Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

INTRODUCTION: Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. METHODS: Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. RESULTS: The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. DISCUSSION: These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Therapeutic drug monitoring of children and adolescents treated with aripiprazole: observational results from routine patient care.

Although aripiprazole is one of the most used antipsychotics, knowledge about serum concentrations in children and adolescents is scarce and age-specific therapeutic ranges have not been established yet. Data of a routine therapeutic drug monitoring service were analyzed in order to evaluate the relationship between dose and serum concentration of aripiprazole in children and adolescents. The study also aimed to evaluate whether the therapeutic reference range defined for adults with schizophrenia (100-350 ng/ml) is applicable for minors. Data from 130 patients (aged 7-19 years) treated with aripiprazole for different indications in doses of 2-30 mg/day were evaluated. Patient characteristics, doses, serum concentrations and therapeutic outcome were assessed by standardized measures. A positive mean correlation between body weight-corrected daily dose and aripiprazole concentration was found (rp = 0.59, p < 0.001) with variation in dose explaining 35% of the variability in serum concentrations. Girls had on average 41% higher dose-corrected concentrations than boys (244.9 versus 173.4 mg/l; p = 0.006). Aripiprazole concentrations did not vary with co-medication (p = 0.22). About 70% of all measured serum concentrations were within the recommended therapeutic range for adults. Using a calculation method in all responding patients with an ICD-10 F2 diagnosis for a rough estimation of a preliminary therapeutic window also demonstrated a similar therapeutic range of aripiprazole in minors (105.9-375.3 ng/ml) than for adults. If confirmed in larger samples and more controlled study designs, these data may contribute to the definition of a therapeutic range of aripiprazole concentrations in children and adolescents.

Therapeutic Drug Monitoring in Children and Adolescents Under Pharmacotherapy With Olanzapine in Daily Clinical Practice.

BACKGROUND: The relationship between daily dose, serum concentrations, and clinical outcomes of olanzapine as well as the influencing factors thereof in children and adolescents treated for different psychiatric disorders were investigated in daily clinical practice. In addition, it was examined whether the current recommended therapeutic range (TR) for adult patients with psychotic disorders is valid for minors. METHODS: The Competence Network for Therapeutic Drug Monitoring (www.tdm-kjp.com) routinely collects demographic and clinical outcome data as well as serum concentrations of children and adolescents treated with psychotropics. The therapeutic effect is documented using the Clinical Global Impression Scale subscale for Global Improvement. Adverse drug reactions (ADRs) are assessed using the Udvalg for Kliniske Undersogelser-Side Effect Rating Scale. RESULTS: One hundred fifteen patients (mean age = 15.9 years; range = 10.4-18.8 years; 40.9% male) were included. The majority (72.1%) was cotreated with other psychotropic drugs. A positive medium linear relationship (r = 0.619; P < 0.001) between olanzapine dose (mean = 11.64 mg/d) and serum concentration (mean = 35.65 ng/mL) was found with a marked interindividual variability of serum concentrations. Neither relationship between olanzapine serum concentration and treatment response (clinical benefit documented in 80%) nor ADRs (documented in 53.3%, in 7.5% judged as severe) was detected. Most of the patients with psychotic and eating disorders (68.8% and 71.8%, respectively) had an olanzapine serum concentration within the TR suggested for adults. CONCLUSIONS: There are several limitations of this study because of the naturalistic design, and our results should therefore be interpreted with caution. As most of the patients showed a clinical benefit under olanzapine concentrations within the TR for adults and only a minority had severe ADRs, it is reasonable to conclude a similar TR for children, adolescents, and adults.

