Body Weight, the Tumor Necrosis Factor System, and Leptin Production during Treatment with Mirtazapine or Venlafaxine

Weight gain is a frequent and important side effect of psychopharmacotherapy. Recent studies suggest that the fat-cell-derived hormone leptin and the tumor necrosis factor-α (TNF-α) cytokine system are pathophysiologically involved. No information is available concerning the influence of the antidepressants mirtazapine and venlafaxine on these immunoendocrine variables. An open-labeled study was performed in 20 patients suffering from major depression treated with either mirtazapine (N = 11) or venlafaxine (N = 9). During 4 weeks, the patients’ weight, body mass index (BMI), and plasma levels of leptin, TNF-α, sTNF-R p55, and sTNF-R p75 were assessed. Mirtazapine induced a significant increase in weight (mean weight gain: 2.4 kg) that was evident after the first week of treatment. In parallel, the plasma levels of TNF-α and both soluble TNF receptors increased. In addition, a slight rise in leptin levels, which occurred slowly and was significant only at the end of the 4^th week of treatment, was observed. Weight decreased slightly but significantly in patients treated with venlafaxine (mean weight loss: 0.4 kg), whereas plasma levels of leptin, TNF-α, or soluble TNF receptors did not change significantly. The present results further support the notion that the activation of the TNF-α cytokine system is an early, sensitive, and specific marker of weight gain induced by psychotropic agents. In contrast, the effects of such drugs on leptin production seem to be less sensitive with respect to weight gain and more variable.

