Second-generation Antipsychotics Treatment Research Articles

16: Increased Risk of Metabolic Dysregulation Following 12 Months of Second-Generation Antipsychotic Treatment in Children: A Prospective Cohort Study

Over the last two decades, prescriptions of second-generation antipsychotics (SGAs) to children have increased significantly. During this time period, there has also been a growing body of literature demonstrating an increased risk of metabolic complications in children treated with SGAs. Prospective studies clearly suggest that SGAs confer increased risk for development of weight gain and dyslipidemia over the short term (<3 months). Although long-term SGA use in children is a common practice, investigation of metabolic complications over the long-term is limited to retrospective reports. Thus, we conducted a prospective longitudinal study to assess the impact of SGAs on metabolic complications during the first 12 months of treatment. To determine the risk of developing obesity and related metabolic complications in children following long-term treatment with risperidone or quetiapine. This was a one-year naturalistic longitudinal study conducted between February 2009 and March 2012. A total of 115 children aged two to 18 years without prior exposure to SGAs were enrolled at initiation of treatment with either risperidone or quetiapine. Metabolic parameters were measured at baseline and months 6, and 12. Data of 37 participants (20 risperidone-treated and 17 quetiapine-treated) who completed 12 month monitoring were used in the analysis. After one year of SGA treatment, mean weight increased significantly by 10.8 kg (95% CI 6.6, 10.5 kg) for risperidone and 9.7 kg (95% CI 6.5, 12.8 kg) for quetiapine. BMI z-score also increased significantly in both groups (P<0.001). There was a high incidence of children becoming overweight or obese [6/15 (40.0%) for risperidone-treated and 7/14 (50.0%) for quetiapine-treated]. The mean levels of fasting glucose (for risperidone-treated) and ratio of total cholesterol to HDL cholesterol (for quetiapine-treated) increased significantly by 0.23 mmol/L (95% CI 0.03, 0.42 mmol/L) and 0.48 mmol/L (95% CI 0.15, 0.80 mmol/L), respectively. Children treated with risperidone or quetiapine are at a significant risk for developing obesity, elevated waist circumference and dyslipidemia over 12 months of treatment. These data emphasize the importance of regular monitoring for early identification and treatment of metabolic side-effects.

Abstract 475: Catechol-O-Methyl Transferase Methylation and Blood Pressure in Children Treated With Second-generation Antipsychotics

Second-generation antipsychotics (SGA) are increasingly being used to treat children for a wide-range of mental health conditions, and are associated with cardiometabolic side effects such as rapid weight gain and elevated blood pressure (BP). The catechol-O-methyl transferase ( COMT) Val158Met variant is associated with BP in the general population. We recently reported higher BP in SGA-treated children with the Met allele, but no such association in SGA-naïve children. Methylation of the COMT promoter is another important regulatory factor governing COMT activity. The aim of this study was to investigate the interaction of the COMT Val158Met variant and COMT methylation on BP in children with mental health conditions. A cross-sectional population of SGA-treated (n=106) and SGA[[Unable to Display Character: &amp;#8211;]]naïve children (n=122), ≤18 y of age, were assessed for markers of cardiometabolic health. Bisulfite pyrosequencing was used to quantify the methylation status of three CpG sites in the COMT promoter. Relationships between SGA treatment, COMT Val158Met genotype and COMT promoter methylation were assessed using general linear models. BMI was standardized for age and sex (zBMI) and systolic and diastolic BP standardized for age, sex, and height (zSBP, zDBP). When analyzed as one group, there were no significant effects of COMT genotype, SGA-treatment, or mental health diagnosis on mean methylation. In SGA-treated children, an interaction between mean methylation and COMT genotype was observed for zSBP ( p =0.015), where zSBP was positively related to methylation in children with the Val/Val genotype, but not in children with the Met allele. After adjustments for ethnicity, SGA-duration, and zBMI the effect was diminished ( p =0.109), with SGA-duration ( p =0.018) and zBMI ( p =0.032) accounting for the variation in zSBP. This association was not found in SGA-naïve children. These findings suggest COMT promoter methylation may influence the effect of the COMT Val158Met variant on blood pressure in SGA-treated children.

