J Neural Transm (2009) 116:109115 DOI 10.

1007/s00702-008-0151-3

BIOLOGICAL CHILD AND ADOLESCENT PSYCHIATRY - ORIGINAL ARTICLE

Leptin and its associations with measures of psychopathology in patients with anorexia nervosa
Stefan Ehrlich Roland Burghardt Nora Schneider Jakob Hein Deike Weiss Ernst Pfeiffer Ulrike Lehmkuhl Harriet Salbach-Andrae

Received: 6 April 2008 / Accepted: 21 October 2008 / Published online: 19 November 2008 Springer-Verlag 2008

Abstract Apart from energy homeostasis leptin has been shown to be involved in a number of neuronal networks. The aim of this study was to investigate how the residual variance of leptin levels, after controlling for BMI, is linked to eating-disorder-specic psychopathology and sexual desire in patients with anorexia nervosa (AN) compared to healthy controls. The sample included 57 subjects with acute AN and 77 healthy controls. Psychopathology was determined by EDI-2 and SCL-90-R and sexual problems were rated according to the Structured Interview of Anorexia Nervosa and Bulimic Syndromes (SIAB-EX). Plasma leptin was assessed by ELISA. Patients with a high drive for thinness had lower leptin levels at a given BMI and low leptin levels were associated with sexual problems, i.e. the absence of sexual desire and intimate relationships. Our results are in accordance with recent animal experiments linking low leptin levels with decreased sexual interest irrespective of body weight. Keywords Anorexia nervosa Leptin Sexual problems Psychopathology

Introduction Leptin is a 16-kDa protein product of the ob gene which is primarily secreted by adipocytes (Zhang et al. 1994). Its main physiological role is to communicate to the central nervous system (CNS) the abundance of available energy stores and to decrease food intake as well as increase energy expenditure (Elmquist et al. 1999; Zhang et al. 2005). The complete absence of leptin leads to increased food intake and morbid obesity (Montague et al. 1997). Leptin receptors are primarily expressed in the hypothalamus but they are also present in numerous extra-hypothalamic regions of the brain, including the hippocampus, cerebellum, amygdala and brain stem (Elmquist et al. 1998). Plasma leptin is generally proportional to body mass index (BMI). Consequently, underweight subjects or patients with acute anorexia nervosa (AN) show suppressed leptin levels (Hebebrand et al. 2007). Nevertheless, variance in leptin levels for a given BMI level or percent body fat is considerable. Fasting and overeating lead to a rapid decrease and increase, respectively, of leptin levels that precede any weight alterations (Boden et al. 1996; Kolaczynski et al. 1996). Cognitive restraints on food intake and respectively restrained eating patterns have been associated with reduced leptin levels independently of BMI in anorectic, healthy underweight and obese females (von Prittwitz et al. 1997; dAmore et al. 2001; Adami et al. 2002; Haas et al. 2005). Furthermore, a series of studies reported decreased leptin levels in many patients with bulimia nervosa despite normal BMI. Leptin seems to be inversely correlated with the frequency of bingeing and vomiting (Jimerson et al. 2000; Monteleone et al. 2000, 2002). Apart from energy homeostasis leptin has been shown to be involved in a number of CNS networks regulating motor activity (Exner et al. 2000; van Elburg et al. 2007), sleep

S. Ehrlich (&) R. Burghardt N. Schneider D. Weiss E. Pfeiffer U. Lehmkuhl H. Salbach-Andrae Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charite, Universitatsmedizin Berlin, CVK, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: stefan.ehrlich@charite.de S. Ehrlich J. Hein Department of Psychiatry and Psychotherapy, Charite, Universitatsmedizin Berlin, CCM, Berlin, Germany

