Calcium and Vitamin D Supplementation in Boys with Risperidone-Induced Hyperprolactinemia: A Randomized, Placebo-Controlled Pilot Study.

BACKGROUND: The chronic use of antipsychotics has been associated with impaired bone mineralization, partially mediated by hyperprolactinemia. We examined if calcium and vitamin D supplementation promote bone mineral accrual in boys with risperidone-induced hyperprolactinemia. METHODS: Between February 2009 and November 2013, medically healthy, 5- to 17-year-old boys were enrolled in a 36-week double-blind, placebo-controlled study, examining the skeletal effects of supplementation with 1250 mg calcium carbonate and 400 IU of vitamin D3 in risperidone-induced hyperprolactinemia. Anthropometric, dietary, physical activity, and psychiatric assessments were conducted at baseline and week 18 and 36. Plasma prolactin and vitamin D concentrations were measured at baseline and week 36. Total body less head bone mineral content (BMC) and radius trabecular bone mineral density (BMD) were measured at baseline, week 18, and week 36, using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, respectively. Linear mixed-effects regression analysis examined the longitudinal effect of treatment on skeletal outcomes. RESULTS: Forty-seven boys (mean age: 11.0 ± 2.6 years) were randomized and 38 completed the study. At study entry, the average dietary calcium intake was below the recommended limit, but the average vitamin D concentration was normal. Calcium and vitamin D supplementation failed to significantly increase BMC or trabecular BMD. It also failed to affect several other skeletal and anthropometric outcomes, including plasma vitamin D concentration. CONCLUSIONS: In this 9-month long pilot study, supplementation with a modest dose of calcium and vitamin D did not increase bone mass accrual in risperidone-treated boys with hyperprolactinemia. Alternative approaches should be investigated to optimize bone health in this population to prevent future morbidity and premature mortality. ClinicalTrials.gov Identifier: NCT00799383.

Does Visceral or Subcutaneous Fat Influence Peripheral Cortical Bone Strength During Adolescence? A Longitudinal Study.

This study evaluated the longitudinal relationships among visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and peripheral bone strength during adolescence. Fat and lean mass, VAT and SAT area, and android/gynoid (A/G) ratio were estimated with DXA. Our main outcome was strength-strain index (SSI), an indicator of peripheral bone strength estimated by pQCT at the radius and tibia. Sex-specific analyses evaluated the longitudinal bone-fat relationship from ages 11 to 19 years with linear mixed models using biological age as the time variable and adjusted for limb length and lean mass in 182 girls and 167 boys. Variables were standardized (mean = 0, SD = 1) prior to model fitting and results shown are parameter estimates ± SE. Fat mass and SAT were positively associated with SSI (radius: 0.07 ± 0.02, p = 0.003 and 0.05 ± 0.02, 0.041, respectively; tibia: 0.09 ± 0.02, p < 0.001 and 0.08 ± 0.02, p < 0.001, respectively) prior to, but not following adjustment for lean mass in girls. In contrast, fat mass and SAT were negatively associated with radial SSI, both before and after adjustment for lean mass in boys (fat mass: -0.05 ± 0.01, p = 0.001; SAT: -0.04 ± 0.01, p = 0.004). In full models, negative associations were limited to VAT in girls and included radial (-0.06 ± 0.02, p = 0.001) and tibial SSI (-0.04 ± 0.02, p = 0.033). For boys, there were no significant associations present between VAT and SSI at the radius or tibia. In analyses limited to obese participants, an A/G ratio was not significantly associated with SSI in girls, but was negatively associated with radial SSI regardless of adjustment for lean mass in boys (-0.06 ± 0.02, p = 0.018). These results that show a negative relationship between peripheral bone strength and VAT in girls, but greater total and central adiposity in boys, suggest these factors play a role in adequate acquisition of bone strength during adolescence. © 2017 American Society for Bone and Mineral Research.

The Effect of Depression, Generalized Anxiety, and Selective Serotonin Reuptake Inhibitors on Change in Bone Metabolism in Adolescents and Emerging Adults.

