Michael Haberhausen

Association between the insulin-induced gene 2 ( INSIG2 ) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003–0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs.

To assess the relative contribution of genetic factors in antipsychotic-induced weight gain, we explored the similarity in body mass index (BMI) (kg/m2) change under clozapine only (clozapine ΔBMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total ΔBMI) of five monozygotic twins in comparison with seven same-sex sibs. Twin and sib pairs were identified by a telephone screening of 786 office-based psychiatrists. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. We found greater similarity in total ΔBMI in monozygotic twins (intrapair difference 2.78±3.41 kg/m2) than in same-sex sibs (5.55±4.35 kg/m2), resulting in heritability estimates of h2=0.8 and A=0.45 (ACE twin model). However, intrapair differences in clozapine ΔBMI were similar between twins (4.18±4.27 kg/m2) and sibs (4.68±4.88 kg/m2). We hypothesize that the weight plateau achieved under clozapine is influenced by genetic factors. The weight gain achieved during pretreatment with other antipsychotics seems to limit clozapine-induced weight gain, thus presumably explaining why heritability/similarity in monozygotic twins in comparison with same-sex sibs is greater for total ΔBMI than for clozapine ΔBMI. An important caveat is that, owing to the sample size, the heritability estimates have a large standard error and thus have to be interpreted with caution.

Body weight gain induced by atypical antipsychotics: an extension of the monocygotic twin and sib pair study

Background and objective:  In our original study based on five monozygotic twin pairs and seven same‐sex sib pairs, we previously showed that genetic factors contribute to body weight gain induced by the atypical antipsychotic clozapine. We aim to study this further by including patients treated with the atypical antipsychotics olanzapine or risperidone as well as opposite‐sex sib pairs.

No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation.

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Clozapine/olanzapine-induced recurrence or deterioration of binge eating-related eating disorders

SummaryObjective. To explore the association between eating disorders (EDs) prior to the use of clozapine/olanzapine (pre-clozapine/olanzapine EDs) and after initiation of these antipsychotics (post-clozapine/olanzapine EDs).Method. Sixty-four consecutively admitted patients receiving clozapine/olanzapine were screened using the M-Composite International Diagnostic Interview (M-CIDI) to identify subjects with pre-clozapine/olanzapine EDs (DSM-IV criteria). We investigated post-clozapine/olanzapine EDs and binge eating behavior using the Questionnaire on Eating and Weight Patterns (QEWP) and used the Naranjo probability scale as objective causality assessment.Results. Post-clozapine/olanzapine EDs were significantly more frequent in patients with pre-clozapine/olanzapine EDs (5 of 6) when compared to patients without pre-clozapine/olanzapine EDs (4 of 58) [χ2 = 26.29; df = 1; p < 0.001] [odds ratio (OR) 67.5; 95% CI: 6.3–25.8]. According to the Naranjo probability scale, recurrence or deterioration of EDs in patients with prior EDs was definitely (n = 1) or probably (n = 4) related to the intake of clozapine/olanzapine.Conclusion. Clozapine/olanzapine may induce recurrence or deterioration of binge eating symptomatology or full-blown EDs in patients with prior EDs.

Large intraindividual variability of olanzapine serum concentrations in adolescent patients.

