Helmut Remschmidt

Rates of psychiatric disorders in a clinical study group of adolescents with extreme obesity and in obese adolescents ascertained via a population based study

OBJECTIVE: To compare rates of DSM-IV psychiatric disorders between (1) a clinical study group of extremely obese adolescents and young adults, (2) gender-matched population-based obese controls and (3) a population-based control group of the same age range.DESIGN: Rates of psychiatric disorders were assessed in (1) the clinical study group of obese adolescents and (2) the population based sample of obese adolescents, and compared to (3) a large population-based control group using a standardized psychiatric interview.SUBJECTS: (1) Clinical study group: 30 female and 17 male extremely obese adolescents and young adults (age range: 15–21 y; mean BMI:42.4 kg/m2). (2) Thirty females and 17 males with the highest BMI (age range 15–21 y; mean BMI:29.8 kg/m2) of a population-based control group encompassing 1655 (805 males) adolescents and young adults. (3) The population based control group excluding the 30 females and 17 males with the highest BMI (n=1608; 788 males).MEASUREMENTS: Munich-Composite International Diagnostic Interview (M-CIDI) allowing for DSM-IV diagnoses.RESULTS: High rates of mood, anxiety, somatoform and eating disorders were detected in the clinical sample of obese adolescents which exceeded those observed in population controls (all P-values<0.01). Rates between population-based obese adolescents and young adults and population controls did not differ. In most patients the psychiatric disorders set in after onset of obesity. 57% and 35% of the female and male patients, respectively, reported eating binges with lack of control. However, less than one-half of these patients qualified for a DSM-IV diagnosis of an eating disorder.CONCLUSIONS: Extremely obese adolescents and young adults who seek long-term inpatient treatment have a high lifetime prevalence for affective, anxiety, somatoform and eating disorders. Because the mean BMI of the clinical study group was considerably higher than that of the obese population controls, we were not able to clarify whether the high rate of psychopathology in the study group was related to the extreme obesity or to their treatment-seeking behavior.

Auditory processing and dyslexia: evidence for a specific speech processing deficit

IN order to investigate the relationship between dyslexia and central auditory processing, 19 children with spelling disability and 15 controls at grades 5 and 6 were examined using a passive oddball paradigm. Mismatch negativity (MMN) was determined for tone and speech stimuli. While there were no group differences for the tone stimuli, we found a significantly attenuated MMN in the dyslexic group for the speech stimuli. This finding leads to the conclusion that dyslexics have a specific speech processing deficit at the sensory level which could be used to identify children at risk at an early age.

Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia.

We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the association--in particular, with the severe phenotype of dyslexia--was confirmed. Our expression data showed that DCDC2, which contains a doublecortin homology domain that is possibly involved in cortical neuron migration, is expressed in the fetal and adult CNS, which--together with the hypothesized protein function--is in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation.

Prospective 10‐year Follow‐up in Adolescent Anorexia Nervosa—Course, Outcome, Psychiatric Comorbidity, and Psychosocial Adaptation

The aim of the present study was to follow up the long-term course of adolescent-onset anorexia nervosa by repeated assessment, to analyze the association between the course of the eating disorder and psychiatric comorbidity, and to evaluate psychosocial outcome. The sample consisted of 39 inpatients who were reinvestigated 3, 7, and 10 years after discharge. The patients and 39 controls matched for age, gender, and occupational status were assessed with structured interviews on DSM-III-R eating disorders, additional axis I and axis II psychiatric disorders, and psychosocial functioning. Results showed that 69 % of the original subjects met the criteria for full recovery at the 10-year follow-up. One patient (3%) still exhibited the full syndrome of restrictive anorexia nervosa, two patients (5%) the full syndrome of bulimia nervosa. None of the patients had died. Of the subjects, 51% currently had an axis I psychiatric disorder and 23% met the full criteria for a personality disorder. Apart from the eating disorder, anxiety disorders and avoidant-dependent and obsessive-compulsive personality disorders were the most common psychiatric diagnoses. There was a significant association between psychiatric comorbidity and the outcome of the eating disorder and between outcome and psychosocial adaptation. With regard to psychiatric morbidity and psychosocial functioning, long-term recovered patients did not differ significantly from normal controls. It is concluded that in most patients adolescent anorexia nervosa takes a prolonged course, although it seems to be more favorable than in adult-onset forms. Those who achieve complete recovery from the eating disorder have a good chance of overcoming other psychiatric disorders and to adapt to social requirements.

