, 21 Kluge et al. 2009, 22 Matsuo et al. 2012 23 No difference Gecici et al. 2005 24 High The effect of treatment on ghrelin levels Schmid et al. 2006 25 Decrease with mirtazapine Pinar et al. 2008 26 Increase with maprotiline Kurt et al. 2007 14 Decrease with ECT ECT: electroconvulsive therapy S Ozsoy et al. "
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    ABSTRACT: Objective Ghrelin and leptin, appetite-regulating hormones, play a role in mood regulation. Current data about the relation between leptin/ghrelin and depression are still controversial. This study aimed to investigate serum leptin and ghrelin levels in patients with depression and the effects of treatment on these levels. Methods Serum ghrelin and leptin levels were measured before and after treatment with antidepressant drugs and/or electroconvulsive therapy in 28 patients with depression and once in 21 healthy controls. Results Serum ghrelin levels of the patients were high in the pre-treatment. After the treatment, ghrelin levels were not different from those of the controls. We found no difference in serum levels of leptin between the patients and controls and no change with treatment. body mass index of the patients increased after the treatment especially in the drug-treated group. Conclusion The present study found increased serum ghrelin levels in depressive patients and normalization with improving of depression but no alteration in leptin levels.
    Psychiatry investigation 04/2014; 11(2):167-72. DOI:10.4306/pi.2014.11.2.167 · 1.15 Impact Factor
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