Day-patient treatment after short inpatient care versus continued inpatient treatment in adolescents with anorexia nervosa (ANDI): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: In-patient treatment (IP) is the treatment setting of choice for moderately-to-severely ill adolescents with anorexia nervosa, but it is costly, and the risks of relapse and readmissions are high. Day patient treatment (DP) is less expensive and might avoid problems of relapse and readmission by easing the transition from hospital to home. We investigated the safety and efficacy of DP after short inpatient care compared with continued IP. METHODS: For this multicentre, randomised, open-label, non-inferiority trial, we enrolled female patients (aged 11-18 years) with anorexia nervosa from six centres in Germany. Patients were eligible if they had a body-mass index (BMI) below the tenth percentile and it was their first admission to hospital for anorexia nervosa. We used a computer-generated randomisation sequence to randomly assign patients to continued IP or DP after 3 weeks of inpatient care (1:1; stratified for age and BMI at admission). The treatment programme and treatment intensity in both study groups were identical. The primary outcome was the increase in BMI between the time of admission and a 12-month follow-up adjusted for age and duration of illness (non-inferiority margin of 0·75 kg/m(2)). Analysis was done by modified intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN67783402, and the Deutsches Register Klinischer Studien, number DRKS00000101. FINDINGS: Between Feb 2, 2007, to April 27, 2010, we screened 660 patients for eligibility, 172 of whom we randomly allocated to treatment: 85 to IP and 87 to DP. DP was non-inferior to IP with respect to the primary outcome, BMI at the 12-month follow-up (mean difference 0·46 kg/m(2) in favour of DP (95% CI, -0·11 to 1·02; pnon-inferiority<0·0001). The number of treatment-related serious adverse events was similar in both study groups (eight in the IP group, seven in the DP group). Three serious adverse events in the IP group and two in the DP group were related to suicidal ideation; one patient in the DP attempted suicide 3 months after she was discharged. INTERPRETATION: DP after short inpatient care in adolescent patients with non-chronic anorexia nervosa seems no less effective than IP for weight restoration and maintenance during the first year after admission. Thus, DP might be a safe and less costly alternative to IP. Our results justify the broad implementation of this approach. FUNDING: German Ministry for Education and Research.

Differential patterns of disordered eating in subjects with ADHD and overweight.

OBJECTIVES: Despite growing evidence for an association between overweight and attention-deficit/hyperactivity disorder (ADHD), still little is known about the mechanisms underlying this relationship. METHODS: Within a two (no ADHD, ADHD) × two (normal weight, overweight) factorial design (n = 94) we tested disordered eating behaviour in a laboratory breakfast procedure as well as delay aversion (DA) in male children aged 7-15 years. RESULTS: While children with ADHD tended to eat above the normal level particularly at the beginning of the meal, children with overweight tended to eat above the normal level throughout the whole meal. Furthermore, preference for immediately available food was predicted by parental ratings of inattention and neuropsychological measures of DA in overweight children, and by impulsivity in children with ADHD. CONCLUSIONS: Our results suggest distinct neuropsychopathological pathways to abnormal eating in ADHD and overweight. Thus, children with overweight might benefit more from specialized treatment programmes that aim at improving attention functions while in children with ADHD the treatment should focus on impulsivity.

[Schizophreniform symptoms in Chorea Minor--case report and literature review]. / Schizophrenieforme Symptomatik bei Chorea minor--Fallbeispiel und Literaturübersicht.

Sydenham's chorea is the most frequently acquired movement disorder in childhood and is characterized by involuntary and abrupt movement patterns. Some patients also show neuropsychiatric dysfunctions and psychiatric disorders, including anxiety, obsessive-compulsive disorders and tic disorders. In contrast, the association with psychotic symptoms has been reported very rarely up to now (n=4, two case reports, one prospective and one retrospective study). We report on a 12-year-old girl with acute paranoid hallucinatory symptoms and choreiform movements. Whereas her paranoid-hallucinatory symptoms responded to antipsychotic therapy, the negative symptoms and choreiform movement patterns only disappeared during additional prednisolone treatment. After tapering prednisolone, her negative symptoms and the choreiform movements reappeared. Dysfunctions of the corpus striatum have been linked to the pathogenesis of schizophrenia. This striatal dysfunction may secondarily affect working memory and the prefrontal cortex, resulting in impaired cognitive flexibility. Choreiform movements in chorea minor are attributed to dysfunction of the basal ganglia based on post-streptococcal autoimmune-mediated mechanisms. Huntington's disease and Wilson's disease are movement disorders caused by basal-ganglia dysfunction and are also associated with psychotic symptoms. In the present case, the association of psychotic and choreiform symptoms might be caused by dysfunction of the basal ganglia. The negative symptoms may result from disturbances of the prefrontal cortex impaired by basal-ganglia dysfunction.

