Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride.

PURPOSE: Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. METHODS: Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. RESULTS: In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. CONCLUSIONS: This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).

Comorbid psychiatric disorders in female adolescents with first-onset anorexia nervosa.

OBJECTIVE: Patients with anorexia nervosa (AN) exhibit high rates of psychiatric comorbidity. To disentangle the effects of duration of illness on comorbid psychiatric symptoms, we investigated the rates of comorbid psychiatric disorders, suicidality and self-harm behaviour in adolescent patients with a first onset of AN. METHODS: In adolescent females (n = 148) with a first onset of AN, body mass index, psychiatric comorbidity (according to DSM-IV), depressive symptoms, suicidality and self-injurious behaviour were assessed. RESULTS: Seventy patients (47.3%) met the criteria for at least one comorbid psychiatric disorder. The binge-purging subtype was associated with increased rates of psychiatric comorbidity, suicidality and self-injurious behaviour. The severity of eating disorder-specific psychopathology influenced current psychiatric comorbidity and suicidal ideation. CONCLUSION: Prevalence rates of comorbid psychiatric disorders and suicidal ideation are considerably lower among adolescents with AN compared with adults. An early and careful assessment, along with adequate treatment of the eating disorder, might prevent the development of severe psychiatric comorbidities.

[Combination treatment in children and adolescent with obsessive compulsive disorders]. / Langzeitprognose verbessern. Kombinierte Therapie hilft kleinen Zwänglern.

Obsessive-compulsive disorders in childhood and adolescence include recurrent undesired (obsessive) thoughts and/or compulsive actions. Modern therapeutic strategies attempt to deal appropriately with the complexity of the condition through the use of multimodal concepts. These include behavioral therapy involving confrontation and the prevention of reactions, family-centered interventions and pharmacotherapy, which, in Germany, currently means the application of fluvoxamine or clomipramine.

[Agranulocytosis in a child with schizophrenia treated with clozapine--clinical findings and therapy, a case report]. / Agranulozytose bei einem Kind mit Schizophrenie unter Clozapintherapie--klinisches Bild und Therapie, eine Kasuistik.

OBJECTIVES: The indication of clozapine therapy is governed by special guidelines due to a 1%-3% risk of clozapine-induced agranulocytosis. Up to now there has never been a report of such a case in a child with schizophrenia. The case report presented here is concerned with the clinical features and the treatment of clozapine-induced agranulocytosis in childhood schizophrenia. METHODS: It deals with the treatment of a 12-yearold boy with a schizophrenic psychosis. The psychotic symptoms before treatment and during inpatient treatment are described. The procedures for the diagnosis and treatment of the clozapine-induced agranulocytosis are presented. RESULTS: Clozapine medication may induce agranulocytosis in the treatment of a child with a schizophrenic psychosis. The highly specific guidelines governing its use must be followed as well in the treatment of very early onset schizophrenia. An agranulocytosis may result following 15 weeks of clozapine medication. The treatment with granulocyte colony-stimulating factor seems to support normalization of the blood picture.

[Possible pathophysiologic, diagnostic and therapeutic implications of new findings on leptin secretion within the scope of anorexia nervosa]. / Mögliche pathophysiologische, diagnostische und therapeutische Implikationen neuer Befunde zur Leptinsekretion im Rahmen der Anorexia nervosa.

OBJECTIVES: Leptin is a hormone synthesized in adipocytes and secreted into the bloodstream. It plays an important role in the regulation of body weight, the adaptation to semi-starvation and in reproductive function. Hence, clinical studies pertaining to anorexia nervosa can serve to further elucidate the functions of this hormone in light of the unique features of this disorder. METHODS: Circulating concentrations of leptin are exceedingly low during the acute stage of anorexia nervosa. Which symptoms result from these diminished concentrations must be clarified. Furthermore, research is required to evaluate whether or not a too rapid weight gain might induce a physiological counter-regulation which would predispose to renewed loss of weight. RESULTS: This review summarizes findings to date pertaining to leptin secretion in patients with anorexia nervosa. In addition, possible diagnostic, pathophysiological and therapeutic implications are discussed.