Hyperactivity in patients with anorexia nervosa and in semistarved rats: evidence for a pivotal role of hypoleptinemia.

Patients with anorexia nervosa (AN) often show normal to elevated physical activity levels despite severe weight loss and emaciation. This is seemingly in contrast to the loss of energy and fatigue characteristic of other starvation states associated with weight loss. Despite the fact that historical accounts and clinical case studies of AN have regularly commented on the elevated activity levels, the behavior has become only recently the subject of systematic study. Because rodents and other species increase their activity upon food restriction leading to weight loss when given access to an activity wheel--a phenomenon referred to as activity-based anorexia or semi-starvation-induced hyperactivity (SIH)-it has been proposed that the hyperactivity in AN patients may reflect the mobilization of phylogenetically old pathways in individuals predisposed to AN. Exogeneous application of leptin in this animal model of AN has recently been shown to suppress completely the development of SIH. Hypoleptinemia, as a result of the food restriction, may represent the initial trigger for the increased activity levels in AN patients and in food-restricted rats. In the first and second parts of our review, we will summarize the relevant findings pertaining to hyperactivity in AN patients and in the rat model, respectively. We conclude with a synopsis and implications for future research.

Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration

Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is characterized by low weight, amenorrhea and specific psychopathological features. In this study plasma leptin concentrations were determined during inpatient treatment of 23 adolescent females with AN using a sensitive radioimmunoassay (RIA) and set into relationship to leptin levels of females matched for age, body mass index (BMI; kg m−2) and/or percent body fat. At referral patients had leptin concentrations well below the female controls. Weight gains led to steep increases of leptin levels which peaked at values well in excess of those observed in controls matched for BMI. In patients who reached the final treatment stage and who were followed-up after discharge, levels subsequently fluctuated and finally dropped into or below the control range. The low leptin levels at referral are likely to be involved in the pathogenesis of amenorrhea and the reduced metabolic state of acutely ill patients. Peak leptin levels reached after weight gain are possibly the cause of increased energy expenditure during this stage of the disorder.

Evidence for Linkage of Spelling Disability to Chromosome 15

We are extremely grateful to the families who participated in this work. We appreciate the assistance of Katarina Muller and Wolfgang Deimel (Marburg). This work was supported by Deutsche Forschungsgemeinschaft grants Re 471/9-1 and Schu 988/2-1//2-3.

Leptin suppresses semi-starvation induced hyperactivity in rats: implications for anorexia nervosa

Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa.

Use of percentiles for the body mass index in anorexia nervosa: Diagnostic, epidemiological, and therapeutic considerations

OBJECTIVE Percentiles for the body mass index (BMI) offer a possibility to epidemiologically assess the linear weight criterion of 85% average body weight commonly used for the diagnosis of anorexia nervosa. METHOD BMI values corresponding to 85% average body weight were calculated and assessed with percentiles derived from epidemiological studies in both the United States and Germany. The underweight range was characterized epidemiologically. RESULTS The weight criterion used for the diagnosis of anorexia nervosa corresponds to BMI values between the 5th and 10th centiles in both populations. In epidemiological terms the lowest BMI values in individuals aged 10 years and older occur during adolescence. In the general population BMI values <16 kg/m2 are rarely observed. Upon the use of higher BMI cutoffs in the underweight range females clearly predominate. The BMI increase associated with the 5th or 10th centile in the age range between 18 and 30 years is quite low suggesting that many underweight females in the general population gain only minimal weight during this age span. DISCUSSION The diagnostic, epidemiological, and therapeutic implications for anorexia nervosa are discussed.

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/ hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2s regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.