Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND: Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD: This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS: A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS: This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice.

INTRODUCTION: Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. METHODS: Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. RESULTS: 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4-10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). CONCLUSION: Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings.

Effects of Prodromal Stage and Untreated Psychosis on Subsequent Psychopathology of Schizophrenia: A Path Analysis.

BACKGROUND: To examine psychopathology present under prolonged antipsychotic treatment in schizophrenia and to analyse their relationship to both the duration of the prodromal stage (DPS; time between onset of first unspecific psychological symptoms and first schizophrenic symptoms) and the duration of untreated psychosis (DUP; time between the onset of psychosis and the initiation of antipsychotic treatment). METHODS: The psychopathology of 93 patients was assessed cross-sectionally using the Scales for the Assessment of Negative and Positive Symptoms and the Brief Psychiatric Rating Scale. DPS and DUP were assessed by means of the patient records and the Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and Other Psychoses. A path analysis using maximum likelihood estimation was conducted with the program Analysis of Moment Structures for Windows. RESULTS: The resulting path model indicated that DPS was predictive for a more severe negative symptomatology in schizophrenia, whereas DUP was associated with a more severe positive symptomatology in the long-term. Furthermore, DUP showed an inverse correlation with the age of the patients at the onset of both first unspecific psychological symptoms and first schizophrenic symptoms. CONCLUSION: A long prodromal stage suggests an increased risk of a long-term progression with negative symptoms in schizophrenia, whereas a delayed start of antipsychotic treatment could lead to an increased manifestation and severity of positive symptoms in the long term. These results underline the need to shorten the duration of the prodrome by an early detection and adequate intervention in patients with increased risk to develop psychosis.

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder.

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins-as crucial moderators of neuroplasticity-impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = -2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η (2) = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.

Early-onset schizophrenia.

The available study findings on the course and outcome of schizophrenia beginning in childhood or adolescence can be summarized as follows. (1) Schizophrenic psychoses that arise before the age of 13 have a very poor prognosis. The disease usually continues to progress in adolescence and adulthood. It can be diagnosed with the same criteria that are used for adults. (2) Patients whose disease is of acute onset, with productive schizophrenic manifestations such as hallucinations and delusions (positive manifestations), have a better prognosis than those whose disease begins insidiously and takes an unfavorable course, with depressive states and continually worsening impairment of cognitive function. (3) The patient's premorbid personality plays a major role. Patients who were described as socially active, intelligent, and integrated children and adolescents before they became ill have a better prognosis than those who were intellectually impaired, timid, introverted and uncommunicative before they became ill. (4) The prognosis seems to be better for patients who have no family history of schizophrenia, those whose families cooperate well, and those whose condition improves rapidly during inpatient treatment. (5) The few available studies on the course and outcome of schizophrenia beginning in childhood and early adolescence confirm that they are much worse than in adult-onset schizophrenia. (6) A 42-year longitudinal study of patients with childhood-onset schizophrenia revealed their suicide rate to be higher than that of patients with adult-onset schizophrenia. No further longitudinal studies are available to confirm this finding.

Subjective and biological weight-related parameters in adolescents and young adults with schizophrenia spectrum disorder under clozapine or olanzapine treatment.

OBJECTIVE: Administration of atypical antipsychotics often induces significant weight gain and metabolic changes. Little is known about subjective weight-related parameters in adolescent patients. Therefore, this cross-sectional, explorative study aimed to assess these parameters and their relationship with biological weight-related parameters. METHOD: 74 patients (mean age: 19.9 [SD ± 2.3] years; 66.2% male) with schizophrenia under clozapine or olanzapine treatment were examined. Subjective well-being, eating behavior, body perception and social functioning were assessed, using the Three-Factor-Eating-Questionnaire, FKB-20 Body Perception Questionnaire, Subjective Well-being under Neuroleptics, Short Form and Global Assessment of Functioning. Patients' biological weight-related parameters were measured as well. Gender differences as well as associations between subjective and biological weight-related parameters were evaluated. RESULTS: Female patients reported significantly worse negative body appraisal and physical functioning than males. An elevated BMI was associated with impaired physical functioning in females and with negative body appraisal and hunger in males. CONCLUSIONS: In our sample of young patients with schizophrenia unter treatment with atypical antipsychotics, an elevated BMI was associated with impaired physical functioning and negative body appraisal, respectively. Bearing in mind the high risk of obesity in this population, the mentioned impairments should be accounted for, especially in terms of compliance and quality of life.

Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course.

