Chadi A. Calarge

Weight Gain and Metabolic Abnormalities During Extended Risperidone Treatment in Children and Adolescents

OBJECTIVE The aim of this study was to investigate the prevalence of clinical and laboratory metabolic abnormalities during long-term risperidone treatment in children and adolescents. METHODS Medically healthy 7- to 17-year-old children chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry clinics. Anthropometric measurements and laboratory testing were conducted. Developmental and medication histories were obtained from medical records. RESULTS In 99 patients treated with risperidone for an average of 2.9 years, a significant increase in age- and gender-adjusted weight and body mass index (BMI) (i.e., z-scores) was observed. Concomitant treatment with psychostimulants did not attenuate this weight gain. Risperidone-associated weight gain was negatively correlated with the BMI z-score obtained at the onset of risperidone treatment. Compared to lean children, overweight and obese children had higher odds of metabolic abnormalities, including increased waist circumference, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C). They also tended to have a higher insulin level and homeostasis model assessment insulin resistance (HOMA-IR) index. As a result, upon recruitment in the study, children with excessive weight were 12 times more likely to have at least one laboratory metabolic abnormality and seven times more likely to have at least one criterion of the metabolic syndrome compared to lean subjects. In contrast to excessive weight status, gaining > or =0.5 BMI z-score point during risperidone treatment was not associated with a significantly higher occurrence of metabolic disturbances. CONCLUSIONS The long-term use of risperidone, especially when weight is above normal, is associated with a number of metabolic abnormalities but a low prevalence of the metabolic syndrome phenotype. Future studies should evaluate the stability of these abnormalities over time.

A cross-sectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys.

OBJECTIVE The aim of the present study was to investigate the effect of risperidone-induced hyperprolactinemia on trabecular bone mineral density (BMD) in children and adolescents. METHOD Medically healthy 7- to 17-year-old males chronically treated, in a naturalistic setting, with risperidone were recruited for this cross-sectional study through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. The clinical diagnoses were based on chart review, and developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultradistal radius was measured using peripheral quantitative computed tomography, and areal BMD of the lumbar spine was estimated using dual-energy x-ray absorptiometry. RESULTS Hyperprolactinemia was present in 49% of 83 boys (n = 41) treated with risperidone for a mean of 2.9 years. Serum testosterone concentration increased with pubertal status but was not affected by hyperprolactinemia. As expected, bone mineral content and BMD increased with sexual maturity. After adjusting for the stage of sexual development and height and BMI z scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultradistal radius (P < .03). Controlling for relevant covariates, we also found treatment with selective serotonin reuptake inhibitors (SSRIs) to be associated with lower trabecular BMD at the radius (P = .03) and BMD z score at the lumbar spine (P < .05). These findings became more marked when the analysis was restricted to non-Hispanic white patients. Of 13 documented fractures, 3 occurred after risperidone and SSRIs were started, and none occurred in patients with hyperprolactinemia. CONCLUSIONS This is the first study to link risperidone-induced hyperprolactinemia and SSRI treatment to lower BMD in children and adolescents. Future research should evaluate the longitudinal course of this adverse event to determine its temporal stability and whether a higher fracture rate ensues.

Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents.

Objective To investigate the association between hyperprolactinemia and variants of the dopamine D2 receptor (DRD2) gene in children and adolescents in long-term treatment with risperidone. Methods Medically healthy 7 to 17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were recruited in a cross-sectional study. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical records. The effect of the TaqIA variants of the DRD2 on the risk of risperidone-induced hyperprolactinemia was the primary outcome measure. Results Hyperprolactinemia was present in 50% of 107 patients (87% males) treated with risperidone for an average of 2.9 years. Age, stage of sexual development, and the dose of risperidone independently predicted a higher prolactin concentration, whereas the dose of psychostimulants was negatively correlated with it. However, these four predictors became nonsignificant when risperidone serum concentration was entered into the model. Adverse events potentially related to hyperprolactinemia were more common in participants with elevated prolactin concentration and in girls (45%) compared with boys (10%). After controlling for risperidone concentration and the dose of psychostimulants, the TaqIA A1 and the A-241G alleles were associated with higher prolactin concentration, whereas the –141C Ins/Del and C957T variants had no significant effect. In addition, adverse events potentially related to hyperprolactinemia were four times more common in TaqIA A1 allele carriers. Conclusion Prolactin concentration is closely related to central DRD2 blockade, as reflected by risperidone serum concentration. Furthermore, the TaqIA and A-241G variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia and its potential adverse events.

Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers.

Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes.

Leptin gene -2548G/A variants predict risperidone-associated weight gain in children and adolescents.