Key words

Immune system - antidepressants - weight - Leptin - TNF-α

References

• 1 Allison D B, Mentore J L, Heo M, Chandler L P, Cappelleri J C, Infante M C,. et al . Antipsychotic-induced weight gain: a comprehensive research synthesis.  Am J Psychiatry. 1999;  156 1686-1696
• 2 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4^th edition. In: APA Press Washington, D.C; 1994
• 3 Argiles J M, Lopez-Soriano J, Busquets S, Lopez-Soriano F J. Journey from cachexia to obesity by TNF.  FASEB J. 1997;  11 743-751
• 4 Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management.  Acta Psychiatr Scand. 1999;  100 3-16
• 5 Baptista T, Lacruz A, Angeles F, Silvera R, de Mendoza S, Mendoza M T, Hernandez L. Endocrine and metabolic abnormalities involved in obesity associated with typical antipsychotic drug administration.  Pharmacopsychiatry. 2001;  34 23-231
• 6 Baptista T, Lacruz A, de Mendoza S, Mendoza Guillen J M, Silvera R, Angeles F, Mendoza M T, Hernandez L. Body weight gain after administration of antipsychotic drugs: correlation with leptin, insulin and reproductive hormones.  Pharmacopsychiatry. 2000;  33 81-88
• 7 Bergmann M, Gornikiewicz A, Sautner T, Waldmann E, Weber T, Mittlbock M. et al . Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis.  Shock. 1999;  12 421-427
• 8 Brömel T, Blum W F, Ziegler A, Schulz E, Bender M, Fleischhaker C. et al . Serum leptin levels increase rapidly after initiation of clozapine therapy.  Mol Psychiatry. 1998;  3 76-80
• 9 Burrows G D, Kremer C M. Mirtazapine: clinical advantages in the treatment of depression.  J Clin Psychopharmacol. 1997;  17 Suppl 34-39
• 10 Cook E B, Stahl J L, Barney N P, Graziano F M. Olopatadine inhibits TNF-α release from human conjunctival mast cells.  Ann Allergy Asthma Immunol. 2000;  84 504-508
• 11 Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss.  J Clin Endocrinol Metab. 1998;  83 2907-2910
• 12 da-Silva V A, Altenburg S P, Malheiros L R, Thomaz T G, Lindsey C J. Postnatal development of rats exposed to fluoxetine or venlafaxine during the third week of pregnancy.  Braz J Med Biol Res. 1999;  32 93-98
• 13 Davis R, Wilde M I. Mirtazapine. A review of its pharmacology and therapeutic potential in the management of major depression.  CNS Drugs. 1996;  5 389-402
• 14 Farooqi I S, Jebb S A, Langmack G, Lawrence E, Cheetham C H, Prentice A M. et al . Effects of recombinant leptin therapy in a child with congenital leptin deficiency.  N Engl J Med. 1999;  341 879-884
• 15 Fava M. Weight gain and antidepressants.  J Clin Psychiatry. 2000;  61 Suppl 11 37-41
• 16 Fernstrom M H, Kupfer D J. Antidepressant-induced weight gain: a comparison study of four medications.  Psychiatry Res. 1988;  26 265-271
• 17 Garland E J, Remick R A, Zis A P. Weight gain with antidepressants and lithium.  J Clin Psychopharmacol. 1988;  8 323-330
• 18 Geha R S, Meltzer E O. Desloratadine: a new, nonsedating, oral antihistamine.  J Allergy Clin Immunol. 2001;  107 751-762
• 19 Guelfi J D, White C, Hackett D, Guichoux J Y, Magni G. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia.  J Clin Psychiatry. 1995;  56 450-458
• 20 Hauner H, Bender M, Haastert B, Hube F. Plasma concentrations of soluble TNF-alpha receptors in obese subjects.  Int J Obes Relat Metab Disord. 1998;  22 1239-1243
• 21 Hinze-Selch D, Deuschle M, Weber B, Heuser I, Pollmächer T. Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight.  Psychopharmacology (Berl). 2000;  149 163-169
• 22 Hinze-Selch D, Schuld A, Kraus T, Kühn M, Uhr M, Haack M. et al . Effects of antidepressants on weight and on the plasma levels of leptin, TNF- and soluble TNF receptors: a longitudinal study in patients treated with amitriptyline or paroxetine.  Neuropsychopharmacol. 2000;  23 13-19
• 23 Hotamisligil G S. The role of TNF-alpha and TNF receptors in obesity and insulin resistance.  J Intern Med. 1999;  245 621-625
• 24 Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
• 25 Jackson H C, Needham A M, Hutchins L J, Mazurkiewicz S E, Heal D J. Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat.  Br J Pharmacol. 1997;  121 1758-1762
• 26 Kraus T, Haack M, Schuld A, Hinze-Selch D, Kühn M, Uhr M. et al . Body weight and leptin plasma levels during treatment with antipsychotic drugs.  Am J Psychiatry. 1999;  156 312-314
• 27 Kraus T, Zimmermann U, Schuld A, Haack M, Hinze-Selch D, Pollmächer T. The physiopathology of weight regulation during treatment with psychotropic drugs.  Fortschr Neurol Psychiatr. 2001;  69 116-137
• 28 Lofgren P, van H V, Reynisdottir S, Naslund E, Ryden M, Rossner S. et al . Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue.  Diabetes. 2000;  49 688-692
• 29 Meltzer H Y, Nash J F. Effects of antipsychotic drugs on serotonin receptors.  Pharmacol Rev. 1991;  43 587-604
• 30 Mercer L P. Histamine and the neuroregulation of food intake.  Nutrition. 1997;  13 581-582
• 31 Mishima Y, Kuyama A, Tada A, Takahashi K, Ishioka T, Kibata M. Relationship between serum tumor necrosis factor-alpha and insulin resistance in obese men with Type 2 diabetes mellitus.  Diabetes Res Clin Pract. 2001;  52 119-123
• 32 Montague C T, Farooqi I S, Whitehead J P, Soos M A, Rau H, Wareham N J. et al . Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997;  387 903-908
• 33 Morimoto T, Yamamoto Y, Mobarakeh J I, Yanai K, Watanabe T, Yamatodani A. Involvement of the histaminergic system in leptin-induced suppression of food intake.  Physiol Behav. 1999;  67 679-683
• 34 Pelleymounter M A, Cullen M J, Baker M B, Hecht R, Winters D, Boone T. et al . Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 1995;  269 540-543
• 35 Pollmächer T, Haack M, Schuld A, Kraus T, Hinze-Selch D. Effects of antipsychotic drugs on cytokine networks.  J Psychiatr Res. 2000;  34 369-382
• 36 Pollmächer T, Hinze-Selch D, Fenzel T, Kraus T, Schuld A, Mullington J. Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol.  Am J Psychiatry. 1997;  154 1763-1765
• 37 Pollmächer T, Hinze-Selch D, Mullington J. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels.  J Clin Psychopharmacol. 1996;  16 403-409
• 38 Pollmächer T, Kraus T, Haack M, Uhr M, Mullington J. Salmonella abortus equi endotoxin does not affect leptin plasma levels in healthy humans.  J Infect Dis. 1999;  179 1047-1048
• 39 Roose S P. Tolerability and patient compliance.  J Clin Psychiatry. 1999;  60 Suppl 17 14-17
• 40 Sarraf P, Frederich R C, Turner E M, Ma G, Jaskowiak N T, Rivet D J. et al . Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.  J Exp Med. 1997;  185 171-175
• 41 Sewter C P, Digby J E, Blows F, Prins J, O’Rahilly S. Regulation of tumour necrosis factor-alpha release from human adipose tissue in vitro.  J Endocrinol. 1999;  163 33-38
• 42 Schuld A, Kraus T, Haack M, Hinze-Selch D, Kühn M, Pollmächer T. Plasma levels of cytokines and soluble cytokine receptors during treatment with olanzapine.  Schizophr Res. 2000;  102 1-3
• 43 Schwartz M W, Peskind E, Raskind M, Boyko E J, Porte D J. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans.  Nat Med. 1996;  2 589-593
• 44 Schwartz M W, Woods S C, Porte D J, Seeley R J, Baskin D G. Central nervous system control of food intake.  Nature. 2000;  404 661-671
• 45 Stanton J M. Weight gain associated with neuroleptic medication: a review.  Schizophr Bull. 1995;  21 463-472
• 46 Tecott L H, Sun L M, Akana S F, Strack A M, Lowenstein D H, Dallman M F. et al . Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.  Nature. 1995;  374 542-546
• 47 Tracey K J, Cerami A. Tumor necrosis factor: an updated review of its biology.  Crit Care Med. 1993;  21 Suppl 415-422
• 48 Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.  Nature. 1997;  389 610-614
• 49 Wang K Y, Arima N, Higuchi S, Shimajiri S, Tanimoto A, Murata Y. et al . Switch of histamine receptor expression from H2 to H1 during differentiation of monocytes into macrophages.  FEBS Lett. 2000;  473 345-348
• 50 Willett W C, Dietz W H, Colditz G A. Guidelines for healthy weight.  N Engl J Med. 1999;  341 427-434
• 51 Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R. et al . Illness, cytokines, and depression.  Ann N Y Acad Sci. 2000;  917 478-487