OBJECTIVE: To explore the impact of premorbid and baseline body mass indices (BMIs) as well as BMI of patient's parents and associated variables on the prediction of antipsychotic-induced body weight gain. METHODS: Retrospective/cross-sectional data of 65 patients receiving clozapine, olanzapine and/or risperidone were assessed according to a systematic categorization of the long-term (7.3+/-9.2 years) weight course and evaluated using descriptive, explorative correlation and regression analyses. RESULTS: Increased values of parents' BMI (p=0.041) and patients' BMI at premorbid stage (p=0.039) and prior to first antipsychotic treatment (p=0.032) as well as female gender (p=0.012), younger age (p=0.005) and non-smoking (p=0.047) have the most predictive value on body weight gain under antipsychotic treatment including pre-treatment with typical antipsychotics. Weight gain under atypical antipsychotics (pre-treatment excluded) is predicted by an increased premorbid BMI (p=0.019). Conversely, a low BMI prior to first antipsychotic treatment predicts a higher acceleration of BMI change (p=0.008) in vulnerable individuals, but not total BMI change itself. Furthermore, a diagnosis of a schizophrenia spectrum disorder showed a trend towards the prediction of an increased atypical DeltaBMI (p=0.067), possibly due to a longer treatment duration with atypical antipsychotics (p<0.001). DISCUSSION: The study indicates increased parents' BMI and patients' premorbid BMI, female gender, younger age and - as a trend - the diagnosis of a schizophrenia spectrum disorder to be predictors for antipsychotic-induced body weight gain involving atypical antipsychotics. Data contribute to the assumption of a strong impact of predispositional factors on weight gain, besides treatment-related factors.

A prospective study of body weight and serum leptin levels in patients treated with topiramate.

OBJECTIVES: We prospectively studied 26 (10 women) patients (age, 37.4 +/- 10.3 years) with different types of refractory focal epilepsy who received topiramate as adjunctive treatment. METHODS: Body mass indices (BMI, kg/m2) and serum leptin levels (SLL) were investigated at baseline (n = 26) and 9.5 +/- 2.9 (T1; n = 21) and 25.0 +/- 3.5 (T2; n = 18) weeks after initiation of topiramate. RESULTS: We found significant reductions in BMI (T1, -0.4 +/- 0.7; T2, -1.3 +/- 2.1 kg/m2) but not in SLL, although a tendency for reduced SLL was observed for women. Serum leptin level changes were mostly within the range between fifth and 95th sex-specific BMI-adjusted reference percentiles. Significant inverse correlations were found between baseline values and changes in both BMI (T2; r = -0.76; P < 0.001) and SLL (T2; r = -0.65; P = 0.003). Patients with BMI of 30.0 kg/m2 or greater showed the highest weight loss at T2 (-4.8 +/- 3.2 kg/m2). CONCLUSIONS: Our findings do not provide evidence for a direct causal involvement of leptin in topiramate-related weight loss.

Large variability of aripiprazole and dehydroaripiprazole serum concentrations in adolescent patients with schizophrenia.

Aripiprazole is a fairly new atypical antipsychotic substance. It acts as a partial D2- and 5-HT1A-agonist and as a 5-HT2A-antagonist. To date, there are few data concerning the dose-serum concentration relationship in children and adolescent psychiatric patients. Also, there are only few data on the influence of age, sex, body mass index, smoking behavior, and comedication on aripiprazole serum concentrations. In 33 consecutively admitted patients of a child and adolescent psychiatric hospital [age (mean +/- standard deviation) 18.7 +/- 1.7 years (range, 13.5-21.6 years)], 117 steady-state serum concentrations (repeated samples from individuals) of aripiprazole and its metabolite dehydroaripiprazole were assessed using high-performance liquid chromatography. The aripiprazole (mean +/- standard deviation) daily dose was 12.9 +/- 6.4 mg (range, 5-30 mg); the aripiprazole serum concentration was 142.0 +/- 122.7 ng/mL (range, 40.0-648.3 ng/mL; interquartile range, 74.0-167.0 ng/mL). The mean dehydroaripiprazole serum concentration was 51.6 +/- 22.3 ng/mL (range, 30.0-111.6 ng/mL; interquartile range, 34.3-62.1 ng/mL). There was a positive correlation between oral dose and serum concentrations of aripiprazole (r = 0.548, P = 0.001) and dehydroaripiprazole (r = 0.740, P < 0.0005). Aripiprazole serum concentrations showed high inter- and intraindividual variability. Intraindividual variability was one- to 9.3-fold (dehydroaripiprazole: one- to 8.6-fold) and maximum interindividual variability 6.4-fold (dehydroaripiprazole: 6.8-fold). No significant influence was detected for age, sex, body mass index, comedication, and smoking on concentration-to-dose aripiprazole serum concentrations. Further studies are required to obtain data on the relationship between serum concentrations and resulting clinical effects.