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(Sinton et al. 1999), the hypothalamicpituitarygonadal axis as well as normal sexual maturation and reproduction (Wauters et al. 2000). For instance, leptin administration can reverse the disruption of ovulation in food-restricted rats (Roman et al. 2005) and also restore fertility and sexual behaviour to the infertile and sexually immature ob/ob mice (Mounzih et al. 1997). Leptin decient humans are not only characterised by obesity but also by the absence of pubertal development, hypogonadism and primary amenorrhoea (Clement et al. 1998; Strobel et al. 1998). In a unique series of animal experiments Schneider et al. (Schneider et al. 2007) demonstrated that a 48-h period of food deprivation signicantly decreased preference for sex in healthy female hamsters while systemic leptin treatment prevented this effect. In order to understand the effects of leptin on human behaviour and vice versa it seems promising to study the course of hypoleptinaemic states such as during the acute phase of AN. This disorder is associated with self-imposed starvation, feeling fat, and amenorrhoea. A restricting type has been distinguished from a binge eating/purging type (Hoge and Andrews 1994). Arising during the period of growth and maturation, AN leads to interruptions of somatic and psychological development. Patients with AN are characterised by a negative body attitude as well as decreased sexual desire (Raboch and Faltus 1991; Tuiten et al. 1993). The aim of the present study was to investigate how the residual variance of leptin levels, after controlling for BMI, is linked to eating-disorder-specic psychopathology and sexual problems. On the basis of previous human and animal studies, we hypothesised that the core eating disorder symptoms drive for thinness, body dissatisfaction and bulimia predict leptin levels, while leptin itself predicts sexual behaviour and cognitions. We used path modelling to test all relationships simultaneously while controlling for the effect of BMI.

physical examination. HCW were excluded if they had any history of psychiatric illness. Patients were excluded if they had a lifetime history of any of the following clinical diagnoses: organic brain syndrome, schizophrenia, substance dependence, bipolar illness, bulimia nervosa or binge eating disorder. Further exclusion criteria for all participants were: IQ less than 85, current inammatory, neurological or metabolic illness, anaemia, pregnancy and breast feeding. This study was approved by the Institutional Review Board, and all subjects (and if underage their guardians) gave written informed consent. Clinical measures The expert form of the Structured Interview of Anorexia Nervosa and Bulimic Syndromes (SIAB-EX) was used to ascertain current and/or past diagnoses of eating disorders in all participants. The SIAB-EX for subjects aged between 12 and 65 years is a semi-standardised interview that assesses the prevalence and severity of specic eatingrelated psychopathology over the past 3 months according to DSM-IV diagnostic criteria. It consists of 87 items and provides diagnoses of eating disorders according to ICD-10 and DSM-IV. Internal consistency was good and the interrater reliability ranged from 0.86 to 0.96 (Fichter and Quadieg 2001). Interviews were conducted by clinically experienced and trained research assistants under the supervision of the attending child and adolescent psychiatrist. The SIAB-EX also includes a subscale for the assessment of sexual desire, sexual anxieties and sexual behaviour within the last 3 months. This sexual problems subscale is applicable to subjects older than 16.0 years and younger subjects if they have had an intimate relationship. It consists of ve items coded on a ve-point scale ranging from 0 (symptom/problem not present) to 4 (symptom/ problem very severely present). Each item and the coding are described in detail in the accompanying manual. The SIAB-EX sexual problem subscale has been shown to be closely correlated with the corresponding items of the Beck Depression Inventory, the Demoralization Scale of the Psychiatric Epidemiological Research Interview and the sexual anxieties subscale of the Anorexia Nervosa Inventory for Self-Rating (ANIS) (Fichter et al. 1991; Fichter and Quadieg 2001). Eating disorder-specic psychopathology was assessed with the Eating Disorders Inventory (EDI-2), a self-report questionnaire comprising 91 items forming 11 scales (Rathner and Waldherr 1997). Response categories range from 1 never to 6 always. The three core subscales drive for thinness, body dissatisfaction and bulimia were part of the conrmatory analyses in this study.

Methods Participants The sample population consisted of 57 female subjects (1428 years old) with acute anorexia nervosa (AN) according to DSM-IV, who were treated within in- or outpatient eating disorder programs of a major university hospital. The control group consisted of 77 normal-weight, eumenorrheic, healthy female control subjects (HCW 14 26 years old), who were recruited by advertisement among middle school, high school and university students. Exclusion criteria were obtained using a semistructured research interview, the SIAB-EX (see below) and by