Familiality and molecular genetics of attention networks in ADHD.

Indices from a more elementary neuropsychological level might be useful in the search for genes for complex psychiatric disorders, such as ADHD. In this study we investigated systematically whether attentional performance as measured with the Attention Network Test (ANT) is suited for the identification of endophenotypes of ADHD. Attentional performance in affected sib pairs with ADHD (n = 181) was compared to unaffected control siblings (n = 121). Intrafamilial correlation patterns were calculated. In addition, linkage and association analyses were conducted between quantitative scores of attentional functions and dopamine receptor D4 (DRD4) and dopamine transporter (DAT1 or SLC6A3) gene variants. Only the executive attention network was significantly impaired in subjects with ADHD compared to controls (P < 0.05) and showed evidence for familiality in both affected and unaffected families. Linkage analyses revealed the highest LOD score for a severity score based on DSM-IV inattentive symptoms in the DAT1 chromosomal region (LOD score 2.6 at 15 cM). However, a SNP (rs6350) at the DAT1 locus showed a tendency for association with both alerting performance (P = 0.02) and executive attention (P = 0.01) although it did not survive alpha adjustment for multiple testing. No evidence was found for association of any of the investigated phenotypes with the VNTR in the DRD4. Thus, our data suggest that the quantitative behavioral ratings of inattentive symptoms might be more useful when searching for new genes associated with ADHD, however, among the ANT measures the executive attention network seems to be best suited for further endophenotype analyses.

Leptin-mediated neuroendocrine alterations in anorexia nervosa: somatic and behavioral implications.

Hypoleptinemia is a key endocrinological feature of anorexia nervosa (AN). Several symptoms in acute AN are related to the low circulating leptin levels including amenorrhea and semi-starvation-induced hyperactivity. The drop in leptin levels results from the loss of fat mass; once leptin levels fall below specific thresholds the hypothalamic-pituitary-gonadal and -thyroid axes are down-regulated; in contrast, the hypothalamic-pituitary-adrenal axis is up-regulated. Hypoleptinemia is the major signal underlying both somatic and behavioral adaptations to starvation. Because the mechanisms involved in this adaptation are similar in rodents and humans, rodent models can be used to investigate the relevant central pathways which underly the respective starvation-induced symptoms. During therapeutically induced weight gain, leptin levels can intermittently increase above normal concentrations. This hyperleptinemia could predispose to renewed weight loss.

[Neuropsychological performance in anorexia and bulimia nervosa]. / Neuropsychologische Befunde bei Anorexia und Bulimia nervosa im Kindes- und Jugendalter.

Anorexia nervosa and Bulimia nervosa are common chronic psychiatric diseases afflicting in particular female adolescents. During the acute phase of starvation a number of hormonal, neuropsychological and cerebral morphological changes occur. Some of these abnormalities are only partly reversible. Psychiatric comorbidities complicate the clinical picture and aggravate appropriate therapeutic interventions. The following review describes in detail the neuropsychological impairments in eating disorders, potential factors influencing cognitive performance, and resulting implications for clinical every day life.

Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone.

The aim of this study was to evaluate long-term weight gain associated with clozapine, olanzapine, and risperidone treatment and its clinical risk factors in children and adolescents. At four child and adolescent psychiatric departments, the weight and body mass index of initially hospitalized patients (aged 9.0-21.3 years) treated with clozapine (n = 15), olanzapine (n = 8), and risperidone (n = 10) were prospectively monitored for 45 weeks. Clinical risk factors (age, gender, baseline weight, dosage, drug-naivety) were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint. The absolute and percentage average weight gains were significantly higher for the olanzapine group (16.2 +/- 8.8 kg; 30.1 +/- 18.9%) than for the clozapine (9.5 +/- 10.4 kg; 14.8 +/- 15.8%) and the risperidone (7.2 +/- 5.3 kg; 11.5 +/- 6.0%) groups. Olanzapine is associated with extreme long-term weight gain in children and adolescents that, in addition, is much higher than that expected in adults. Clozapine and risperidone are associated with a less marked weight gain in children and adolescents but also much higher than that expected in adults. These differences may affect compliance with medication and health risk.

