Because there are reports on cytotoxic and cytoprotective effects of antipsychotics, the aim of the present study was to evaluate the impacts of different concentrations (1.6—50 μg/mL) of atypical antipsychotics on the survival of human neuronal (neuroblastoma SH-SY5Y) and immune (monocytic U-937) cells and on energy metabolism (ATP level after the incubation with antipsychotics in the concentration of 25 μg/mL). Statistical analysis showed that incubation for 24 h with the antipsychotics quetiapine, risperidone, 9-hydroxyrisperidone and ziprasidone led to a significantly enhanced cell survival in both cell lines in the lower concentrations. Higher concentrations exerted in part cytotoxic effects with the exception of quetiapine, but therapeutically relevant concentrations of the drugs were not cytotoxic in our experiments. Measurement of ATP contents in the neuronal cell line showed significantly increased levels after a 24-h treatment with 25 μg/mL risperidone and 9-hydroxyrisperidone. The other substances produced no effects. Our results show that the antipsychotic substances under investigation exert concentration-dependent effects on cell survival in both cell lines examined.

There is evidence that reactive oxygen species (ROS) are involved in the pathophysiology of psychiatric disorders such as schizophrenia. Indirect biochemical alterations of ROS formation have been shown for patients treated with antipsychotics as well as for untreated patients. Only one study measured directly the ROS formation after treatment with antipsychotics by using electron spin resonance spectroscopy. The aim of the present examination was to demonstrate the effects of haloperidol, clozapine and olanzapine in concentrations of 18, 90 and 180 μg/mL on the formation of ROS in the whole blood of rats by using electron spin resonance spectroscopy after incubation for 30 min. To test the protective capacity of vitamin C we incubated the highest concentration of each drug with vitamin C (1 mM). Under all treatment conditions, olanzapine led to a significantly higher formation of ROS compared with control conditions, whereas in the cases of haloperidol and clozapine the two higher concentrations induced a significantly enhanced formation of ROS. Vitamin C reduced the ROS production of all drugs tested and for haloperidol and clozapine the level of significance was reached. Our study demonstrated that antipsychotics induce the formation of ROS in the whole blood of rats, which can be reduced by the application of vitamin C.

The oxidative and antioxidative properties of psychostimulants such as methylphenidate and amphetamine are discussed controversially. The aim of the present study was to evaluate the impact of psychostimulants and atomoxetine in different concentrations between 31.25 and 5000 ng/ml on the survival of human neuronal (neuroblastoma SH-SY5Y) and immune (monocytic U-937) cells and the impact of psychostimulants and atomoxetine in different concentrations between 500 and 5000 ng/ml on energy metabolism (adenosine triphosphate [ATP] content) in SH-SY5Y cells. Statistical analysis revealed that incubation for 24 h with amphetamine led to a significantly enhanced cell survival in both cell lines after treatment with various (32.5, 125, 250 and 1250 ng/ml) concentrations. Methylphenidate and atomoxetine induced a significantly enhanced cell survival at lower concentrations in the SH-SY5Y cell line, whereas in the U-937 cell line higher concentrations increased the cell survival. Incubation with the highest concentration of methylphenidate (5000 ng/ml) caused a significant reduction of cell survival in both cell types. Measurement of ATP contents in the neuronal cell line revealed no significant effects of the investigated compounds. Our results show that the examined substances exert concentration-dependent effects on cell survival in both applied cell lines.

Obsessive-compulsive disorder (OCD) is a disease of complex aetiology with a marked genetic component. Impact of the serotonergic system has been reported but the contribution of additional transmitter systems to the pathogenesis seems likely. The extraneuronal monoamine transporter, EMT (SLC22A3), is implicated in non-neuronal termination of noradrenergic signalling in the central nervous system and a candidate gene for a variety of neuropsychiatric disorders. We conducted a case-control study of 84 Caucasian children and adolescents with OCD according to DSM-IV criteria, and healthy adults by comprehensive sequencing of the EMT gene. Additionally, targeted genotype analysis was done with patient-parent trios. Known polymorphisms and frequent haplotypes were not associated with OCD in the present sample. Transmission disequilibrium test was negative for the presumptive cryptic splice site 1233G>A polymorphism. However, we identified two novel independent mutations exclusively in affected patients. A thus far unknown -106/107delAG mutation was detected in three male patients of unaffected parents but was not prevalent in 204 healthy subjects (p=0.024). In a luciferase reporter assay the mutant allele conferred increased promoter activity by 36%. Furthermore, we describe the first non-synonymous substitution in the EMT gene, Met370Ile, in a family of affected female members that co-segregated with the disease. The residue exhibits a high degree of inter-species conservation. Heterologous expression of mutant cDNA revealed a 40% decline of transport capacity for norepinephrine. Rare mutations in the EMT gene suggest a causative or modulating role in genetic subtypes of OCD.