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Other psychiatric symptoms such as self-reported depression were determined using the Symptom Checklist 90 Revised (SCL-90-R) (Franke 2002). Blood collection and biochemical assessments Within the rst days of treatment initiation venous blood samples of 9 ml were collected into vacutainer tubes containing EDTA between 7:30 and 9:30 a.m. after the subjects had fasted overnight. After centrifugation of the blood at 2509g plasma leptin concentrations were measured by Enzyme Linked Immunosorbent Assay with a commercial kit (Human Leptin Dual Range ELISA, Millipore, Billerica, MA, USA) according to the manufacturers instructions. Depending on the dilution factor specied in the protocol sensitivity was 0.12520 or 0.5100 ng/ml. Statistical Analyses In addition to simple nonparametric statistical procedures and partial correlations (SPSS 14.0, Chicago, Illinois), we applied path modelling following the guidelines set forth by Arbuckle and Wothke (1999). Path-Models were estimated using AMOS 4.0 with full maximum likelihood estimation. Table 1 shows descriptive statistics of the predictor and outcome variables used for the path models below. The rst column shows that the measures of interest were not available for each subject. Reasons for missing data were unsuccessful venipuncture (leptin), unanswered items in the EDI-2 questionnaires, age below 16 years and no prior intimate relationship for the SIAB-EX sexual problems subscale. Path modelling using the Maximum Likelihood Estimation allows all subjects to be included in the analyses, including those with missing data points, by using all available information to calculate specic path coefcients. This approach is considered to be superior to

conventional listwise deletion (Anderson 1957; Little and Rubin 1987). Variables used for path modelling need to meet certain statistical assumptions. Close inspection of skewness and kurtosis exceeded the normal range of 1 [ x [ -1 in the case of plasma leptin and the EDI-2 subscale bulimia. In line with previous research we used a logarithmic (log 10) transformation for leptin. In order to correct the positive skew of the bulimia subscale we used an inverse transformation (1/(x ? 1)). In order to compare nested path models t indices from the three major categories, the v2 index, the incremental t indices (TLI, CFI) and the indices based on residuals (RMSEA) were examined. Decisions about the rejection of a model in comparison with an alternative nested model were based on change in the v2 overall goodness-of-t test statistic (Arbuckle and Wothke 1999). If no signicant difference between the t of nested models was observed (at the P \ 0.05 level), the most constrained tting model with the largest degrees of freedom was accepted as the nal model. Because of height and weight changes during adolescence it is important to provide age-adapted BMI scores. Therefore, BMI standard deviation scores (BMI-SDS) were calculated according to age-adapted values as based on a large German reference data set (Kromeyer-Hauschild et al. 2001). If not otherwise indicated, means are given with standard deviations (SD) and a signicant differences are reported at a P \ 0.05 level.

Results Table 1 shows signicant differences between AN and HCW in BMI, plasma leptin and all psychometric measures. There were no differences in age, BMI, leptin levels, sexual

Table 1 Descriptive statistics, results of MannWhitney U tests and partial correlations with log 10-leptin levels controlling for BMI-SDS N (HCW/AN) Age BMI BMI-SDS Log 10-leptin DT BD B Sexual problems 77/57 77/57 77/57 77/53 76/57 75/57 76/57 58/29 HCW Mean 17.88 21.57 0.24 1.07 1.79 5.13 0.13 0.83 SD 2.86 2.15 0.80 0.32 3.23 6.50 0.55 0.78 AN Mean 17.74 15.15 -2.06 -0.40 9.46 13.05 1.53 2.35 SD 3.15 1.45 0.50 0.80 6.84 7.47 2.41 1.14 MWU P 0.579 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001 \0.001 HCW r -0.18 / / / -0.10 0.16 0.03 -0.16 P 0.127 / / / 0.425 0.184 0.813 0.243 AN r -0.14 / / / -0.30 -0.22 0.06 -0.36 P 0.325 / / / 0.038 0.122 0.685 0.058

