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 Dunja Hinze-Selch, M.D., Andreas Schuld, M.D., Thomas Kraus, M.D., Martin Kühn, M.D., Manfred Uhr, M.D., Monika Haack, M.A., and Thomas Pollmächer, M.D. Leptin, tumor necrosis factor-␣ (TNF-␣), and soluble TNF preceded by a significant increase in soluble TNF receptor p75 receptors are involved in weight regulation. Antipsychotic plasma levels. Circulating levels of leptin were not affected. agents, such as clozapine, induce weight gain and increase Paroxetine and drug-free treatment did not affect any of these circulating levels of these cytokines. To assess whether obesity- parameters. We conclude that weight gain induced by inducing antidepressants have a similar effect, we measured psychotropic agents may occur without increased circulating plasma cytokine levels in depressive inpatients during the first levels of leptin. However, activation of the TNF-␣ system six weeks of treatment with tricyclic agents (amitriptyline or might be an early and sensitive marker of ensuing weight nortriptyline, n ϭ 12), with paroxetine (n ϭ 10), or without gain. [Neuropsychopharmacology 23:13–19, 2000] medication (n ϭ 14). There was an increase in the body mass © 2000 American College of Neuropsychopharmacology. index at week 6 of treatment with the tricyclics, which was Published by Elsevier Science Inc. All rights reserved KEY WORDS: Soluble TNF receptors; Leptin; Body mass al. 1996; Kraus et al. 1999). Although the effects of these index; Tricyclic antidepressants; Serotonin reuptake drugs on several neurotransmitter systems such as the inhibitor; Drug-free serotonergic, dopaminergic, and histaminergic systems Weight gain is a common side-effect of several psycho- may contribute to weight gain, the underlying mecha- tropic drugs and may seriously limit treatment compli- nisms have remained obscure (Pijl and Meinders 1996). ance (Pijl and Meinders 1996). Increases in weight occur Recently, however, research on obesity and weight in particular during treatment with tricyclic antidepres- regulation has contributed new perspectives through the sants (Berken et al. 1984) and the atypical neuroleptics discovery of leptin, a protein hormone involved in clozapine and olanzapine (Brömel et al. 1998; Bustillo et weight regulation (Pelleymounter et al. 1995; for review see Auwerx and Staels 1998), and tumor necrosis factor-␣ (TNF-␣), a cytokine with its soluble receptors as Janus- From the Max Planck Institute of Psychiatry, Munich, Germany. faced mediators of weight gain and weight loss (for re- Address correspondence to: Thomas Pollmächer, M.D., Max view see Argiles et al. 1997). Leptin induces reduced Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, food intake, and dysregulated leptin signaling is ac- Germany. Received April 9, 1999; revised August 12, 1999; accepted January companied by obesity in animals and humans (for re- 3, 2000. view see Auwerx and Staels 1998). Animals that are de- NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 1 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. All rights reserved 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00089-0 14 D. Hinze-Selch et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 1 ficient in leptin or its receptor are obese and and has numerous hematological effects (for review see supplementation of this protein in leptin-deficient ani- van der Poll and Lowry 1995). In addition, we took the mals reverses obesity, supporting a pivotal role of lep- opportunity to investigate soluble interleukin-2 recep- tin in the regulation of appetite and weight (Lee et al. tor (sIL-2r) levels, which have been reported to be in- 1996, Pelleymounter et al. 1995). creased in patients with the diagnosis of major depres- In humans, plasma levels of leptin are higher in sion (Maes et al. 1995b) or schizophrenia (Gaughran et obese people than in lean controls and decrease with al. 1998). However, it has already been shown that psy- weight loss, suggesting a less sensitive receptor system chotropic medication, such as clozapine (Pollmächer et in obese people (Considine et al. 1996). In addition, the al. 1995, 1996), and cigarette smoking (Pollmächer and cytokine TNF-␣ and its soluble receptors sTNFR-p55 Hinze-Selch 1998) can also induce sIL-2r plasma levels. and sTNFR-p75 are associated with weight regulation. In a cross-sectional investigation on antidepressive TNF-␣ was described in 1981 as the molecule responsi- medication, no effect on circulating levels of sIL-2r was ble for the wasting syndrome in chronic diseases and found (Maes et al. 1995a), but a systematic longitudinal was named cachectin (Kawakami and Cerami 1981); study