Our study investigated premorbid functioning, course, and outcome in early-onset schizophrenia. All inpatients with DSM-III-R diagnoses of schizophrenia (n = 101) consecutively admitted between 1983 and 1988 to the Department of Child and Adolescent Psychiatry at the University of Marburg in Germany were included. To assess premorbid adaptation and precursor symptoms, we administered the Instrument for the Retrospective Assessment of the Onset of Schizophrenia, which we modified to assess children and adolescents. Symptomatology was measured by the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, and the Brief Psychiatric Rating Scale. In addition, the Global Assessment of Functioning was applied. Followup data for 81 patients (80.2%) were available. The mean duration of schizophrenia at followup was 9.5 +/- 2.2 years. Assessment of the highest level of adaptive functioning revealed very good or good outcome in 19.8 percent of the patients, fair or poor outcome in 38.2 percent, and very poor outcome and gross impairment in 42.0 percent. Premorbid adjustment was the best predictor of outcome in our schizophrenia sample. A poor prognosis was found in patients with premorbid developmental delays and those who were introverted and withdrawn before their psychotic state.

In 1998, Horvatli et al. (1998) observed a marked improvement in speech, eye contact, and attention in autistic children 5 weeks after treatment with secretin, during all endoscopic investigation. We investigated the in vivo effects of secretin oil extracellular amino acids in the rat brain. Studies were carried out on freely moving rats with microdialysis probes in the hippocampus. Amino acids were examined using tandem mass spectroscopy and HPLC/fluorometric detection. Following secretin injection intrapetitorieally (8.7 mu g/kg), as well as intracerebroventricularly (0.015 mu g/0.5 mu g/5 mu g), considerable increases in microdialysate gamma-aminobutyric acid (GABA) and glutamate levels, as well as a slight increase in microdiallysate aspartate levels were observed; other amino acids were not affected. The observed increased microdialysate concentrations of GABA and glutamate following secretin application may contribute to observed effects of secretin in autistic patients.

Zusammenfassung. In Deutschland ist Tod durch Suizid die zweithäufigste, in den USA die dritthäufigste Todesursache im Jugendalter. Als Risikofaktoren für vollendete Suizide werden impulsive Handlungsmuster, Selbstverletzungen, Depressionen, Sozialstörungen sowie frühkindlicher Missbrauch benannt. Für Patienten mit einer Borderline-Störung liegt die Suizidrate bei fünf bis zehn Prozent. Die Dialektisch-Behaviorale Therapie (DBT) wurde von Marsha Linehan zur Behandlung von Frauen mit Borderline-Persönlichkeitsstörungen (Diagnosestellung nach DSM-Kriterien) entwickelt, die entweder chronisch suizidal sind und/oder sich selber verletzen. Gegenüber der Standard-DBT wurde für die Arbeit mit Jugendlichen eine Reihe von Modifikationen vorgenommen, um die Behandlung der jugendlichen Zielgruppe anzupassen. Durch unsere Arbeitsgruppe wurde die Dialektisch-Behaviorale Therapie für Adoleszente (DBT-A) für den deutschen Sprachraum überarbeitet und angepasst. In der vorliegenden Arbeit werden die ersten Ergebnisse der DBT-A-Pilotstudie mit zwölf Jugendlichen vorgestellt. Die Ergebnisse sind sehr vielversprechend.

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).

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.

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.