[Personality disorders and psychiatric morbidity in adolescent anorexia nervosa. Results of a prospective 10 year catamnesis]. / Persönlichkeitsstörungen und psychiatrische Morbidität im Verlauf der adoleszenten Anorexia nervosa. Ergebnisse einer prospektiven 10-Jahres-Katamnese.

The aim of the current prospective study was to examine at regular intervals the course of the eating disorder symptoms and the psychiatric (co-) morbidity including personality disorders among juvenile patients who fulfilled the DSM-III-R criteria for anorexia nervosa. Ten years after release from hospital all 39 patients (100%), as well as a control group parallelized for age, gender and occupational status were personally followed-up. Symptoms of eating disorders were documented by means of the Standardized Interview for Anorexia and Bulimia nervosa (SIAB, Fichter et al., 1991), the Composite International Diagnostic Interview (WHO, 1990) was applied to diagnose psychiatric (co-) morbidity, and the Structured Clinical Interview (SKID-II, Spitzer et al., 1993) to assess personality disorders. Compared to the control group, at the time of follow-up a significantly greater number of patients were suffering from a psychiatric disorder, primarily an anxiety disorder, an affective disorder or from drug, respectively alcohol abuse. Personality disorders, chiefly anxious-avoidant types on the DSM-III-R were diagnosed among almost one-fourth of the patients. Our findings indicate that anorexia nervosa is not a developmental disorder limited to puberty but a disorder associated both cross-sectionally as well as longitudinally with other psychiatric disorders.

[Long-term course of childhood or adolescence onset obsessive-compulsive disorder: psychosocial adaptation in adulthood]. / Der Langzeitverlauf von Zwangsstörungen mit Beginn im Kindes- und Jugendalter: Psychosoziale Adaptation im Erwachsenenalter.

OBJECTIVE: The aim of the study was to investigate the long-term course of obsessive-compulsive disorder (OCD) with onset in childhood or adolescence. This presentation focuses on the social adjustment of the former patients in adulthood. METHODS: Fifty-five out of 116 patients with childhood OCD classified according to DSM-IV criteria were interviewed personally using structured interviews. Mean age at onset of OCD was 12.5 years, and mean follow-up time was 11.2 years. RESULTS: Despite the evident burden of mental disorder at the time of the follow-up, 76% led their own lives without being overly dependent upon their parents. 84% had no problems that impaired either school or their occupation. 73% were rated as maintaining satisfying social contacts, but only 54% were in a relationship at follow-up. CONCLUSIONS: In agreement with other studies we found an association between the level of psychosocial adjustment and the course of obsessive-compulsive symptoms. Summing up, social adjustment and psychosexual functioning seem to be more impaired than occupational functioning. The relatively good adjustment of our sample indicates that most patients have found a way of managing their lives, albeit still suffering from mental disorders.

Children and adolescents with obsessive-compulsive disorder and comorbid attention-deficit/hyperactivity disorder: preliminary results of a prospective follow-up study.

In the present study, we have investigated the influence of comorbid attention deficit hyperactivity disorder (ADHD) on early onset obsessive compulsive disorder (OCD). For that purpose, we compared 20 patients with "OCD with ADHD" and 20 randomly selected patients with "OCD without ADHD". "OCD with ADHD" patients tended to show an earlier age of OCD onset, a higher severity of symptoms and a higher persistence rate than OCD patients without ADHD. Both groups appear to develop different patterns of comorbid disorders.

Association and linkage of allelic variants of the dopamine transporter gene in ADHD.

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

[Long term prognosis in anorexia nervosa]. / Der Langzeitverlauf der Anorexia nervosa.