has not yet been published. later, it was sequenced and named tumor necrosis fac- We hypothesized that treatment with amitriptyline tor-␣ (Old 1985). TNF-␣ in concert with its receptors, or nortriptyline would induce weight gain and increase which are either bound to membranes of various cell plasma levels of leptin, TNF-␣, and soluble TNF recep- types or are shed into circulation, act on protein, glu- tors, whereas treatment with paroxetine and drug-free cose and lipid metabolism (for review see Argiles et al. treatment would not. 1997). Circulating levels of TNF-␣ and its soluble recep- tors are increased in obese subjects compared to lean controls and decrease with weight loss (Dandona et al. 1998; Hauner et al. 1998). It has been hypothesized that METHODS decreased TNF-␣ receptor sensitivity might lead to a Patients lack of body weight control and consequently to an in- crease in caloric intake (for review see Argiles et al. Twenty-two inpatients meeting the DSM-IV diagnostic 1997). In addition, in vitro and some in vivo data sug- criteria (American Psychiatric Association 1994) for ma- gest that the TNF-␣ system and leptin are linked to- jor depressive disorder or dysthymic disorder but not gether (Finck et al. 1998). Leptin with its class-I cytokine for bipolar disorder and 14 inpatients meeting the DSM- receptor modulates the cellular immune response, and IV diagnostic criteria for various other mental disorders, inflammatory cytokines such as TNF-␣ liberate leptin including anxiety disorders (n ϭ 5), adjustment disor- from adipocytes (for review see Argiles et al. 1997; Au- ders (n ϭ 3), schizophreniform disorder (n ϭ 1), and werx and Staels 1998). personality disorders (n ϭ 5), gave written informed Psychotropic drugs that typically lead to weight consent before participating in this study, which had gain, such as clozapine and olanzapine, have been been approved by an independent ethics committee. shown to activate the TNF-␣ system and leptin by in- None of the patients met the criteria for substance abuse creasing plasma levels of these cytokines and soluble or dependence, nor for any eating disorder. cytokine receptors (Brömel et al. 1998; Kraus et al. 1999; Physical examination, medical history and baseline Pollmächer et al. 1996). Therefore, the induction of laboratory investigations (white blood cell count, differ- these multifunctional mediators might play a role in ential counts, red blood cell count, creatinine, electro- drug-induced changes of body weight. lytes, GOT, GPT, AP, ␥GT, Quick, partial thromboplas- In the present study, designed to further evaluate tin time, serum electrophoresis, blood sedimentation this hypothesis, we investigated the time course of rate, C-reactive protein, serum iron, transferrin, glu- body weight and circulating levels of cytokines in de- cose, thyroid-stimulating hormone) did not reveal acute pressive inpatients during the first six weeks of treat- or chronic inflammation and infection or autoimmuno- ment with two antidepressant drugs with known dif- logical, endocrinological or hematological disease. Of ferent impacts on body weight. We also studied a the 22 patients with depressive or dysthymic disorder, group of unmedicated inpatients to control for unspe- 12 were medicated with amitriptyline (n ϭ 9) or cific effects of hospitalization per se. We chose the selec- nortriptyline (n ϭ 3) and 10 with paroxetine. The deci- tive serotonin reuptake inhibitor paroxetine that gener- sion about which substance to administer was based on ally does not affect body weight (Pijl and Meinders clinical considerations. 1996), and the tricyclic antidepressants amitriptyline or None of the patients had been treated during the its major active metabolite nortriptyline (Kessel and preceding six months with the substance he/she was to Simpson 1995) that induce weight gain (Berken et al. receive during the present study. Six of the 12 patients 1984). We also measured tympanic temperature and to be treated with amitriptyline/nortriptyline were not did white blood cell counts because TNF-␣ is pyrogenic psychopharmacologically treated during the preceding NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 1 Antidepressants, Weight, and Cytokines: A Longitudinal Study 15 six months. In the remaining six patients, psychotropic ml for leptin. The body mass index (BMI) was calcu- medication included fluspirilene, maprotilene, moclobe- lated as BMI ϭ body weight [kg] / height [m]2. mide, oxazepam, diazepam, and valproic acid and was discontinued before the enrollment in the study except Statistics for valproic acid, which was continued as mood stabi- lizer in one patient. Four of the 10 patients