Christian Fleischhaker

Dialectical Behavioral Therapy for Adolescents (DBT-A): a clinical Trial for Patients with suicidal and self-injurious Behavior and Borderline Symptoms with a one-year Follow-up

BackgroundTo date, there are no empirically validated treatments of good quality for adolescents showing suicidality and non-suicidal self-injurious behavior. Risk factors for suicide are impulsive and non-suicidal self-injurious behavior, depression, conduct disorders and child abuse. Behind this background, we tested the main hypothesis of our study; that Dialectical Behavioral Therapy for Adolescents is an effective treatment for these patients.MethodsDialectical Behavioral Therapy (DBT) has been developed by Marsha Linehan - especially for the outpatient treatment of chronically non-suicidal patients diagnosed with borderline personality disorder. The modified version of DBT for Adolescents (DBT-A) from Rathus & Miller has been adapted for a 16-24 week outpatient treatment in the German-speaking area by our group. The efficacy of treatment was measured by a pre-/post- comparison and a one-year follow-up with the aid of standardized instruments (SCL-90-R, CBCL, YSR, ILC, CGI).ResultsIn the pilot study, 12 adolescents were treated. At the beginning of therapy, 83% of patients fulfilled five or more DSM-IV criteria for borderline personality disorder. From the beginning of therapy to one year after its end, the mean value of these diagnostic criteria decreased significantly from 5.8 to 2.75. 75% of patients were kept in therapy. For the behavioral domains according to the SCL-90-R and YSR, we have found effect sizes between 0.54 and 2.14.During treatment, non-suicidal self-injurious behavior reduced significantly. Before the start of therapy, 8 of 12 patients had attempted suicide at least once. There were neither suicidal attempts during treatment with DBT-A nor at the one-year follow-up.ConclusionsThe promising results suggest that the interventions were well accepted by the patients and their families, and were associated with improvement in multiple domains including suicidality, non-suicidal self-injurious behavior, emotion dysregulation and depression from the beginning of therapy to the one-year follow-up.

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive–compulsive disorder

Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.

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.

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.

Forty-two-years later: the outcome of childhood-onset schizophrenia

SummaryThis paper describes the long-term course of 76 patients who had been consecutively admitted to the Department of Child and Adolescent Psychiatry, Philipps University, between 1920 and 1961 with a suspected diagnosis of childhood-onset schizophrenia. By means of a consensus analysis of available data in accordance with ICD-10 criteria, the diagnosis of schizophrenia was confirmed in only 50% of the original sample (n = 38, childhood-onset schizophrenia group); whereas the rest of the sample were allotted other diagnoses (n = 38, non-schizophrenia group). A follow-up investigation was conducted, interviewing all available patients, if possible, or their first-degree relatives or doctors. In the childhood-onset schizophrenia group, age at onset (mean ± S.D.) was 12.7 ± 2.5 (range 5–14) years and age at follow-up was 55.0 ± 4.8 (range 42–62) years. The outcome of this group was poor. According to the Global Assessment Scale (GAS), only 16% had a good (GAS score 71–100) and 24% had a moderate (GAS score 41–70) outcome. In the 16 childhood-onset schizophrenia patients who could be personally investigated at follow-up, 10 (62.5%) displayed severe or moderate depressive symptoms according to the BPRS depressive score. The death rate (including suicide) was significantly higher in the schizophrenia group (n = 15; 39.5%) than in the non-schizophrenia group (n = 7; 18.4%). A comparison of the life-time diagnoses of the total sample (n = 76) at follow-up with the ICD-10 diagnoses made retrospectively revealed a diagnostic stability in 69 (91%) and a change of diagnosis in 7 (9%) cases, among them 4 who were originally diagnosed as having childhood-onset schizophrenia.

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

Summary.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.

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.

Dialektisch-Behaviorale Therapie für Adoleszente (DBT-A) - Eine Pilotstudie zur Therapie von Suizidalität, Parasuizidalität und selbstverletzenden Verhaltensweisen bei Patientinnen mit Symptomen einer Borderlinestörung

OBJECTIVES In Germany suicide ranks as the second leading cause of death in adolescents. Risk factors for suicide are impulsive and self-injurious behaviour, depression, and conduct disorder. The main hypothesis of our study is that Dialectical Behavior Therapy (DBT) for adolescents is an effective method of treatment for these patients. METHODS DBT was developed by Marsha Linehan specifically for the outpatient treatment of chronically parasuicidal female patients with a diagnosis of borderline personality disorder. Miller & Rathus modified DBT for use with adolescents (DBT-A). and our group adapted the DBT-A for use in an outpatient treatment setting in Germany. In a pre-post comparison, the efficacy of treatment was measured using standardized instruments (SCL-90-R, CBCL, YSR, ILK, CGI, etc.). RESULTS In a pilot study of 12 adolescents, we found effect sizes between 1.1 and 2.9. During treatment, self-injurious behaviour declined significantly. Prior to entering therapy, 8 of the 12 patients had attempted suicide at least once. During treatment according to DBT-A there were no suicide attempts. CONCLUSIONS These results are so promising that we are now planning a randomized, multi-centre study.

Brain-derived neurotrophic factor V66M polymorphism in childhood-onset obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is characterized by recurrent, intrusive, and disturbing thoughts, as well as by repetitive stereotypic behaviour. Insight into the senseless nature of the symptoms is generally preserved. Patients try, albeit usually unsuccessfully, to suppress the obsessive thoughts and compulsive behaviours. Acting out the stereotypic behaviours reduces the anxiety generated by the obsessions and compulsions (APA, 2000). In 60% of patients OCD develops before the age of 25 yr, and onset of disease can already occur in childhood (Flament et al., 1990). Familial loading is higher in early-onset OCD, indicating that genetic factors may be of greater importance in OCD with early onset (Pauls et al., 1995).

Blood biogenic amines during clozapine treatment of early-onset schizophrenia

SummaryThe aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14–22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 ± 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11–20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n=7) and nonresponders (n=8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.