Frank M. Theisen

Spectrum of binge eating symptomatology in patients treated with clozapine and olanzapine.

Summary. The authors explored the binge eating symptomatology in 74 patients receiving clozapine (N = 57) or olanzapine (N = 17), and compared body mass index (BMI, kg/m2) and weight gain in patients with and without binge eating symptomatology. Subjects who screened positively for binge eating were interviewed using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP). Current BMIs were assessed cross-sectionally, BMIs at initiation of clozapine/olanzapine treatment retrospectively. Thirty-seven subjects (50%) screened positively. Taking clozapine and olanzapine together, 6/27 (22.2%) females and 3/47 (6.4%) males fulfilled criteria for binge eating disorder, 3/27 (11.1%) females and 2/47 (4.3%) males for bulimia nervosa. Patients who screened positively showed higher current BMIs (26.8 ± 3.9 vs. 24.7 ± 3.7 kg/m2) and higher BMI increments during clozapine/olanzapine treatment (3.9 ± 3.1 vs. 2.6 ± 3.4 kg/m2) than patients who screened negatively. We conclude that clozapine/olanzapine may induce binge eating and full blown eating disorders which may have predictive value for weight gain. For future research in this field we suggest a novel DSM-IV research classification “Medication-induced eating disorders”.

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/m2) 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.

Prevalence of obesity in adolescent and young adult patients with and without schizophrenia and in relationship to antipsychotic medication

The prevalence of obesity in inpatients of a German psychiatric rehabilitation center for adolescents and young adults (mean age 19.5 years) is assessed and set into relationship to diagnosis and medication regimen. In a cross-sectional naturalistic study body weights and heights of 151 inpatients, 109 of whom presented with ICD-10 schizophrenia spectrum disorders, were measured for the calculation of body mass indices (BMI, kg/m2); current medication regimen including the duration of treatment was assessed from medical records. BMIs were plotted into gender- and age-specific BMI-percentiles representative for the German population. Among the whole study population, obesity (BMI > or =90th percentile) was apparent in 44/98 (45%) of the male and in 31/53 (59%) of the female inpatients (overall: 50%). With respect to schizophrenia spectrum disorders, 36/70 (51%) males and 25/39 (64%) females (overall: 56%) were obese in contrast to 14/42 (33%) among the individuals without schizophrenia. Set into relationship to the treatment groups, the prevalence rates of obesity were 64% in patients treated with clozapine (n=69), 56% for other atypical antipsychotics (olanzapine, sulpiride, risperidone; n=27), 30% for classic antipsychotics (haloperidol, flupentixol, perazine; n=20) and 28% for the currently drug-free group (n=25). Together with other published findings in adults, these results suggest an increased prevalence of obesity among young patients with schizophrenia and especially among patients chronically treated with atypical antipsychotics.

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.

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.

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.

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.

Schizophrenia and related disorders in children and adolescents.

This paper reviews the concept and recent studies on childhood and adolescent psychoses with special reference to schizophrenia. After a short historical introduction, the definition, classification, and epidemiology of child- and adolescent-onset psychoses are described, pointing out that some early-onset psychotic states seem to be related to schizophrenia (such as infantile catatonia) and others not (such as desintegrative disorder). The frequency of childhood schizophrenia is less than 1 in 10,000 children, but there is a remarkable increase in frequency between 13 and 18 years of age. Currently, schizophrenia is diagnosed according to ICD-10 and DSM-IV criteria. The differential diagnosis includes autism, desintegrative disorder, multiplex complex developmental disorder (MCDD) respectively multiple developmental impairment (MDI), affective psychoses, Asperger syndrome, drug-induced psychosis and psychotic states caused by organic disorders. With regard to etiology, there is strong evidence for the importance of genetic factors and for neurointegrative deficits preceding the onset of the disorder. Treatment is based upon a multimodal approach including antipsychotic medication (mainly by atypical neuroleptics), psychotherapeutic measures, family-oriented measures, and specific measures of rehabilitation applied in about 30% of the patients after completion of inpatient treatment. The long-term course of childhood- and adolescent-onset schizophrenia is worse than in adulthood schizophrenia, and the patients with manifestation of the disorder below the age of 14 have a very poor prognosis.

A prospective study of serum ghrelin levels in patients treated with clozapine

Summary.We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.