The purpose of this study was to prospectively examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) use to changes in bone metabolism in older adolescents and emerging adults. Medically healthy 15- to 20-year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Every 4 months, trabecular and cortical volumetric bone mineral density (vBMD) at the radius and markers of bone metabolism were evaluated. Every 8 months, total body less head areal bone mineral content and lumbar spine (LS) areal BMD (aBMD) were determined. Linear mixed-effects regression analysis examined associations between bone measures on the one hand and MDD, GAD, and SSRI indices on the other. A total of 264 participants were followed for 1.51 ± 0.76 years. After adjusting for age, sex, vitamin D concentration, physical activity, lean mass or grip strength, and time in the study, MDD severity was associated with increasing LS aBMD. Similarly, SSRI use was associated with increasing LS aBMD and bone formation in female participants. In contrast, SSRI use was associated with decreasing LS aBMD in males. After accounting for depression, GAD was independently, albeit weakly, associated with increased bone mineralization. In older adolescents and emerging adults, MDD and GAD are associated with increasing bone mass, particularly in the lumbar spine and in females, whereas SSRIs are associated with increasing bone mass in females but decreasing bone mass in males. © 2017 American Society for Bone and Mineral Research.

Bone Mass in Boys with Autism Spectrum Disorder.

To examine bone mass in children and adolescents with autism spectrum disorders (ASD). Risperidone-treated 5 to 17 year-old males underwent anthropometric and bone measurements, using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Multivariable linear regression analysis models examined whether skeletal outcomes differed among participants with (n = 30) versus without ASD (n = 156). After adjusting for potential covariates, having ASD was associated with significantly lower trabecular bone mineral density and bone strength at the radius, and with marginally lower total body less head bone mineral content (p < 0.09). No differences at the lumbar spine were observed. ASD are associated with lower bone mass. Future studies should investigate interventions to optimize skeletal health in ASD.

The Relationship Between Greater Prepubertal Adiposity, Subsequent Age of Maturation, and Bone Strength During Adolescence.

This longitudinal study investigated whether greater prepubertal adiposity was associated with subsequent timing of maturation and bone strength during adolescence in 135 girls and 123 boys participating in the Iowa Bone Development Study. Greater adiposity was defined using body mass index (BMI) data at age 8 years to classify participants as overweight (OW, ≥85th percentile for age and sex) or healthy weight (HW). Maturation was defined as the estimated age of peak height velocity (PHV) based on a series of cross-sectional estimates. Measurements were taken at ages 11, 13, 15, and 17 years for estimates of body composition by dual-energy X-ray absorptiometry (DXA), bone compression (bone strength index), and torsion strength (polar strength-strain index) at the radius and tibia by pQCT, and femoral neck bending strength (section modulus) by hip structural analysis. Bone strength in OW versus HW were evaluated by fitting sex-specific linear mixed models that included centered age (visit age - grand mean age of cohort) as the time variable and adjusted for change in fat mass, and limb length in model 1. Analyses were repeated using biological age (visit age - age PHV) as the time variable for model 1 with additional adjustment for lean mass in model 2. BMI was negatively associated with age of maturation (p < 0.05). OW versus HW girls had significantly greater bone strength (p < 0.001) in model 1, whereas OW versus HW boys had significantly greater bone strength (p < 0.001) at the tibia and femoral neck but not radius (p > 0.05). Analyses were repeated using biological age, which yielded reduced parameter estimates for girls but similar results for boys (model 1.) Differences were no longer present after adjustment for lean mass (model 2) in girls (p > 0.05) whereas differences at the tibia were sustained in boys (p < 0.05). These findings demonstrate sex- and site-specific differences in the associations between adiposity, maturation, and bone strength. © 2016 American Society for Bone and Mineral Research.

Fat distribution and major depressive disorder in late adolescence.

OBJECTIVE: Substantial evidence exists to indicate bidirectional relationships between obesity and depressive disorders and the importance of fat distribution to this relationship. This analysis used a well-characterized sample of individuals in late adolescence to determine the association between depressive illness and fat distribution. METHOD: Medically healthy 15- to 20-year-olds, one-half of whom had recently begun treatment with a selective serotonin reuptake inhibitor, underwent a comprehensive psychiatric evaluation that resulted in diagnostic classification and weekly psychiatric disorder ratings over the prior 4 months using the Longitudinal Interval Follow-Up Evaluation. A whole-body scan, using dual-energy x-ray absorptiometry, allowed estimations of total body less head (TBLH), total mass, fat mass, and visceral adipose tissue (VAT) mass. Assessments occurred between September 2010 and April 2014. Multivariable linear regression analyses, adjusted for relevant covariates, examined the association between DSM-IV-TR-diagnosed major depressive disorder (MDD) and VAT, the primary outcome of interest. These procedures also determined whether significant associations were confined to overweight/obese participants. RESULTS: The analysis included data from 200 participants (71% female; mean age = 19.0 ± 1.6 years), of whom 128 had current MDD. The presence of MDD was associated with increased fat mass among overweight/obese participants (Cohen d = 0.79, P < .02), but not normal weight participants. This was true of both visceral and nonvisceral fat mass measures. Accounting for the presence of generalized anxiety disorder (GAD) did not alter the findings. CONCLUSION: In adolescents, relationships between central adiposity and MDD may be confined to those who are overweight/obese. Despite the high comorbidity of GAD and depressive disorders, only the latter appeared to be significantly associated with central adiposity.