DT drive for thinness, BD body dissatisfaction, B bulimia

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problems and core eating disorder psychopathology except bulimic symptoms between AN patients of the restrictive (n = 42) and binge/purging subtype (n = 15; data not shown). Controlling for BMI-SDS, plasma log 10-leptin correlates signicantly negatively with the EDI-2 subscale drive for thinness in AN but not in HCW. Furthermore, there is a statistical trend for a negative partial correlation between log 10-leptin and sexual problems in AN. Drive for thinness, body dissatisfaction and bulimia do not correlate with the sexual problem subscale within the group of AN and HCW (data not shown). Figure 1 presents a general path model we hypothesised for the relationships between drive for thinness, body dissatisfaction, bulimia, BMI-SDS, log 10-leptin and sexual problems in AN. Drive for thinness, body dissatisfaction and bulimia were regarded as observed exogenous variables and allowed to correlate with each other. BMI-SDS, log 10-leptin and sexual problems were modelled as observed endogenous variables. Since we assumed additional inuences on the endogenous variables, each is also connected to an independent error term with a regression weight xed to one. The path model was calculated for the group of AN patients (A) and for the total group (B). Signicant relationships in the path models are highlighted by bold arrows. The size and direction of the effects are given as standardised path coefcients. In the group of AN patients drive for thinness but not body dissatisfaction had a signicant moderate negative effect on log 10-leptin (standardised beta coefcient of 0.25 to 0.5 or -0.25 to -0.5). There was a statistical trend for a moderate negative effect of bulimia on log 10-leptin. As expected, BMI-SDS had a large positive effect on log 10-leptin (standardised beta coefcient [0.5 or \-0.5). However, BMI-SDS had no direct effect on sexual problems whereas we observed a statistical trend for a moderate negative effect of log 10-leptin on the sexual problem subscale (P = 0.060, Fig. 1a). After including all participants, AN and HCW, into our path model, drive for thinness had a highly signicant moderate positive effect on BMI-SDS, and log 10-leptin had a highly signicant large negative effect on the sexual problem subscale (Fig. 1b). To test if the direct effects of body dissatisfaction on BMI-SDS and log 10-leptin, the direct effect of bulimia on BMI-SDS as well as the direct effect of BMI-SDS on sexual problems can be neglected, we compared nested alternative path models. For both, the group of AN patients and the whole sample the differences in v2 statistics between our baseline models and each of the alternative models were not signicant. The nal models, where all four above mentioned paths were constrained to zero, t the data well as indicated by TLI [ 0.95, CFI [ 0.95 and RMSEA B 0.06 (Hu and Bentler 1999).

Fig. 1 Path models predicting sexual problems in (a) AN patients and (b) AN patients and HCW. Path coefcients are standardised. DT drive for thinness, BD body dissatisfaction, B bulimia

In an exploratory analysis we also tested for associations between all other self-reported symptoms (EDI-2, SCL-90R) and log 10-leptin while controlling for BMI-SDS: in the group of AN patients the SCL-90-R depression score showed a signicant negative partial correlation with logleptin (r = -0.31, P \ 0.05). All other relationships failed to reach signicance.

Discussion The results of our study show relationships between leptin and two major domains of human behaviour and cognition independently of BMI: First, AN patients with a high drive for thinness have lower leptin levels at a given BMI. Second, low leptin levels predict sexual problems, i.e. the absence of sexual desire and intimate relationships. In addition, our exploratory analyses revealed a signicant negative relationship between depressive symptoms and leptin in AN patients. The EDI-2 subscale drive for thinness refers to issues directly related to weight control, such as preoccupation with weight and dieting. Several (von Prittwitz et al. 1997; dAmore et al. 2001; Adami et al. 2002; Haas et al. 2005), but not all (Frey et al. 2003) previous studies found a negative relationship between a construct called restraint and leptin. Most often restraint was measured with the Three Factor Eating Questionnaire scale for cognitive control. High values on this scale characterise subjects with distinct, restrained eating behaviour and a predominantly high cognitive control of eating behaviour

