Article

Leptin Plasma Concentrations Increase During Antidepressant Treatment With Amitriptyline and Mirtazapine, But Not Paroxetine and Venlafaxine

∥Peptide Hormone Research Laboratory, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen
Journal of clinical psychopharmacology (Impact Factor: 3.24). 12/2012; 33(1). DOI: 10.1097/JCP.0b013e31827cb179
Source: PubMed

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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    • "Pathophysiological mechanisms have been increasingly identified over the past decade. These include antihistaminergic drug effects (Kroeze et al., 2003), activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) (Kim et al., 2007), modulation of ghrelin (Himmerich et al., 2005a, 2005b; Pinar et al., 2008; Zhang et al., 2013) and leptin (Atmaca et al., 2003; Schilling et al., 2013) signaling and changes in the production of cytokines and adipocytokines such as adiponectin (ADIPOQ) (Pinar et al., 2008), and the modulating impact of several genes, most of all melanocortin 4 receptor (MC4R), serotonin 2C receptor (HTR2C), and leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1) genes (Müller et al., 2009). Metabolic disturbances during treatment with these drugs may occur independent of weight gain. "
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    ABSTRACT: Weight gain is a major problem during psychopharmacological treatment. Research has concentrated on the appetite inducing properties and mechanisms of these drugs in the central nervous system. The potential contribution of direct effects of drugs on metabolically relevant peripheral cells such as adipocytes is less well understood. We examined the influence of the antidepressant imipramine, the antipsychotic clozapine, and the mood stabilizer lithium on preadipocytes and adipocytes in vitro, using Simpson-Golabi-Behmel syndrome (SGBS) cells, an established human preadipocyte model. Parameters of cell differentiation and signaling, and cell metabolism were measured. We found significantly increased triglyceride accumulation in adipocytes after supplementation with imipramine and lithium at therapeutic concentrations, compared to non-supplemented control samples. However, gene expression levels of an early marker of adipogenesis, the peroxisome proliferator-activated receptor gamma (PPAR-γ) and a late marker of adipogenesis, the fatty acid binding protein 4 (FABP4), as well as expression of adiponectin (ADIPOQ) did not change significantly in the presence of these psychopharmacological agents. The results suggest a direct influence of imipramine and lithium but not clozapine on fat storage of adipocytes. The underlying mechanisms of fatty acid storage and adipocyte differentiation however remain to be elucidated.
    No preview · Article · Nov 2015 · Journal of Psychiatric Research
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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.
    Full-text · Article · Aug 2014 · Journal of Psychiatric Research
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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.
    Full-text · Article · Jul 2014 · Behavioural Pharmacology
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