Large intraindividual variability of olanzapine serum concentrations in adolescent patients.

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.

Relations between movement disorders and psychopathology under predominantly atypical antipsychotic treatment in adolescent patients with schizophrenia.

OBJECTIVE: To examine relations between movement disorders (MD) and psychopathological symptoms in an adolescent population with schizophrenia under treatment with predominantly atypical antipsychotics. METHOD: MD symptoms and psychopathology were cross-sectionally assessed in 93 patients (aged 19.6 +/- 2.2 years) using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS), Brief Psychiatric Rating Scale (BPRS) and the Schedule for Assessment of Negative/Positive Symptoms (SANS/SAPS). RESULTS: All patients with MD symptoms (n = 37; 39.8 %) showed pronounced global psychpathological signs (SANS/SAPS, BPRS: p = 0.026, p = 0.033, p = 0.001) with predominant anergia symptoms (p = 0.005) and inclinations toward higher anxiety- and depression-related symptoms (p = 0.051) as well as increased thought disturbance (p = 0.066). Both negative symptoms and anergia showed trends for positive correlations with tardive dyskinesia (p = 0.068; p = 0.065) as well as significant correlations with parkinsonism symptoms (p = 0.036; p = 0.023). Akathisia symptoms correlated significantly with hostile and suspicious symptoms (p = 0.013). A superfactor-analysis revealed four factors supporting the aforementioned results. CONCLUSION: MD symptoms and psychopathology are in some respects related to each other. Motor symptoms representing on the one hand trait characteristics of schizophrenia might additionally be triggered by antipsychotics and finally co-occur with more residual symptoms within a long-term treatment.

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.

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.

[A university department as a psychiatric service centre for children and adolescents]. / Eine Universitätsklinik als psychiatrisches Versorgungszentrum für Kinder und Jugendliche.

The article reports on a system of care for psychiatrically ill children and adolescents that has been designed, established and expanded since 1980 by a university department in a rural region. The department is responsible for the mental health care of three counties with altogether 807 000 inhabitants. The development of this system of care was due in great part to the model program of the German Federal Government for the reform of mental health care that comprised 14 model regions, out of which the region of Marburg and its surrounding counties was the only one with a focus on the situation of psychiatrically ill children and adolescents. With the aid of this model program, a comprehensive evaluation of existing psychiatric services was carried out and at the same time, new services for this clientele were established such as a mobile child and adolescent psychiatric service and a day hospital. A particular focus was laid on the development of a complete network of psychiatric services with manifold, and over the years well proven, cooperation measures. Finally, the quality of mental health care was significantly increased by a continuous evaluation of services and the implementation of two institutes for psychotherapeutic training. Several research initiatives in the field of social psychiatry have contributed to this amelioration and at the same time, to a successful integration of mental health care and research.

Prevalence of movement disorders in adolescent patients with schizophrenia and in relationship to predominantly atypical antipsychotic treatment.

OBJECTIVE: To examine prevalence of movement disorders (MDs) such as tardive dyskinesia (TD), parkinsonism or akathisia in an adolescent population with schizophrenia and in relationship to predominantly atypical antipsychotic treatment. METHOD: Ninety-three patients (aged 19.6+/-2.2 years) were ascertained in this cross-sectional/retrospective study. 76 patients (81.7%) received atypical, 10 (10.8%) typical antipsychotics and 7 (7.5%) combinations of atypical/typical antipsychotics. MD symptoms were assessed using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS). RESULTS: Movement disorder symptoms were found in 37 patients (39.8%) fulfilling strict/subthreshold criteria for TD (5.4/11.8%), parkinsonism (2.2/25.8%) or akathisia (1.1/11.8%), respectively. Patients treated with typical antipsychotics displayed a significantly higher EPS-score (P=0.036) and a tendency towards a higher BAS-score (P=0.061) compared to patients with atypical antipsychotics. Treatment durations with typical/atypical antipsychotics showed trends towards advantages of atypical antipsychotics with regard to parkinsonism/akathisia symptoms (P=0.061; P=0.054), but not with regard to TD symptoms (P=0.003), possibly due to confounding effects. CONCLUSION: Under treatment with atypical antipsychotics MD symptoms are less prevalent and less pronounced than under typical antipsychotics. We speculate that the finding of relatively high prevalence rates of subthreshold MD symptoms may be, at least partially, explained by previous or combined therapy with typical antipsychotics.