Clozapin hat sich auch im Jugendalter als wirksame und klinisch gut praktikable Medikation bei schizophrenen Erkrankungen erwiesen. Seit Beginn der achtziger Jahre haben wir uns klinisch und wissenschaftlich mit dieser Substanz beschäftigt. In unserer ersten Publikation (Siefen u. Remschmidt 1986) konnten wir bei über der Hälfte der Patienten eine deutliche Besserung oder ein Schwinden der meisten noch bestehenden psychopathologischen Symptome bei 21 schizophrenen Jugendlichen feststellen. Die Indikation für die Umstellung von einem konventionellen Neuroleptikum auf Clozapin waren damals entweder ungenügendes Ansprechen auf andere Neuroleptika, drohende Chronifizierung der psychotischen Symptomatik oder ausgeprägte extrapyramidale Begleitwirkungen. Wir kamen seinerzeit zu dem Schluss, dass Clozapin eine hilfreiche Ergänzung der medikamentösen Behandlung schizophrener Störungen im Kindes- und Jugendalter darstellt. Dies wurde mittlerweile durch eine Reihe von Studien bestätigt (Tabelle 1.1). In der Zwischenzeit haben wir weitere Untersuchungen durchgeführt, die in Tabelle 1.2 wiedergegeben sind.

Gewichtszunahmen unter neuroleptischer Medikation sind jedem Kliniker bekannt. Mit der Erhebung einer Gewichtsanamnese und der epidemiologischen Einordnung eines gemessenen Körpergewichts bei schizophrenen Patienten sind die behandelnden Ärzte jedoch bislang wenig vertraut. Die Veränderungen vollziehen sich im Verlauf von längeren Zeitabschnitten, so daß sie im Rahmen von kurzen stationären Behandlungen kaum bemerkt werden. Eine registrierte Gewichtszunahme von einigen Kilogramm wird vielfach als „harmlose“ Nebenwirkung der Pharmakotherapie billigend in Kauf genommen. Einige Monate später kann die Gewichtszunahme 20 Kilogramm und mehr betragen. Der Patient ist dann einer psychosozialen Doppelbelastung ausgesetzt; neben der Stigmatisierung durch die Schizophrenie kommt die einer Adipositas hinzu.

Weight gain is a major side-effect of treatment with clozapine, In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment, Serum clozapine levels and levels of its metabolites were simultaneously assessed, Alterations of body weight and body composition were determined, During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001), During the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. The maximal relative increase over baseline was 536%, Low doses of clozapine were sufficient to induce this effect. Within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. Based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.

The purpose of the present study was to assess the relationship between plasma monoamine levels and changes in psychopathology in a sample of children and adolescents with schizophrenia (DSM-III-R criteria) during conventional neuroleptic therapy and during short-term treatment with clozapine. After failing on conventional neuroleptics in open-labeled 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 non-responders (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 32.2-90.3 pg/ml; non-responders ranging from 92.5-473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of methoxyhydroxyphenylglycol (MHPG) and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic.

Objectives: The purpose of this study was to assess the relationships between neuroleptic medication, biogenic amines and symptomatology in a sample of adolescents with schizophrenia (ICD-IO critria).Method: Psychopathological symptoms were rated weekly by means of standard rating scales (BPRS, SANS, SAPS), parallel to weekly blood samplings for measurement of biogenic amines and serum levels of clozapine. These measures were obtained for the 6 weeks of conventional neuroleptic treatment and the subsequent 6-week open-label clozapine trial.Results: Serum levels of serotonin and plasma norepinephrine were significantly higher during treatment with clozapine than during preteatment with typical neuroleptics. A comparison of the plasma norepinephrine levels in responders (n = 7) and non-responders (n = 8) to those of clozapine revealed that response to clozapine can be predicted on the basis of the epinephrine levels prior to initiation of clozapine treatment. Additionally, plasma concentrations of methoxyhydroxyphenylglycol (MHPG) and epinephrine were both increased in clozapine responders in comparison to the levels measured during pretreatment with typical neuroleptics. Finally, our results demonstrate that depressive symptomatology prior to initiation of clozapine treatment is also predictive of response to this atypical neuroleptic. schizophrenia.

The 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.

This study explored the hypothesis that body weight is reduced in male children and adolescents with schizoid personality disorder or Asperger's disorder. The body weights of 33 consecutively admitted male subjects with one of these disorders were retrospectively assessed with percentiles for the body mass index (BMI). The mean percentile (±SD) for the BMI was 31.6±27.6 and differed significantly from the expected value of 50 (P < 0.001). Ten subjects had a BMI of ≤10th age percentile. Post hoc comparisons revealed that BMI percentiles were (a) reduced to a similar extent in patients with schizoid personality disorder and Asperger's disorder and (b) reduced to a greater extent in patients with abnormal eating behaviour. During childhood and adolescence both diagnoses are associated with an increased risk of being underweight. Population‐based BMI percentiles are useful for detecting associations between specific psychopathological syndromes and body weight.