Serum levels of S100B are decreased in chronic starvation and normalize with weight gain.

S100B protein is mainly synthesized in glial cells and modulates the balance between cell proliferation and differentiation in neurons and glial cells. However, S100B is not CNS-specific since its production was detected in numerous non-cerebral tissues e.g. adipocytes. In this study we investigated the influence of chronic fasting and subsequent weight gain on serum levels of S100B in patients with anorexia nervosa. We found that nutritional status was an important factor influencing serum levels of S100B.

High prevalence of increased trisialotransferrin concentrations in patients with anorexia nervosa: implications for determination of carbohydrate-deficient transferrin.

BACKGROUND: Carbohydrate-deficient transferrin (asialo-+monosialo-+disialotransferrin, CDT) is currently the most specific laboratory marker of chronic alcohol abuse. We tested whether previous findings of false-positive CDT results for anorexia nervosa patients have been due to invalid CDT analysis methods or anorexia nervosa by itself. METHODS: Serum CDT from 49 anorexia nervosa patients, 14 bulimia nervosa patients and 22 healthy controls (all adolescent, female and age-matched) was determined in a retrospective study by HPLC (Clin-Rep-CDT-in-serum-online, cut-off > or =1.8%, Recipe), by capillary electrophoresis (Capillarys-CDT, cut-off > or =1.3%, Sebia) and (due to limited surplus serum volume for a subset of 18 anorexia nervosa patients with increased trisialotransferrin detected by HPLC) by immunoassay based on anion-exchange CDT and non-CDT fractionation (%CDT-TIA, cut-off > or =2.6% CDT, Bio-Rad). RESULTS: HPLC and capillary electrophoresis: No false-positive CDT results were obtained. Asialo- and monosialotransferrin were not detected and disialotransferrin (CDT) was in each case clearly below the test-specific cut-offs. Trisialotransferrin (a non-CDT isoform) was increased (cut-off > or =5.0% for HPLC) in 33 anorexia patients, 2 bulimia patients and 2 controls. %CDT-TIA: 8 false-positive CDT results of > or =2.6% out of the 18 samples tested (CDT-range/mean/median 2.6-4.6/3.2/2.8%). CONCLUSIONS: Anorexia nervosa does not cause by itself increased CDT results. False-positive CDT values from the past are most likely due to an incomplete separation of trisialotransferrin from CDT and thus overdetermination of CDT. Immunological CDT testing without confirmatory analysis by HPLC or CE is no longer acceptable.

Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics.

OBJECTIVE: The aim of this study was to improve and evaluate the practibility of a method for the assessment of drug-associated side effects, and we implemented a clinical drug monitoring for atypical neuroleptics. METHODS: Side effects of initially hospitalized patients treated with clozapine (n = 16), olanzapine (n = 16), and risperidone (n = 19) were prospectively monitored on a weekly basis for the first 3 weeks. In the case of stable medication, measurements of all variables were made every 4 weeks or upon discharge. We used the Dosage Record Treatment Emergent Symptom Scale (DOTES) in a supplemented version to measure the presence and severity of side effects. RESULTS: Drowsiness and decreased motor activity were common, especially in the first 2 weeks. Orthostatic hypotension, increased salivation, constipation, and nasal congestion were seen in more than 30% to 60% of patients treated with clozapine and were less common in adolescents treated with olanzapine and risperidone. Rigidity, tremor, and dystonia were seen in 5% to 15% of patients treated with risperidone and olanzapine. The average weight gain after 6 weeks of treatment with the atypical neuroleptics was significantly higher for the olanzapine group (4.6 +/- 1.9 kg) than for the risperidone (2.8 +/- 1.3 kg) and clozapine (2.5 +/- 2.9 kg) groups. CONCLUSIONS: The authors' supplemented DOTES version is generally applicable to clinical use in mental health centers. The differences among the side effects of these three agents may affect compliance with medication and medical risks of metabolic syndrome, diabetes, and cardiovascular disease. More research on the short- and long-term safety of psychotropic drugs in children and adolescents, using standardized methods, should be considered.