Mania associated with aripiprazole treatment in schizophrenia: a case report

Mania associated with aripiprazole treatment in schizophrenia: a case report Aripiprazole is a novel antipsychotic medication that is used to treat a number of psychiatric conditions, including schizophrenia, bipolar disorder, and major depressive disorder. Clinical trials have established its efficacy and favorable tolerability profile. Nevertheless, infrequent undesirable adverse events are often encountered during wide-scale everyday clinical use. There are a few mania/hypomania cases associated with second-generation antipsychotic treatment. Induction of mania, described for almost all secondgeneration antipsychotic, may be one of the rare adverse events of aripiprazole therapy. In this study, a female patient with chronic schizophrenia who had never presented history of mood episodes, in which manic symptoms developed after increasing aripiprazole dosage to 30mg/day and disappeared after cessation of the treatment was presented. During the second-generation antipsychotic use, clinicians should be cautious to patients’s mania/hypomania symptoms.

Pharmacogenetic study of second-generation antipsychotic long-term treatment metabolic side effects (the SLiM Study): Rationale, objectives, design and sample description

AimWeight gain is an important and common side effect of second-generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs. Materials and methodsThe SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve pediatric and adult patients (age range 8.8–90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8–73.2 years) were recruited. ResultsThis paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline. ConclusionsResults from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment.

Second generation antipsychotic-induced obsessive-compulsive symptoms in schizophrenia: a review of the experimental literature.

Second generation antipsychotics (SGAs) have been implicated in the de novo emergence and exacerbation of obsessive-compulsive symptoms (OCS) in patients with schizophrenia. Among SGAs, clozapine, olanzapine, and risperidone are the most prominent agents associated with these sequelae, according to case reports. Comorbid OCS can impede recovery by compromising treatment benefits, medication compliance, and clinical prognoses. Previous reviews of SGA-induced OCS have predominantly focused on descriptive case reports, with limited attention paid toward experimental findings. To address this paucity of data, we sought to review the effects of SGAs on OCS in schizophrenia in the experimental literature, while addressing the role of different treatment (duration, dose, serum levels) and pharmacogenetic factors. Our findings suggest that clozapine confers the greatest risk of OCS in schizophrenia, with 20 to 28% of clozapine-treated patients experiencing de novo OCS, in addition to 10 to 18% incurring an exacerbation of pre-existing OCS. Clozapine can also yield full threshold obsessive-compulsive disorder (OCD), in some cases. Olanzapine is another high risk drug for secondary OCS which occurs in 11 to 20% of schizophrenic patients receiving olanzapine therapy. At this time, there is insufficient experimental evidence to characterize the effects of other SGAs on OCS. Despite some experimental support for the involvement of longer treatment duration and genetic factors in mediating drug-induced OCS, more research is needed to clearly elucidate these associations. Based on these results, schizophrenic patients should be routinely monitored for OCS throughout the course of SGA treatment, particularly when clozapine or olanzapine is administered.

Interaction between the Val158Met catechol-O-methyltransferase gene variant and second-generation antipsychotic treatment on blood pressure in children.

Second-generation antipsychotic (SGA) medications are associated with cardiometabolic risk factors such as obesity and elevated blood pressure (BP) in some individuals. The goal of this study is to determine whether the Val158Met variant (rs4680) in the catechol-O-methyltransferase (COMT) gene, associated with BP in adults, is associated with elevated BP in SGA-treated children. A cross-sectional population of SGA-treated (n=134) and SGA-naive (n=168) children, ⩽18 years of age, were genotyped and assessed for markers of cardiometabolic health. An interaction was found between SGA treatment and COMT genotype for BP. After adjusting for covariates, SGA-treated children with the Met allele had higher systolic and diastolic BP (P=0.014 and P=0.034, respectively), and higher fasting glucose concentrations (P=0.030) compared with children with the Val/Val genotype. This was not observed in SGA-naive children. The Met allele of the COMT Val158Met variant may identify SGA-treated children at risk for elevated BP and fasting blood glucose concentrations.

The longitudinal course of cognitive impairment in schizophrenia: an examination of data from premorbid through posttreatment phases of illness.