Objective As the use of atypical antipsychotics in children and adolescents has increased, concerns have been raised about their long-term safety. We aimed to investigate the association between risperidone-induced weight gain, leptin concentration, and the leptin gene (LEP) –2548G/A variants in youths. Methods Medically healthy 7- to 17-year-old children and adolescents, in extended naturalistic treatment with risperidone, were recruited through pediatric psychiatry clinics. Anthropometric measures and laboratory testing were conducted. Growth and medication history was obtained from the medical record. The effect of the LEP genotypes on leptin concentration and on the slopes of the weight and body mass index (BMI) Z-score curves before and after the onset of risperidone treatment was investigated. Results In 74 individuals, chronically treated with risperidone, the A allele was associated with higher leptin concentration at low weight and BMI Z-scores. There was no effect of the LEP genotypes on weight or BMI Z-scores before risperidone was started. Afterwards, however, the A-allele carriers showed a steeper rate of increase in weight and BMI Z-scores. As a result, the GG-genotype carriers were 2.5 times less likely to be overweight/obese (i.e. having a BMI above the 85th percentile). This genetic effect on risperidone-associated weight gain did not extend to weight loss related to psychostimulants. Conclusion The LEP −2548G/A variants seem to moderate the weight-altering effect of risperidone but not psychostimulants. This may be related to genetic differences in tissue sensitivity to leptin, resulting in differential body composition.

Serum Ferritin and Amphetamine Response in Youth with Attention-Deficit/Hyperactivity Disorder

INTRODUCTION Iron deficiency (ID) has been associated with attention and behavioral problems, in general, and with attention-deficit/hyperactivity disorder (ADHD), in particular. The study aim was to explore whether iron stores, as reflected by serum ferritin concentration, predicted response to psychostimulants. METHODS Six- to 14-year-old children with ADHD enrolled in a multiphase, double-blind, randomized, placebo-controlled trial investigating zinc supplementation in treating ADHD and optimizing response to psychostimulants. The Swanson, Nolan, and Pelham (SNAP) ADHD rating scale was the primary clinical instrument. Serum ferritin concentration was obtained at baseline and 8 weeks later. Partial correlations, adjusting for age and sex, were computed. RESULTS Fifty-two participants (83% males) had a mean age of 10 years. Their ADHD symptoms were moderately severe at baseline (SNAP item mean = 2.1). Their mean ferritin concentration was 18.4  ng/mL, with 23% of the participants having a level below 7, the assay-defined threshold for ID. Serum ferritin was inversely correlated with baseline inattention, hyperactivity/impulsivity, and total ADHD symptom scores (Partial Spearmans r = -0.31, p = 0.04; r = -0.42, p < 0.006; and r = -0.43, p < 0.004, respectively) and with the weight-adjusted dose of amphetamine used to optimize clinical response (Partial Spearmans r = -0.45, p < 0.007). Psychotropic-treatment history moderated some, but not all, of these associations, with previously medicated children showing a stronger association between ferritin concentration and ADHD symptom severity. CONCLUSION These findings add to the growing literature implicating ID in ADHD. The prediction of amphetamine optimal dose by ferritin concentration suggests that iron supplementation should be investigated as a potential intervention to optimize response to psychostimulants at a lower dose in individuals with low iron stores and ADHD.

Major Depressive Disorder and Bone Mass in Adolescents and Young Adults

Depression has been associated with reduced bone mass in adults, but the mechanisms remain unclear. In addition, little is known about the association between depression and bone health during growth and development. To address this knowledge gap, we examined bone density and structure in 222 adolescents and young adults (69% females, mean ± SD age: 19.0 ± 1.5 years), enrolled within 1 month of starting a selective serotonin reuptake inhibitor (SSRI) or unmedicated. Psychiatric functioning was assessed with self‐report and researcher‐administered instruments, including the Longitudinal Interval Follow‐up Evaluation for Adolescents (A‐LIFE). Anthropometric and laboratory measures included dual‐energy x‐ray absorptiometry and peripheral quantitative computed tomography scans. Linear multivariable regression analysis tested the association between depression and bone mass, after accounting for relevant confounders. The presence of current depression was associated with a significant reduction in age‐sex‐height‐race‐specific bone mineral density (BMD) and content (BMC) of total body less head and lumbar spine. The findings varied by assessment method with self‐report scales, capturing symptom severity over the prior week or two, yielding the weakest associations. Depression was also associated with reduced cortical thickness and a trend for increased endosteal circumference. In contrast, generalized anxiety disorder was not associated with bone deficits. In sum, depressive illness is associated with significantly lower bone mass in youths. Future investigations must examine whether bone recovery is possible following depression remission or whether remedial interventions are warranted to optimize bone mass in order to minimize the long‐term risk of osteoporosis.