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(Stunkard and Messick 1985). Low values characterise individuals with spontaneous and unrestrained eating behaviour that is regulated mostly via internal signals of autonomous appetite and satiety regulation. While many of the questions of the EDI-2 self-report used the rst time in this study correspond to the Three Factor Eating Questionnaire items, the EDI-2 subscale drive for thinness also comprises items assessing typical dysfunctional beliefs and attitudes in individuals with eating disorders (Rathner and Waldherr 1997). Cognitive preoccupation with weight and dieting is likely to impact on eating behaviour. Already short periods of food restriction lead to rapid and dramatic drops in leptin levels (Boden et al. 1996; Nakai et al. 1999; Haluzik et al. 2001). Thus, abnormal eating patterns, in particular dieting, may represent the underlying behavioural mechanism of the aforementioned negative relationship between drive for thinness and leptin. In a different sample of long-term weight-recovered patients with AN we found a similar pattern: Recovered patients with disproportional low leptin levels, when adjusted for BMI, showed more drive for thinness when compared to recovered patients with adequate leptin levels (unpublished results). In contrast, mere dissatisfaction with ones own body shape (body dissatisfaction) does not seem to alter BMI and leptin levels. Although additional binge/purging behaviour was not very frequent in our patients, we also found some evidence supporting the previously reported leptin-lowering effect of bulimic symptoms (Monteleone et al. 2000, 2002). Decreased interest in intimate relationships and sexual anxieties are common clinical phenomena in patients with AN (Raboch and Faltus 1991; Tuiten et al. 1993). In a recent 12-year longitudinal study, sexual problems have been identied as an indicator of unfavourable long-term prognosis (Fichter et al. 2006). However, other authors suggest that AN patients had normal sexual attitudes before they became anorectic and that masturbation experience, as well as self-ratings of current sexual satisfaction, are inversely related to the degree of food restriction (Tuiten et al. 1993; Wiederman et al. 1996). These data point to an association of sexual problems with the state of semistarvation. Up to now, the underlying biological processes have not been investigated in humans. As mentioned above, animal experiments give evidence for leptin as the main regulatory messenger. A short period of fasting with a subsequent fall in leptin levels decreased sexual interest in hamsters of normal weight. Systemic leptin administration was able to reverse the effect of fasting (Schneider et al. 2007). In another study the reduction of sexual arousal and the degree of attraction following chronic calorie restriction in rats could be explained by a decrease in leptin levels rather than testosterone levels (Govic et al. 2008). Our study is the rst to suggest the same mechanism in humans,

although it remains unclear if the sexual drive is directly controlled by leptin. In fact, the effects of leptin on reproductive functioning are mediated by the hypothalamicpituitarygonadal axis. Leptin stimulates the release of follicular stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland (Yu et al. 1997; McCann et al. 1998). Furthermore, leptin receptors are present in gonadal tissue, suggesting that leptin could exert a direct endocrine action on the gonads (Karlsson et al. 1997). Conversely, androgens and oestrogens were shown to stimulate leptin secretion in adipocytes (Wabitsch et al. 1997; Kristensen et al. 1999). The close relationship between the thyroid axis and leptin could explain the association between low leptin levels and depressive symptoms. (Nakai et al. 1999; Wauters et al. 2000). Clinical data on the possible association of leptin levels with depression in non-eating disordered subjects are heterogeneous. Studies reported normal, elevated or decreased leptin levels in patients with major depression (Deuschle et al. 1996; Westling et al. 2004; Pasco et al. 2008). Systemic administration of leptin in rats showed antidepressant-like properties (Lu et al. 2006). The ndings of this study should be considered in light of the following limitations. First, we did not measure body fat, which may have differed between groups independently of BMI. However, it has been shown that BMI represents average body fat estimates in healthy controls (Heitmann 1990). Second, ndings interpreted in this manuscript also include statistical trends. Because of the pilot character of this study and the fact that sexual problem scores were not available for all participants, limiting the power of our analyses, this strategy seems to be justied. Third, sexual desire is inuenced by many environmental and physiological factors, including sexual hormone and thyroid hormone levels that have not been studied (Basson 2007). Finally, despite a high convergent validity of the SIAB-EX sexual problem subscale with the corresponding items of other questionnaires (Fichter and Quadieg 2001) assessment of this domain in adolescents and young adults remains a challenge. In order to verify our hypotheses, future studies should include larger sample sizes, include patients with bulimia nervosa and employ more complex assessments of sexual problems. In summary, low plasma leptin may be a sensitive indicator not only of the overall nutritional status in AN, but also of the current severity of eating disorder psychopathology as well as reduced sexual activity. Circulating leptin may regulate both, the physiological prerequisites of reproductive functioning as well as sexual interest and behaviour.
Acknowledgments The authors would like to thank R. Schott for help with the recruitment of the participants and P. I. Pohl for help with the manuscript preparation.

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