Kristian Holtkamp

The role of leptin in anorexia nervosa: clinical implications.

Leptin is a hormone with pleiotropic functions affecting several tissues. Because leptin has a crucial role in the adaptation of an organism to semi-starvation, anorexia nervosa (AN) serves as a model disorder to elucidate the functional implications of hypoleptinaemia; vice versa, several symptoms in patients with this eating disorder are related to the low leptin levels, which are characteristic of acute AN. Weight gain in AN patients can induce relative hyperleptinaemia in comparison to controls matched for body mass index; circulating leptin concentrations in AN patients thus transverse from subnormal to supranormal levels within a few weeks. We review findings on leptin secretion in AN and focus on implications, particularly for the hypothalamus–pituitary–gonadal axis, bone mineral density and physical hyperactivity. Undoubtedly, the elucidation of leptins function as a trigger of diverse neuroendocrine adaptations to a restricted energy intake has substantially advanced our knowledge of the pathogenesis of distinct symptoms of AN, including amenorrhoea that represents one of the four diagnostic criteria. The fact that hypoleptinaemia can induce hyperactivity in a rat model for AN has led to a series of studies in AN patients, which support the notion that application of leptin to severely hyperactive patients might prove beneficial.

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.

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.

Depression, anxiety, and obsessionality in long-term recovered patients with adolescent-onset anorexia nervosa

Anorexia nervosa (AN) is frequently associated with symptoms of depression, anxiety, and obsessive-compulsive behavior which also develop secondary to semistarvation. It is less certain if these symptoms persist after recovery. A few studies have already reported on high prevalence rates of anxious, depressive, and obsessive features in long-term recovered patients with AN, but several of these so called “long-term” recovered patients had only maintained weight restoration for six to twelve months. The aim of this study was to determine whether depressive, anxious, and obsessive-compulsive symptoms persist in truly long-term recovered patients (BMI 20.3±2.5 kg/m2) who no longer had any eating disorder symptoms (including weight phobia) for at least 3 years. Seventeen subjects of an AN sample (n=39) previously described in a 10-year follow-up met our strict criteria of at least 3 years of complete recovery of AN. In comparison to 39 age-, sex-, and occupation-matched healthy subjects without a history of psychiatric or eating disorder, long-term recovered patients had higher levels of depressive (p=0.002), anxious (p=0.006), and obsessive-compulsive (p=0.015) features but did not differ with regard to psychiatric morbidity and psychosocial adaptation. In conclusion, depressive, anxious, and obsessive-compulsive symptoms may be personality traits in subjects with former adolescent anorexia nervosa.

High serum leptin levels subsequent to weight gain predict renewed weight loss in patients with anorexia nervosa

It has repeatedly been shown that high serum leptin levels at target weight ensue from therapeutically induced weight gain in patients with anorexia nervosa (AN). It was hypothesized that elevated leptin levels may be an important factor underlying the difficulties of maintaining the target-weight in AN patients after re-feeding. The aim of this study was to examine if serum leptin levels at discharge from inpatient treatment predict renewed weight loss within 2 months after discharge and upon a 1 yr follow-up. Univariate variance analysis (ANOVA) revealed that 60% (cor. R2=0.60, P=0.002) of the variance in the BMI standard deviation score (BMI-SDS) 2 months after discharge was explained by the model consisting of the independent variables lg10 leptin levels at discharge (P=0.019) and at admission (P=0.069) and BMI-SDS at admission (P=0.002) and delta BMI between admission and discharge (P=0.047). Similarly, 60% (cor. R2=0.60, P=0.005) of the variance in BMI-SDS 1 yr after discharge was explained by lg10 leptin levels at discharge (P=0.046) and at admission (P=0.052) and BMI-SDS at admission (P=0.008) and 2 months after discharge (P=0.007) and delta BMI between admission and discharge (P=0.933). Patients with a poor outcome after 1 yr (n=9, ANCOVA, group: descriptive P=0.041), but not recovered patients (n=9, P=0.649), had lg10 leptin levels at discharge higher than those of controls when adjusted for BMI and % body fat at discharge. In conclusion, high serum leptin levels at discharge from inpatient treatment may indicate a risk for renewed weight loss and an unfavorable 1 yr outcome in AN.