Longitudinal examination of the skeletal effects of selective serotonin reuptake inhibitors and risperidone in boys.

OBJECTIVE: In a previous cross-sectional study, we found lower bone mass during treatment with selective serotonin reuptake inhibitors (SSRIs) and risperidone in youths. Here, we evaluate the skeletal effects of these psychotropics at follow-up. METHOD: Between April 2005 and July 2011, medically healthy 7- to 17-year-old males treated with risperidone for 6 months or more were enrolled through child psychiatry outpatient clinics and returned for follow-up 1.5 years later. Treatment history was extracted from the medical and pharmacy records. Anthropometric, laboratory, and bone mass measurements were obtained. Multivariable linear regression analyses compared participants who remained on risperidone at follow-up to those who had discontinued risperidone treatment as well as SSRI-treated versus SSRI-unexposed participants. RESULTS: The sample consisted of 94 boys with a mean age of 11.8 ± 2.7 years at study entry. The majority had an externalizing disorder and had received risperidone and SSRIs for 2.5 ± 1.7 years and 1.6 ± 1.9 years, respectively, at study entry. By follow-up, 26% (n = 24) had discontinued risperidone. Compared to discontinuing risperidone, continuing it was associated with a decline in participants' age-sex-height-race-specific areal bone mineral density (BMD) z score at the lumbar spine (P < .04) and failure to increase radius trabecular volumetric BMD (P < .03), after accounting for significant covariates. In addition, receiving an SSRI was associated with reduced lumbar spine areal BMD z score and radius trabecular volumetric BMD at both study entry (P < .02 and P < .03, respectively) and follow-up (P < .06 and P < .03, respectively), but without further decline between the 2 visits. CONCLUSIONS: Chronic SSRI treatment in children and adolescents is associated with reduced, albeit stable, bone mass for age, while chronic risperidone treatment is associated with failure to accrue bone mass.

The effect of psychostimulants on skeletal health in boys co-treated with risperidone.

OBJECTIVES: To examine the skeletal effects of chronic psychostimulant treatment in children and adolescents. STUDY DESIGN: Medically healthy 5- to 17-year-old males from 4 different clinic-based studies were combined for this analysis. They were divided by psychostimulant use into 3 groups: none to negligible, intermittent, and continuous use. Most (95%) had also received risperidone for 6 months or more. Treatment history was extracted from medical and pharmacy records. Anthropometric and bone measurements, using dual-energy x-ray absorptiometry and peripheral quantitative computed tomography, were obtained at each research visit. Multivariable linear regression analysis models examined whether age-sex-specific height Z-score and skeletal outcomes differed among the 3 psychostimulant-use groups. RESULTS: The sample consisted of 194 males with a mean age of 11.7 ± 2.8 years at study entry. The majority had an externalizing disorder. There was no significant difference across the 3 treatment groups in height Z-score or in skeletal outcomes at the radius, lumbar spine, or whole body. One hundred forty-four boys had valid follow-up skeletal data 1.4 ± 0.7 years after study entry. Again, neither height Z-score nor the skeletal outcomes were different among those who remained on psychostimulants between the 2 visits, started psychostimulants anew, or had not taken psychostimulants. CONCLUSIONS: Following chronic treatment, psychostimulants did not appear to significantly affect bone mass accrual in children and adolescents taking risperidone. There was a small, but statistically not significant, negative impact on longitudinal growth.

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 Fisher's 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.

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.

Possible mechanisms for the skeletal effects of antipsychotics in children and adolescents.