Physical activity and restlessness correlate with leptin levels in patients with adolescent anorexia nervosa.

BACKGROUND: In food-restricted rats, leptin suppresses semistarvation-induced hyperactivity (SIH) and decreases exploratory behavior. Leptin ameliorates anxiety-related movement in ob/ob mice. In this study, we assessed the relationship between leptin and qualities of physical activity and restlessness in acute anorexia nervosa (AN). METHODS: Serum leptin, body mass index (BMI), % body fat, and self- and expert-ratings of qualities of physical activity and restlessness were assessed in 26 inpatients with acute AN. Accelerometry was also performed. Regression analyses were used to predict activity and restlessness using BMI, % body fat, and leptin levels as predictor variables. RESULTS: Leptin levels significantly contributed to the prediction of all measures of activity and restlessness. CONCLUSIONS: This is the first study linking hypoleptinemia in AN patients to subjective and objective measures of higher physical activity and motor and inner restlessness. Leptin may directly or indirectly (or both) influence behaviors and cognitions contributing to hyperactivity and motor restlessness.

The influence of sertraline on attention and verbal memory in children and adolescents with anxiety disorders.

This study investigated the cognitive side effects of a 6-week course of sertraline treatment on verbal memory and attention in children and adolescents. Children with various anxiety disorders (social phobia, generalized and separation anxiety disorder; n = 28), between 8 and 17 years of age, received a standardized, computerized neuropsychological assessment before treatment and another 6 weeks after treatment onset with sertraline (daily dose range between 25 and 100 mg). The patient group was compared to healthy controls (n = 28), who were matched for age and IQ and were also tested twice over a 6-week period. Sertraline did not have any negative effects on attentional performance (p > 0.05) but did increase response speed in a divided attention paradigm (p = 0.02). By contrast, performance of the interference part of a verbal memory task decreased (p = 0.05). The described results also remained stable over a 12-week period after treatment onset. Thus, the cognitive side effects of sertraline seemed to differ slightly between pediatric patients and those described in adult patient groups, should, therefore, be carefully assessed.

[Adolescent eating disorders]. / Essstörungen in der Adoleszenz.

Anorexia and Bulimia nervosa are common psychiatric disorders in adolescent girls. In discrepancy to ICD-10 and DSM-IV we would propose the 10th BMI percentile as weight criterium for anorexia nervosa. Both disorders have a high somatic and psychiatric comorbidity; the most severe complication at long term follow-up is osteoporosis. The most prevalent psychiatric disorders are affective disorders, anxiety and obsessive-compulsive disorder and substance abuse. There is undoubtedly a genetic predisposition and a range of general and personal environmental risk factors. Treatment of adolescent eating disorders mostly requires a multimodal approach which consists of several components, e.g. weight rehabilitation, nutritional counselling, individual and family psychotherapy, and treatment of comorbid psychiatric disorders.

Group psychoeducation for parents of adolescents with eating disorders: the Aachen program.

Family-based treatment in adolescents and individual psychoeducation in adults are accepted components in a multimodal treatment of eating disorders. However, only few studies have been conducted on the use of parent-based psychoeducation. This paper presents the structure and content, as well as a preliminary evaluation, of a group psychoeducation program for parents of adolescent patients with eating disorders. The program is limited to five 90-minute sessions and aimed at increasing the parents' understanding of the disorder and promoting high transparency with regard to our treatment principles. The vast majority of parents rated the group psychoeducation as helpful in coping with their child's disorder and would recommend others to take part in the program.

Improvement of nutritional status as assessed by multifrequency BIA during 15 weeks of refeeding in adolescent girls with anorexia nervosa.

