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.

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.

[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.

Transmission disequilibrium studies in children and adolescents with obsessive-compulsive disorders pertaining to polymorphisms of genes of the serotonergic pathway.

Pharmacological and challenge study data showed an involvement of the serotonergic system in the development of obsessive-compulsive disorder (OCD). We studied transmission disequilibrium of polymorphisms in three candidate genes of the serotonergic pathway in 64 trios comprising patients with early onset OCD and both of their parents. Polymorphisms of the following genes were studied: tryptophan hydroxylase 1 (rs1800532), serotonin transporter (polymorphism in the promoter region; 5-HTTLPR) and the serotonin 1 B receptor (rs6296). This is, to our knowledge, one of the first family based association studies pertaining to children and adolescents with OCD. We did not detect transmission disequilibrium of the investigated polymorphisms in OCD. Hence, these polymorphisms do not play a major role in the genetic predisposition to early onset OCD.

5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders.

Positive association between obsessive compulsive disorder (OCD) and the A-allele of the 5-HT(2A)-receptor promoter polymorphism -1438G/A has recently been reported in adults. We performed an association analysis of this polymorphism in 55 children and adolescents with OCD and in 223 controls consisting of unrelated students. We detected statistically significant differences in genotype (P < 0.05) and allele frequencies (P < 0.05) between individuals with OCD and controls. In this, to our knowledge, first association study based on children and adolescents with OCD, we confirm an association of the A-allele of the 5-HT2A receptor gene with OCD.

[Personality disorders and psychiatric comorbidity in obsessive-compulsive disorder and anorexia nervosa]. / Persönlichkeitsstörungen und psychiatrische Komorbidität im Verlauf der Zwangsstörung und der Anorexia nervosa. Vergleich zweier 10-Jahres-Katamnesen.

The aim of this prospective longitudinal study was to examine the course of adolescent anorexia nervosa and obsessive-compulsive disorder (OCD) (fulfilling DSM-III-R criteria) to compare psychiatric comorbidity and personality disorders of both groups. Because anorexia nervosa patients are mainly female, we compared them only with female OCD patients. Ten years after discharge the whole sample (32 female patients; 100%) of a group of 39 (32 female; 7 male) anorexia nervosa patients could be reexamined personally. 25 (61%) female patients of a group of 116 patients (41 female; 75 male) with obsessive-compulsive disorder were also reexamined. The anorexia nervosa patients were interviewed using the Structured Interview for Anorexia and Bulimia nervosa (SIAB [39]) to assess eating disorder symptomatology. To examine comorbid psychiatric disorders we used the Composite International Diagnostic Interview, WHO [44] and SCID-II [45] for personality disorders. One fourth of the patients with anorexia nervosa (AN) and 20% of the patients with obsessive-compulsive disorder had a personality disorder according to DSM-III-R. Most of them were "Cluster C"-personality disorders (AN: 28%; OCD: 20%). In the group of the female OCD patients 8% schizoid, 4% schizotype and 12% paranoid personality disorders were observed. The most prevalent psychiatric disorders were anxiety (AN: 28%; OCD: 20%) and affective disorders (AN: 16%; OCD: 16%). Our results support the view that in the course of anorexia nervosa and in obsessive-compulsive disorder there is a high prevalence of psychiatric comorbidity and "Cluster C"-personality disorders according to DSM-III-R. These results might confirm a model of a high vulnerability of the serotonergic neurotransmitter system in patients with anorexia nervosa or OCD.

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.

[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.

Long-term outcome and prognosis of obsessive-compulsive disorder with onset in childhood or adolescence.

The aim of the catch-up follow-up study is to describe the long-term outcome of obsessive-compulsive disorder (OCD) with onset in childhood and adolescence. The psychiatric morbidity in adulthood including personality disorders was assessed and predictors in childhood for the course of obsessive-compulsive symptoms were examined. The total study group consisted of the entire patient population treated for OCD at our departments for child and adolescent psychiatry between 1980 and 1991. We reassessed 55 patients personally by way of structured interviews. The mean age of onset of OCD was 12.5 years and the mean follow-up time was 11.2 years. At the follow-up investigation 71% of the patients met the criteria for some form of psychiatric disorder, while 36% were still suffering from OCD. Of the patients with a present diagnosis of OCD 70% had at least one further clinical disorder (especially anxiety and affective disorders). The most frequent personality disorders diagnosed were obsessive-compulsive (25.5%), avoidant (21.8%), and paranoid (12.7%) personality disorders. In-patient treatment, terminating treatment against advice and tics in childhood or adolescence significantly correlated with more severe OC symptoms in adulthood.

[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.

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.

[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.

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.

Dermatologic findings in anorexia and bulimia nervosa of childhood and adolescence.

The cutaneous signs of anorexia nervosa (AN) and bulimia nervosa (BN) have been described previously in adult patients. For the first time, we present here dermatologic findings in children and adolescents suffering from eating disorders. Thirty consecutive young anorexic and bulimic inpatients (8 to 17 years of age, mean 15.1 years) underwent a standardized dermatologic examination. Patients were checked for abnormalities of the skin including atopic stigmata, dermographism, hair, nails, and oral cavity. Serum was obtained for hemoglobin, iron, zinc, GPT, thyroid, and sex-hormone levels. In 13 patients, the total serum IgE was determined, and a prick test was carried out with defined type I allergens. Findings in order of frequency included xerosis of the skin, white dermographism, diffuse hypertrichosis, acrocyanosis, scars, diffuse effluvium, artifacts, brittle nails, and onychophagia. Significant co-relations were found between the presence of hypertrichosis and the existence of amenorrhea or a body mass index of less than 16. In 22 patients a low T3 level was found. In summary, children and adolescents suffering from AN or BN show dermatologic features similar to those reported in older patients. Special findings in this age group are extensive lanugo hair and signs of autoaggressive behavior.

[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.