Follow-up studies using the same prognostic criteria have shown that about 48% of the patients had recovered at follow-up, while 28% revealed further difficulties with eating, weight and figure, and 24% remained anorectic. Our own study on 103 patients who underwent inpatient treatment, revealed unexpectedly good results: according to the criteria of Morgan and Russell, 72% (n = 58) showed a good prognosis, 11% (n = 9) a fair, and 17% (n = 14) an unfavourable prognosis. 3 patients had died during the follow-up interval. It was possible to predict the long-term outcome from weight recovery during inpatient treatment, more successfully in patients with favourable than unfavourable outcome. The best predictors were: time until weight stabilization, the ratio ideal weight/stabilized weight, and age at onset of the eating disorder.

[Current developments in the treatment of obsessive-compulsive disorders in children and adolescents]. / Aktuelle Entwicklungen in der Therapie von Zwangsstörungen im Kindes- und Jugendalter.

For the treatment of obsessive-compulsive disorders during childhood and adolescence, multidimensional therapeutical approaches have proven useful in clinical practice. First controlled studies have demonstrated the efficacy of both psychotherapeutical and pharmacological strategies. Exposure and response prevention are considered the most efficient psychotherapeutical methods. On the basis of the available data, the question of the pharmacological dose can not be answered definitely. For Clomipramin, the dose most probably is between 75 mg and 150 mg, where as for Fluoxetine and Fluvoxamine 20 mg-60 mg and 100 mg-250 mg respectively. However, it has to be kept in mind that sometimes improvement of symptoms is not seen after 8-10 weeks of treatment. Basically it can be stated that to date there is an urgent need for therapeutical studies of obsessive-compulsive disorders in the childhood and adolescence. Most relevant would be studies evaluating pharmacological treatment versus a placebo control groups and carefully designed controlled psychotherapeutical treatment studies as well studies comparing pharmacological and psychotherapeutical approaches.

The predictive value of depression in anorexia nervosa. Results of a seven-year follow-up study.

This study investigated the predictive value of depression in patients with adolescent anorexia nervosa. Thirty-four anorectic inpatients were assessed for DSM-III-R comorbid major depression at admission and at 3-year and 7-year follow-ups. Two standardized instruments, the Zung Self-rating Depression Scale and the Hamilton Depression Rating Scale, were applied to improve objective rating of depression. The findings suggest that severity of depressive symptoms at admission does not correlate with the severity of depression at follow-up, initial depressive psychopathology is not a valid prognostic indicator for the outcome of the eating disorder and at follow-up there is a highly significant relationship between depression and the outcome of anorexia nervosa. Patients with persisting eating disorder are also very likely to suffer from comorbid depression.

Body image distortion in Anorexia Nervosa--is there really a perceptual deficit?

Perceived and ideal body image were analysed in 36 inpatients with Anorexia Nervosa (AN) and 18 control patients (age 11-23 years). A computer-based image distortion technique allowed distortion of the whole body and of body parts. Subjects rated their own image. A body perception index (BPI) was calculated by dividing estimated dimension with real dimension. There was no general overestimation of body dimensions in AN patients in comparison to controls but AN patients more often under- or overestimated their body dimensions. Control patients showed a significant lower ideal BPI than AN patients, whose ideal body shape was similar to the observed body shape. Profile analyses of the body part estimation procedure revealed significant differences between groups in the ideal body shape at the body regions thigh, hip, waist and chest with control patients again showing a lower BPI.

Olanzapine in children and adolescents with chronic anorexia nervosa. A study of five cases.

Psychopathology in severely anorexic patients often seems to be of compulsive and delusional quality rendering therapeutic approaches extremely difficult. With conventional therapeutic regimes failing, administration of the novel antipsychotic olanzapine induced remarkable improvement in five cases reported here. Paranoid ideation concerning body image or weight gain decreased and sedative effects helped to reduce inner tensions and phobia with respect to food intake. Olanzapine, therefore, might represent an important therapeutic tool in anorexic patients who present the following characteristics: long-term history of anorexia nervosa mostly with several hospitalisations, missing perception of their severe state of illness, refusal of therapy, delusional quality of anorexic thinking, risk of discontinuation of therapy with life-threatening consequences.