Predictors of Risperidone and 9-Hydroxyrisperidone Serum Concentration in Children and Adolescents

INTRODUCTION Little is known about risperidone metabolism in a clinical sample, where polypharmacy is common. Such knowledge is important since several of its side effects are dose dependent. METHODS Medically healthy patients aged 7 to 17 years old treated with risperidone for at least 6 months were enrolled. Trough serum risperidone and 9-hydroxyrisperidone concentrations were measured. RESULTS One hundred seven participants (92% males) were recruited, representing a heterogenous clinical group with attention-deficit/hyperactivity disorder, disruptive behavior disorders, pervasive developmental disorders, anxiety disorders, mood disorders, tic disorders, or psychotic disorders. Risperidone had been used at a mean dose of 0.03 mg/kg, for a mean 2.5 years, predominantly to treat irritability and aggression. Cytochrome CYP2D6 inhibitors were divided into prominent (fluoxetine, bupropion, and lamotrigine), intermediate (sertraline), and weak inhibition groups (citalopram or escitalopram). The concentrations of risperidone and its metabolite were strongly associated with the dose of risperidone and time since the last dose and, to a lesser extent, with male sex. In addition, risperidone concentration increased with pubertal stage (p < 0.05), while body mass index z-score (p = 0.001) predicted a higher 9-hydroxyrisperidone concentration. The use of CYP2D6 inhibitors was much more strongly associated with risperidone concentration (p < 0.0001) than with its metabolites (p = 0.06). CONCLUSIONS In chronically treated youths, the metabolism of risperidone depends on the stage of sexual development, whereas that of 9-hydroxyrisperidone varies with body fat. Moreover, CYP2D6 inhibitors more strongly affect risperidone metabolism than that of its metabolite. The clinical implications of these findings, in relation to efficacy and tolerability, deserve further investigation.

Cardiometabolic outcomes in children and adolescents following discontinuation of long-term risperidone treatment

OBJECTIVE Second-generation antipsychotics (SGAs) cause weight gain and cardiometabolic abnormalities in children and adolescents. Less well-investigated is the outcome of these adverse events following SGA discontinuation, which we examined. METHODS Medically healthy 7 to 17-year-old patients treated with risperidone for ≥6 months were enrolled and returned for follow-up, 1.5 years later. Treatment history was extracted from the medical and pharmacy records. Anthropometric and laboratory measurements were obtained at each research visit. Multivariable linear regression analysis and Fishers exact test were used to compare participants who remained on risperidone at follow-up (Risp Cont Group) with those who had discontinued SGA treatment (SGA Disc Group) and those who had switched to another SGA (SGA Cont Group). Correlational analyses examined the association between change in age-sex specific body mass index (BMI) z score between study entry and follow-up and change in cardiometabolic outcomes. RESULTS The sample consisted of 101 participants (93% male) with a mean age of 11.7±2.6 years at study entry. The majority had an externalizing disorder and received 0.03±0.02 mg/kg/day of risperidone, for 2.5±1.6 years. At follow-up, 18% (n=18) were in the SGA Disc Group and 9% (n=9) were in the SGA Cont Group. BMI z score decreased in the SGA Disc Group, remained unchanged in the Risp Cont Group (n=74), and increased in the SGA Cont Group. Importantly, the change in BMI z score between study entry and follow-up was significantly correlated with the change in systolic and diastolic blood pressure z scores, heart rate, waist circumference, percent body fat, inflammatory markers, fasting total insulin, homeostatic model assessment insulin resistance index (HOMA-IR), C-peptide, total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, triglycerides, triglycerides/HDL ratio, and leptin. CONCLUSIONS Following several years of treatment, risperidone discontinuation is associated with a reversal of the excessive weight gain, mediated by a negative energy balance, and a corresponding improvement in cardiometabolic parameters.

Prolactin Serum Concentrations During Aripiprazole Treatment in Youth

OBJECTIVE This study aimed to: document the extent of the reduction of serum prolactin (PRL) levels induced by aripiprazole (ARI) treatment in children and adolescents, compare this effect by age group, and shed light on this phenomenon. METHODS PRL serum levels in unmedicated subjects were compared to those in subjects treated with aripiprazole to calculate the rate of subnormal PRL levels during aripiprazole treatment. Next, a literature search was performed to better understand the effects of dopaminergic drugs on PRL levels by age group. RESULTS Sixty percent of those treated with aripiprazole exhibited subnormal PRL serum levels versus 8% of unmedicated subjects. The rate of PRL subnormality in response to aripiprazole was half as frequent in adolescents and was minimal in adults. The drug-induced reduction of PRL serum levels became more prominent with increasing doses of aripiprazole and with an increased treatment duration. CONCLUSIONS With the increasing use of aripiprazole in the United States population, it is important that future research be conducted to explore the potential sequelae of subnormal PRL serum levels in children and adolescents.