Abstract: Olanzapine (OLZ) is a widely used antipsychotic substance. Therapeutic drug monitoring (TDM) of OLZ is recommended but is based on known reference ranges derived from intraindividual and interindividual variability measurements. There have been few studies on the interindividual variability of OLZ serum concentrations in adolescents, and no data on intraindividual variability are available. This study explored the intraindividual variability of OLZ serum concentrations in 85 patients attending a child and adolescent psychiatric hospital (age at first assessment: mean ± SD, 16.7 ± 2.0; range, 10.3-20.6 years; 54 male, 31 female). A total of 577 steady-state OLZ serum concentrations (2 to 24 measurements per patient; mean, 6.8, and SD, ±5.4) were measured, using high-performance liquid chromatography (HPLC). Intraindividual variability of dose-corrected OLZ serum concentrations was 1.04- to 10.7-fold. The intraindividual variabilities of the metabolites OLZ N-desmethyl (DMO) and OLZ 2-hydroxymethyl (2OH) were 1.08- to 83.2-fold and 1.0- to 47-fold, respectively. Intraindividual variability of OLZ (DMO; 2OH) serum concentration accounted for 47% (89.8%, 74.9%) of total variance. OLZ daily dose, number of co-medications, body mass index (BMI), age, and post-dose interval had a significant influence on the intraindividual variability of dose-corrected OLZ serum concentrations (all P < 0.001). The serum concentrations of OLZ and OLZ metabolites in adolescents show high intraindividual variability, potentially limiting the value of TDM. It is recommended that repeated serum concentration measurements are made in individuals treated with OLZ, in order to obtain a more precise estimate of the intraindividual variability of serum concentrations.

Serum levels of olanzapine and its N-desmethyl and 2-hydroxymethyl metabolites in child and adolescent psychiatric disorders: effects of dose, diagnosis, age, sex, smoking, and comedication.

Abstract: The aim of this study was to assess dose-related steady-state serum concentrations of olanzapine (OLZ) and its metabolites N-desmethyl OLZ (DMO) and 2-hydroxymethyl OLZ (2-OH-OLZ) (assessed by high-performance liquid chromatography) in 122 child and adolescent psychiatric patients (age 16.9 ± 2.2, range, 10-21 years; 74 males, 48 females) with a variety of diagnoses: schizophrenia group (n = 80); nonschizophrenia group (n = 29); anorexia nervosa (AN) group (n = 13). Median OLZ serum concentrations were 32.7 (range, 1-118; all patients), 37.7 (2-115; schizophrenia group), and 18.7 (1-63, AN group) ng/mL. The median OLZ concentration-to-dose (C/D) ratio (n = 122) was 2.6, with 90% of the distribution between 0.8 and 5.5 (ng/mL)/(mg/d). OLZ concentration was significantly correlated with DMO (r = 0.567; P < 0.0005) but not with 2-OH-OLZ (r = 0.122; P = 0.188). Daily OLZ dose was correlated with OLZ concentration in all (r = 0.684; P < 0.0005), schizophrenic (r = 0.542; P < 0.0005), and AN (r = 0.805; P = 0.001) patients, respectively. Patients aged less than 16 years displayed similar C/D for OLZ (P = 0.58) but higher C/D for DMO (P = 0.003) than those 16 years or older. AN patients received lower median OLZ doses (7.5; 5-15 mg) than schizophrenic patients (12.5; 2.5-40 mg), even after correcting for body mass index (P = 0.02). OLZ dose did not differ (P = 0.088) between smokers and nonsmokers, but smokers showed lower C/D for OLZ than nonsmokers (P = 0.008). C/D for OLZ was 38% higher (P = 0.041) under comedication with selective serotonin reuptake inhibitors when compared with OLZ monotherapy. Multiple linear regression analysis revealed that 46% of the variation of OLZ concentration can be explained by dose, diagnosis, age, sex, smoking, and comedication. The data are compared with the literature, and the relevance of therapeutic antipsychotic drug monitoring in previously sparsely investigated subgroups, such as children and adolescents or patients with AN, is emphasized.