In patients with anorexia nervosa (AN), an assessment of changes in body composition and nutritional status is crucial for adequate nutritional management during refeeding therapies. Phase-sensitive multifrequency bioelectrical impedance analysis (BIA) is an inexpensive and noninvasive technique with which to determine nutritional status and body composition. We investigated 21 female adolescents with AN (initial BMI 15.5 +/- 1.1 kg/m(2)) 4 times between wk 3 and 15 of inpatient refeeding and 19 normal-weight, age-matched female controls. From wk 3 to 15, BMI, fat mass, body cell mass (BCM), total body water (TBW), intracellular water (ICW) but not extracellular mass (ECM), and extracellular water (ECW) increased significantly. Reactance (Xc), phase angle (PhA), and the ECM/BCM index as parameters of nutritional status improved significantly in patients and no longer differed from controls in wk 15, although the BMI of patients was significantly lower than those of controls. Changes in the ECM/BCM index were due to accretion of BCM, which was associated with an increase of ICW. Multifrequency phase-sensitive BIA seems to be a promising tool for the assessment of changes in nutritional status and body composition in patients with AN. An individually determined and controlled hyperenergetic diet as part of a multidimensional, interdisciplinary treatment program for eating disorders seems to quickly improve the nutritional status of AN patients.

The contribution of anxiety and food restriction on physical activity levels in acute anorexia nervosa.

OBJECTIVE: Excessive exercise is present in 40%-80% of anorexia nervosa (AN) patients. Hyperactivity often plays a role in developing and maintaining AN and represents an obstacle to weight gain in refeeding. Interconnections among caloric restriction, psychopathology, and physical activity in humans with AN are poorly investigated. METHODS: Physical activity and food restriction during the last 3 months and status of body image/slimness ideal were assessed by the Structured Interview of Anorexia and Bulimia Nervosa (SIAB) in 30 adolescent patients with acute AN at admission to inpatient treatment. Anxiety, depression, and obsessive-compulsiveness were assessed with the Symptom Check-List-90-Revised (SCL-90-R). A regression model based on the independent variables body mass index, food reduction, body image/slimness ideal, anxiety, depression, and obsessive-compulsiveness was calculated to determine the relevant prediction variables of physical activity. RESULTS: The regression model explained 64% (R(2) = .64, p = .000) of the variance of physical activity. Only food restriction (p = .006) and anxiety (p = .004) contributed significantly to the variance. DISCUSSION: Our results indicate that anxiety symptoms and food restriction synergistically contribute to increased levels of physical activity in the acute phase of AN.

Elevated physical activity and low leptin levels co-occur in patients with anorexia nervosa.

Low leptin levels are an endocrinological hallmark of acute anorexia nervosa (AN); a subthreshold leptin secretion in adipocytes as a consequence of a reduced energy intake is presumed to be the major trigger of the adaptation of an organism to semistarvation. The aim of the current study is to define symptoms of AN that are potentially linked to low leptin levels. For this purpose, quantitative somatic and psychopathological variables were obtained in 61 inpatients with acute AN (study group 1) upon referral for inpatient treatment, and they were concomitantly blood sampled to allow determination of serum leptin levels. Correlations between these variables and logarithmic transformed (lg10) leptin levels were descriptively assessed. Apart from the well-known correlations between leptin levels and anthropometric measurements, the strongest correlation was observed between lg10 serum leptin levels and expert ratings of motor restlessness (r = -0.476; nominal P = 0.003) upon use of visual analog scales. We thus generated the hypothesis that physical activity levels in AN patients are related to serum leptin levels. This hypothesis was tested in an independent study group of 27 adolescent inpatients (study group 2) who were also assessed upon referral. Physical activity levels, which, in this study group, were assessed with the activity module of the expert rating form of the Structured Inventory for Anorexic and Bulimic Syndromes, were significantly correlated with lg10 leptin levels (r = -0.51; one-sided P = 0.006). A regression model based on the independent variables body mass index and lg10 leptin levels explained 37% of the variance of physical activity (R(2) = 0.37; P = 0.003); only the lg10 leptin levels contributed significantly to the variance (P = 0.003). Our results suggest that, similar to semistarvation-induced hyperactivity in rats, hypoleptinemia in patients with AN may be one important factor underlying the excessive physical activity.