Olanzapine overdose in children and adolescents: two case reports and a review of the literature.

Although the atypical antipsychotic olanzapine is increasingly being used in child and adolescent psychiatry, reports of olanzapine overdose in this young population are scarce. We report on two cases of adolescents who attempted suicide with an overdose of olanzapine: (1) A 14-year-old female ingested 275 mg olanzapine, which produced the highest reported nonlethal serum level (1503 ng/mL) and caused somnolence, agitation (acutely), and extrapyramidal symptoms (EPS; after 54 hours) but no major clinical complications. The serum olanzapine level dropped to 129 ng/mL within 48 hours; and (2) a 17-year-old male ingested 400 mg olanzapine, the highest reported nonlethal dose of olanzapine in adolescents, which produced respiratory suppression requiring intubation and mechanical ventilation; he recovered after 3 days. Based on clinical monitoring and postmortem data, the 2 patients survived the ingestion of high doses of olanzapine. We also provide a review of the literature, encompassing all reported cases of olanzapine overdose in children and adolescents and discuss symptoms, diagnosis, and treatment options, based on pharmacokinetic and pharmacodynamic considerations.

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/m(2)) change under clozapine only (clozapine DeltaBMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total DeltaBMI) 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 DeltaBMI in monozygotic twins (intrapair difference 2.78+/-3.41 kg/m(2)) than in same-sex sibs (5.55+/-4.35 kg/m(2)), resulting in heritability estimates of h(2)=0.8 and A=0.45 (ACE twin model). However, intrapair differences in clozapine DeltaBMI were similar between twins (4.18+/-4.27 kg/m(2)) and sibs (4.68+/-4.88 kg/m(2)). 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 DeltaBMI than for clozapine DeltaBMI. 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.

Weight change in monozygotic twins treated with valproate.

OBJECTIVE: To evaluate whether genetic factors contribute to weight gain associated with valproate (VPA) therapy. RESEARCH METHODS AND PROCEDURES: We retrospectively and prospectively evaluated five pairs of monozygotic twins concordant for epilepsy and treated with VPA regarding weight course. RESULTS: In all twin pairs, both twins showed similar weight courses under therapy with VPA. DISCUSSION: These results suggest that genetic factors may have an influence on the weight change induced by VPA. Further studies are necessary to obtain heritability estimates regarding this effect of VPA therapy and to identify the relevant genes.

Clozapine: weight gain in a pair of monozygotic twins concordant for schizophrenia and mild mental retardation.

Clozapine is an atypical antipsychotic known to cause considerable weight gain. The extent to which genetic factors determine weight gain is unknown. Here we report on a pair of female monozygotic twins concordant for schizophrenia and mild mental retardation who were treated with clozapine over 5.5 years. One twin gained a total of 53.1 kg and had a weight of 107.5 kg (BMI=38.1 kg/m2) at the end of the observation period. The other twin gained a total of 48.2 kg and finally had a weight of 100.4 kg (BMI=33.8 kg/m2). Because both patients experienced considerable weight gain during treatment, our observation suggests that the antipsychotic-induced weight gain is under strong genetic control.

Lack of association between the -759C/T polymorphism of the 5-HT2C receptor gene and clozapine-induced weight gain among German schizophrenic individuals.

Weight gain is a major side effect of treatment with clozapine and other antipsychotics. Recent studies suggest an important role of the serotonin type 2C receptor gene (5-HT2CR) in antipsychotic-induced weight gain. However, investigations pertaining to a possible association between a -759C/T polymorphism (C allele) of the 5-HT2CR and weight gain induced by clozapine and/or other antipsychotics have yielded inconsistent results. We investigated the -759C/T polymorphism of the 5-HT2CR in relation to clozapine-induced change in body mass index (BMI) (kg/m) in 97 German patients with schizophrenia and found no association between the -759C allele and weight gain after 12 weeks of clozapine treatment. In addition, confounding effects of initial BMI, age, sex and duration of illness on change in BMI could not be detected by multiple linear regression analysis. Our data do not support an involvement of the -759C/T polymorphism of the 5-HT2CR in clozapine-induced weight gain in German patients with schizophrenia. Further pharmacogenetic studies pertaining to antipsychotic-induced weight gain are warranted.