The increasing use of antipsychotics (APs) to treat pediatric psychiatric conditions has led to concerns over the long-term tolerability of these drugs. While the risk of cardiometabolic abnormalities has received most of the attention, preclinical and clinical studies provide preliminary evidence that APs can adversely impact bone metabolism. This would be most concerning in children and adolescents as suboptimal bone accrual during development may lead to increased fracture risk later in life. However, the potential mechanisms of action through which APs may impact bone turnover and, consequently, bone mineral content are not clear. Emerging data suggest that the skeletal effects of APs are complex, with APs directly and indirectly impacting bone cells through modulation of multiple signaling pathways, including those involving dopamine D2, serotonin, adrenergic, and prolactin receptors, as well as by affecting gonadotropins. Determining the action of APs on skeletal development is further complicated by polypharmacy. In children and adolescents, APs are frequently coprescribed with psychostimulants and selective serotonin reuptake inhibitors, which have also been linked to changes in bone metabolism. This review discusses the mechanisms by which APs may influence bone metabolism. Also covered are preclinical and pediatric findings concerning the impact of APs on bone turnover. However, the dearth of clinical information despite the potential public health significance of this issue underscores the need for further studies. The review ends with a call for clinicians to be vigilant about promoting optimal overall health in chronically ill youth with psychopathology, particularly when pharmacotherapy is unavoidable.

Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline.

OBJECTIVE: The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. PARTICIPANTS: The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.

Update in pituitary 2010.

This manuscript is based on an invited lecture entitled "The Year in Pituitary," presented at the 91st Annual Meeting of The Endocrine Society in San Diego, California, on June 21, 2010. The purpose of the lecture was to highlight new or evolving issues in the management of pituitary disease. Papers selected were published in major journals between January 2009 and June 2010. Issues addressed include the safety of cabergoline in pregnancy, recurrence of hyperprolactinemia after dopamine agonist withdrawal, pegvisomant and hepatic dysfunction, and high-dose hydrocortisone as a predictor of mortality in patients with acromegaly.

Demographic differences in incidence for pituitary adenoma.

Incidence estimates for pituitary adenomas vary widely, suggesting the effects of numerous risk factors or varying levels of tumor surveillance. We studied the epidemiology of pituitary adenomas using 2004-2007 data collected by 17 Surveillance, Epidemiology, and End Results Programs in the United States (N = 8,276). We observed that incidence rates generally increased with age and were higher in females in early life and higher in males in later life. Males are diagnosed with larger tumors on average than females. Diagnosis may be delayed for males, giving tumors a chance to grow larger before clinical detection. We also observed that American Blacks have higher incidence rates for pituitary adenomas compared with other ethnic groups. There are several potential explanations for this finding with some evidence that at least part of the effect may be due to differential diagnosis between races.

Variants of the serotonin transporter gene, selective serotonin reuptake inhibitors, and bone mineral density in risperidone-treated boys: a reanalysis of data from a cross-sectional study with emphasis on pharmacogenetics.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may reduce bone mineral density (BMD). Here, we investigate whether variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene moderate this association in boys. METHOD: Between November 2005 and August 2009, medically healthy boys, aged 7 to 17 years, were enrolled in a cross-sectional study exploring the effect of risperidone-induced hyperprolactinemia on BMD. 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. Multiple linear regression analysis tested whether the 5-HTTLPR genotypes interacted with SSRI treatment status to affect BMD, adjusting for relevant confounders. Participant enrollment was conducted at the University of Iowa, Iowa City. RESULTS: Of 108 boys (mean ± SD age = 11.7 ± 2.8 years), with DSM-IV clinical diagnoses based on chart review, 52% (n = 56) had been taking an SSRI for a median duration of 2.8 years. After adjusting for pubertal development, anthropometric measures, physical activity, calcium intake, and prolactin concentration, there was a significant 5-HTTLPR genotype × SSRI treatment interaction effect on total lumbar spine BMD z score (P < .05) in non-Hispanic whites. The interaction effect on BMD at the ultradistal radius failed to reach statistical significance. Among LS genotype carriers, those treated with SSRIs had lower lumbar BMD z score and trabecular BMD at the radius compared to those not treated (P < .02 and P < .008, respectively). CONCLUSIONS: These findings add to the growing evidence implicating the serotonin system in bone metabolism. They suggest the potential use of 5-HTTLPR genotypes to guide the safer long-term prescribing of SSRIs in youths. However, prospective confirmation in a controlled matched population is warranted.

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.

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.

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.

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.