Time to Initiation of Clozapine Treatment in Children and Adolescents with Early-Onset Schizophrenia

Introduction: Early-onset schizophrenia (EOS) has a poor prognosis and is difficult to treat, which often leads to the initiation of clozapine treatment. Studies in adults have shown that the initiation of clozapine treatment is often delayed. There is a lack of studies concerning the initiation of clozapine in children and adolescents with EOS. The aim of this study was to investigate the time span from first EOS-related psychiatric hospitalization to clozapine initiation. Methods: We retrospectively studied a consecutive cohort of children and adolescents with EOS and first-time clozapine prescriptions from a tertiary care child and adolescent psychiatric center in Germany. Results: Clinical records with data on clozapine initiation were available for 112 patients (35.7% females, mean age: 15.2±1.6 years). The mean time from first EOS-related hospitalization to clozapine initiation was 1.1 (±1.0) years, with an average of 2.3 (±1.1) prior antipsychotic treatment episodes. Higher age and higher IQ predicted earlier clozapine initiation. At the time of clozapine initiation, 40.2% of patients received antipsychotic polypharmacy. Prior to clozapine, 33.9% of patients had received 3 or more antipsychotic treatment episodes. Discussion: In our study, clozapine treatment was initiated markedly earlier than in the few existing studies, which may partly be due to the expected poor prognosis of EOS. The significant portion of patients undergoing 3 or more antipsychotic trials or antipsychotic polypharmacy prior to clozapine may indicate a need for improved dissemination of knowledge on the effectiveness of clozapine in treatment-resistant schizophrenia in order to promote timely clozapine prescriptions in these cases.

Impact Factors und Publikationszeitspannen kinder- und jugendpsychiatrischer Journals

Zusammenfassung: Fragestellung: Der Impact Factor (IF) einer wissenschaftlichen Zeitschrift hat eine wichtige Bedeutung fur die Uberlegung eines Wissenschaftlers, seine Forschungsergebnisse dort zu publizieren. Ebenso ist die Publikationsspanne, d.h. die Zeit, die vom Einreichen eines Artikels bis zur endgultigen Publikation vergeht, fur den Autor von Interesse. In der vorliegenden Arbeit wird deshalb eine Ubersicht uber IF und Publikationsspannen deutscher und internationaler kinder- und jugendpsychiatrischer Zeitschriften gegeben. Methodik: Es wurde eine Datenbankrecherche in den Journal Citation Reports hinsichtlich IF und IF-Entwicklung der einschlagigen kinder- und jugendpsychiatrischen Zeitschriften 2002-2007 sowie eine Per-Hand-Auswertung dieser Zeitschriften hinsichtlich der Publikationsspannen fur das Jahr 2007 durchgefuhrt. Ergebnisse: Aktuell existieren neun kinder- und jugendpsychiatrische Fachzeitschriften, von denen acht uber einen IF verfugen. Die Spannbreite der IF bewegt sich von 0,419 (P...

Forschungsschwerpunkt Gewichtszunahme und Gewichtsregulation unter Neuroleptika

Gewichtsveranderungen unter Psychopharmaka sind seit Beginn des Einsatzes dieser Substanzen bekannt und etwa seit den 50er Jahren des vorigen Jahrhunderts Gegenstand systematischer Erforschung. Gewichtszunahmen unter neuroleptischer Therapie besitzen weitaus groere klinische Relevanz und sind auch wesentlich haufiger als Gewichtsabnahmen. Vor dem Hintergrund einer schizophrenen Psychose wird die Gewichtszunahme allerdings anfanglich kaum bemerkt oder als eher „harmlose“ Nebenwirkung billigend in Kauf genommen. Nach einigen Monaten jedoch kann sie 20 Kilogramm und mehr betragen, und der Patient tragt neben seiner Grunderkrankung die Last einer pharmakologisch induzierten Adipositas. Wahrend unter der Behandlung mit klassischen Neuroleptika besonders Nebenwirkungen des extrapyramidalmotorischen Systems hervorgerufen werden, stellt die Gewichtszunahme eine der haufigsten unerwunschten Wirkungen der neueren atypischen Neuroleptika dar. Die Gewichtszunahme wird durch den steigenden Einsatz der atypischen Substanzen und die gesundheitspolitische Fokussierung auf Adipositas zunehmend an Bedeutung gewinnen.