Metabolic side effects of risperidone in early onset schizophrenia

Background. Atypical antipsychotics have a favourable risk/benefit profile in early onset schizophrenia (EOS). However, despite increasing use of psychotropic medication in children and adolescents, their endocrine and metabolic side-effects (weight gain, obesity, and related metabolic abnormalities such as hyperglycaemia and dyslipidemia) are of particular concern, especially within this paediatric population that appears to be at greater risk as compared with adults for antipsychotic-induced metabolic adverse effects. In addition to medication, many factors contribute to weigh gain in psychiatric patients, including sedentary lifestyle and poor diet. Excessive weigh gain has several deleterious effects in psychiatric patients, including stigmatization and further social withdrawal, and non compliance with medication. Furthermore, excessive corpulence may evolve to a metabolic syndrome with a high-risk state for future cardiovascular morbidity and mortality in adult age. Because youths are still developing at the time of psychotropic drug exposure, in a context of physiological changes in hormonal and endocrines levels and body composition, most reference values need to be adjusted for gender, age and growth charts. Hence, sex- and age-adjusted BMI percentiles and BMI Z scores are crucial to assess weight gain in children and adolescents. Literature findings. Obesity thresholds have been proposed to define "at risk" categories of patients. In recently issued guidelines, thresholds for antipsychotic-induced weight gain in adults have been set at a 5% increase or one point increase in BMI unit. To date, no definition has reached a consensus in childhood and adolescence. However, some at risk states requiring action are proposed in literature: more than 5% increase in weight within a three-month period; more than half a point increase in BMI Z score; between 85th and 95th BMI percentile plus one adverse health consequence (i.e. hyperglycaemia, dyslipidemia, hyperinsulinemia, hypertension, or orthopaedic, gallbladder, or sleep disorder); or more than 95th BMI percentile or abdominal obesity (i.e. abdominal circumference above 90th percentile). As a matter of fact, numerous studies that have assessed weight gain during antipsychotic treatment are clearly limited, either because of their short duration (a few weeks), or because of their methodology: indeed, only weight gain is generally reported as an assessment tool. Merely noting an increase in body weight over time does not in itself signify a problem, and may underscore the importance of excessive corpulence growth as compared with controls. Adjusted BMI percentiles and BMI Z scores were calculated in only a few studies. Aim of the study. This pilot study focuses on the metabolic effects of risperidone in children and adolescents up to 16 years of age. This study is part of a larger, regional study on metabolic side effects of antipsychotic medication in adults, promoted by the university hospital centre in Lille, France. Design of the study. Patients included in the study were referred to our department of child and adolescent psychiatry for EOS (K-SADS). They had received no antipsychotic treatment prior to their inclusion. Weight, height, sex- and age-related BMI percentiles and BMI Z scores, waist circumference, blood pressure, fasting triglyceride levels, fasting total and high-density lipoprotein cholesterol levels, and fasting glucose level were measured at M0, M3, and M6. BMI, sex- and age-related BMI percentiles and adjusted BMI Z scores were obtained from tables and calculator (www.kidsnutrition.org). Results. Twenty-six children and adolescents (21 males, five females) aged 7 to 15.5 years (mean = 12.9 years, sd = 2.3) were included. They all received a diagnosis of schizophrenia according to the schedule for affective disorders and schizophrenia for school-aged children (K-SADS). They all received risperidone from 1 mg/day to a maximum of 6 mg/day. Statistical analysis principally shows a significant link between prescription of risperidone in EOS and six-months increases of BMI (increase of 4.7 kg/m(2), p < 0.0001), sex- and age-adjusted BMI percentile (increase of 29.3 points, p < 0.0025), and BMI Z scores (increase of 1.1 point, p < 0.0001). No patient showed metabolic syndrome, but one girl presented with a 1 g/l increase of fasting total cholesterol at two-months. Discussion. Despite the limited number of children included, our results confirm a strong link between prescription of risperidone in EOS and risk of obesity. Clinicians and caregivers need to be aware of the potential endocrine and metabolic adverse effects of atypical antipsychotics, and systematically ask for family history of metabolic disorder, life style, diet and habits. With adolescents, the sole monitoring of weight gain, and even of BMI, underestimates the gain of corpulence. One methodological implication of our study is that adjusted BMI Z scores are the best-suited measure to assess long-term drug-induced weight gain in comparison to developmental changes. Conclusion. Alternative treatment should be considered in some cases. Other antipsychotics, like aripiprazole, may have a better benefit/risk ratio and then may be prescribed as a first prescription or as a switch. Associations of antipsychotics may also be of interest but we lack controlled studies in children and adolescents. In some cases, alternative treatments like repetitive trans-cranial magnetic stimulations (rTMS) may be required. Their efficacy and their place in the therapeutic strategy of pharmacoresistant schizophrenia in children and adolescents have to be assessed in regard to metabolic and blood side effects of clozapine. (C) L'Encephale, Paris, 2009.