Weight gain associated with clozapine, olanzapine and risperidone in children and adolescents

Summary.The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

Reproductive function during weight gain in anorexia nervosa. Leptin represents a metabolic gate to gonadotropin secretion

Summary. The adipocyte hormone leptin plays an important part in the reproductive function and in energy homeostasis. Only single studies have addressed the relationship between leptin and the hypothalamus-pituitary-gonadal axis (HPG) in anorexia nervosa (AN). In the present study 18 female adolescents with AN were investigated during weight gain. Leptin, LH, FSH, fT3, BMI and body composition were measured in the 1st, 3rd, 7th and 11th week of inpatient treatment. 18 eumenorrheic age- and gender-matched controls were examined once during the early follicular phase of their menstrual cycle. Our results demonstrate a critical leptin level of 1.2 ng/ml for an increase of FSH and confirmed a leptin threshold level of 1.85 ng/ml for LH. It may be concluded that leptin represents a metabolic gate to gonadotropin secretion. Once this is exceeded other biological mechanisms seem to be important for the complete recovery of the reproductive function and the resumption of menses.

The effect of therapeutically induced weight gain on plasma leptin levels in patients with anorexia nervosa

Previously it was shown that hyperleptinemia ensues from the therapeutically induced weight gain in patients with anorexia nervosa (AN). However, not all studies have been able to confirm this finding. To further investigate leptin secretion during weight gain in AN and potential functional implications serum leptin levels, body mass index (BMI),% body fat, fT3, fT4 and TSH of 18 adolescent AN patients (BMI at admission: 14.4+/-1.2) were examined four times during 11 weeks of re-feeding and compared to 18 weight stable controls. Additionally, serum leptin levels, BMI and % body fat were determined in patients reaching target weight after 11-20 weeks (mean 14.3+/-3) of inpatient re-feeding. At admission patients showed lower lg10 leptin levels (P=0.000) and BMI (P=0.000) than controls. At target weight patients still had significantly lower BMI (P=0.000) and% body fat (P=0.000) than controls but lg10 leptin levels of patients were higher than those of controls when adjusted for BMI and% body fat (ANCOVA, group P=0.038). In patients, correlation coefficients between lg10 leptin levels and BMI increments increased during the 11 weeks of re-feeding. BMI,% body fat and fT3 levels were not significantly correlated to lg10 leptin levels in week 11, however, 53% of the variance of leptin levels (corrected R(2)=0.53, P=0.001) was explained by BMI increments between weeks 7 and 11 (P=0.001) and lg10 leptin level at admission (P=0.002). In conclusion, we confirmed weight gain induced hyperleptinemia in AN. Further research is required to assess if this phenomenon contributes to renewed weight loss.

Oculomotor inhibition in children with and without attention-deficit hyperactivity disorder (ADHD)

Summary.The aim of the present study was to distinguish between a general deficit in oculomotor control and a deficit restricted to inhibitory functions in children with attention deficit hyperactivity disorder (ADHD). In addition, we were interested in differentiating between a general inhibition deficit and deficient subfunctions of inhibition. We used a prosaccade task to measure general oculomotor abilities in 22 children with ADHD and in age- and gender-matched healthy controls. A fixation, an antisaccade and a countermanding saccade task were used to measure specific aspects of oculomotor inhibition. Two major results were obtained: First, our prosaccade task suggests similar saccadic response preparation and saccadic accuracy in the ADHD compared to the control children. Secondly, the fixation and the countermanding saccade task indicate deficits on measures of oculomotor inhibition in the ADHD group. While patients were specifically impaired in stopping an already initiated response or in suppressing exploratory saccades in a novel situation, inhibition of a prepotent response was not deficient. Our data thus indicate an underlying impairment in cognitive inhibition in ADHD that has been associated with prefrontal lobe functions. More specifically, as the anterior cingulate gyrus has been associated with the countermanding saccade task and group differences were most pronounced in this paradigm our data are in line with imaging data stressing the importance of this cortical structure in the pathophysiology of ADHD.

A 2-year prospective study of bone metabolism and bone mineral density in adolescents with anorexia nervosa

SummaryOsteopenia and osteoporosis are complications of adolescent anorexia nervosa (AN) and may result in a permanent deficit of bone mass in adulthood. It is still unclear if a complete catch-up in bone mineral density (BMD) is possible after weight rehabilitation in AN.Methods. We investigated bone formation (bAP, PICP), bone resorption (CTX) and BMD (lumbar spine, femoral neck) along with endocrinological parameters in 19 girls with AN (14.4 ± 1.6 years) and in 19 healthy controls for 2 years after inpatient re-feeding.Results. Re-feeding normalised bone formation activity in patients. The pattern of bone turnover in patients after 2 years was similar to the pattern healthy controls had shown 2 years before. BMD of patients was significantly lower than in controls and did not change throughout the entire study.Conclusions. Weight rehabilitation leads to prolonged normalization of bone turnover in adolescent AN. Since we could not observe a “catch up” effect in BMD of girls with AN in a 2-year follow-up, BMD of these patients needs to be carefully monitored until adulthood to detect early osteoporosis.