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1.  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.
doi:10.1177/2045125313487548
PMCID: PMC3805387  PMID: 24167704
antipsychotics; bone metabolism; hyperprolactinemia; osteoporosis; psychopathology; skeletal development
2.  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 
The Journal of clinical psychiatry  2011;72(12):1685-1690.
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.
doi:10.4088/JCP.10m06198
PMCID: PMC3653135  PMID: 22244026
3.  Demographic Differences in Incidence for Pituitary Adenoma 
Pituitary  2011;14(1):23-30.
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 (SEER) 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.
doi:10.1007/s11102-010-0253-4
PMCID: PMC3652258  PMID: 20809113
pituitary; adenoma; incidence; race; sex
4.  Bone Mineral Density After Spinal Cord Injury: A Reliable Method for Knee Measurement 
Objectives
To test the interrater reliability of a standardized method to analyze knee bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA); to compare spine, hip, and knee BMD of people with spinal cord injury (SCI) with able-bodied controls; and to determine the relation between hip BMD and knee BMD in SCI and able-bodied subjects.
Design
Criterion standard and masked comparison.
Setting
Primary care university hospital.
Participants
A convenience sample of 11 subjects with complete SCI was age and sex matched with 11 able-bodied control subjects.
Interventions
Not applicable.
Main Outcome Measures
Four raters analyzed regions of interest according to operational definitions recently developed to standardize the analysis of BMD of the knee. Subjects with chronic SCI and matched controls underwent conventional DXA scans of the spine and hips and “less conventional” scans of the distal femurs and proximal tibias. The relation between hip and knee BMD was analyzed.
Results
The knee measurements were highly reliable (femur intraclass correlation coefficient model 2,1 [ICC2,1]=.98; tibia ICC2,1=.89). Subjects with SCI had lower BMD values than controls at all hip and knee sites (P<.05). Lumbar spine BMD did not differ between groups. Hip BMD was moderately predictive of distal femur BMD (R2=.67), but less correlated with the proximal tibia (R2=.38).
Conclusions
Knee BMD can be reliably analyzed using DXA with this protocol. Subjects with SCI have diminished knee and hip BMD. Low hip BMD is associated with low distal femur BMD.
doi:10.1016/j.apmr.2005.06.001
PMCID: PMC3272271  PMID: 16213240
Fractures; Osteoporosis; Paralysis; Rehabilitation; X-ray absorptiometry; dual energy
5.  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.
Methods
Medically healthy 7–17yo males chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. Developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultra-distal radius was measured using peripheral quantitative computerized 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 an average 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, height and BMI Z-scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultra-distal radius (p<0.03). 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=0.03) and BMD Z-score at the lumbar spine (p<0.05). These findings became more marked when the analysis was restricted to non-Hispanic Caucasians. Of 13 documented fractures, only two occurred after risperidone and SSRIs were started and none 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.
doi:10.4088/JCP.08m04595gre
PMCID: PMC2845988  PMID: 20331935
6.  Leptin promoter -2548G/A variants predict risperidone-associated weight gain in children and adolescents 
Psychiatric genetics  2009;19(6):320-327.
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 7-17yo 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 subjects, 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.
Conclusions
The LEP -2548G/A variants appear 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.
PMCID: PMC2919234  PMID: 19873684
Leptin gene; Antipsychotics; Weight Gain; Children; Adolescents; Variants; Predictors
7.  Variants of the dopamine D2 receptor and risperidone-induced hyperprolactinemia in children and adolescents 
Pharmacogenetics and genomics  2009;19(5):373-382.
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 7–17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were selected for a cross-sectional evaluation. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical record. 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 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 AQ1and 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.
doi:10.1097/FPC.0b013e328329a60f
PMCID: PMC2699901  PMID: 19339912
adolescents; antipsychotics; children; dopamine receptors; DRD2; genetic variants; hyperprolactinemia; risperidone; TaqIA
8.  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 ≥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.
doi:10.1089/cap.2008.007
PMCID: PMC2715008  PMID: 19364288
9.  Weight Gain and Metabolic Abnormalities During Extended Risperidone Treatment in Children and Adolescents 
Abstract
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 ≥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.
doi:10.1089/cap.2008.007
PMCID: PMC2715008  PMID: 19364288

Results 1-9 (9)