Cognitive impairment is a core feature of schizophrenia that is present across the course of the illness. However, due to complexities of studying cognitive decline in patients prior to the onset of illness, the longitudinal course is not fully understood. The cognitive effects in patients with schizophrenia are robust, with a 1.5 to 2.5 standard deviation gap between patients and healthy controls on composite scores. People with schizophrenia manifest a prior history of cognitive impairment in the premorbid phases of the illness. Examination of school records suggests that children who will eventually develop schizophrenia begin school at a level of functioning that is a full grade behind their peers, with the gap increasing by the time they finish high school. Epidemiologic work suggests that there are both static cognitive impairments and developmental lags in these patients during childhood, well before the illness is fully manifest. Although there was initial promise of improved cognitive function with second-generation antipsychotic treatment, more recent studies have suggested no differences among antipsychotics, with the initial appearance of improvement very likely attributable to practice effects, inappropriate medication dosing, and poor study design. Two large, prominent studies evaluating first- and second-generation antipsychotics suggested that, although there was slight to modest improvement in cognitive function for all treatments, there were no differences among medications, regardless of the generation of the agents. In summary, patients who develop schizophrenia, on average, demonstrate cognitive impairment beginning as early as the first grade, with deterioration seen across school years. Further, these patients had substantial cognitive deficits after the initiation of psychosis. Finally, while antipsychotic treatment improves symptoms, antipsychotics have little impact on cognition, and there appear to be no differences in the degree of cognitive improvement between first- and second-generation agents.

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

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. 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. 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. 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.

EPA-1415 – Pharmacogenetics of antipsychotic-induced weight gain in schizophrenic patients

Background Antipsychotic-induced weight gain (AIWG) is a major drawback in the treatment of schizophrenic patients with second-generation antipsychotics (SGAs). Pharmacogenetic studies have established several polymorphisms in genes of different pathways contributing to the development of weight gain in schizophrenic patients. However interactions of genetic polymorphisms and clinical predictors have not been studied extensively enough to reliable predict weight gain before initiating antipsychotic treatment. Methods We analyzed several single-nucleotide polymorphisms (SNPs) of candidate genes (e.g. APOA, GHRL, SNAP-25, LDLR, LPL, INSIG2, Resistin, 5HTR2C, MC4R) and clinical predictors (e.g. age gender, BMI at baseline, number of episodes, pretreatment, PANSS-scores) in a sample of 259 (n=138 for regression analyses) schizophrenic patients participating in different monotherapeutic trials of atypical antipsychotics (risperidone, olanzapine, quetiapine, amisulpride, aripiprazole) with up to six weeks of treatment. We used Univariate tests, regression analysis and Classification and Regression-Tree (CART)-analysis to determine relevant clinical and genetic predictors and their interactions. Results We found younger age, male gender and weight at baseline as strongest clinical predictors. APOA variants and the Resistin -420 C/G rs1862513 polymorphism were associated with weight gain in the overall patient sample. Heterocygotic GC-allele carriers (n=53) gained less weight (1 kg) compared to 2,2 kg in homocygotic G-allele carriers (n=76) ( p p =0.09). The Resistin -420 C/G rs1862513 polymorphism showed significant interaction in patients treated with risperidone ( p 0.0001) and amisulpride ( p =0.0006) in a model adjusted for all clinical predictors. CART-analyses support to some extend the relevance of the Resistin polymorphism. Discussion In this sample we found a polymorphism in the Resistin gene (-420 C/G rs1862513) to potentially contribute to AIWG. CART-analysis shows interactions of several clinical predictors and this polymorphism. Our approach of combining clinical and genetic predictors may help to identify subgroups of patients a priori of SGA treatment in order to reduce development of severe weight gain. Further investigations on larger samples are necessary to confirm our results.

Second Generation Antipsychotics in Asperger’s Disorder and High Functioning Autism: A Systematic Review of the Literature and Effectiveness of Meta-Analysis.

Second generation antipsychotics (SGA) have gained increased evidence for the treatment of irritability and aggression in children and adolescents with lower functioning autistic disorder. Individuals with Asperger's Disorder (AD) and High Functioning Autism (HFA) experience significant emotional and behavioral problems and psychiatric comorbidity. There is a need to review the published literature on SGA treatment efficacy in the AD and HFA populations to provide more effective treatment choices for these subgroups. We conducted a systematic review and meta-analysis of the recent English literature on SGA use in children and adolescents (ages 0-24 years) with AD and HFA using the Medline/PubMed and PsychINFO computerized databases. Key search words were 'Asperger', 'high functioning autism', 'autism spectrum disorders (ASD)', and 'pervasive developmental disorder (PDD)' in combination with 'second generation antipsychotics', 'aripiprazole; 'olanzapine', 'quetiapine', 'risperidone', or 'ziprasidone'. Our search yielded 214 citations, however only open-label or randomized-controlled trials (RCT) with ≥25% of their subjects having an IQ≥71 were included in our review. Eleven original studies met our inclusion parameters for review; eight studies for the meta-analysis. These studies, although limited in methodological rigor, and the meta-analytic results suggest that SGAs provide improvement in behavioral symptoms associated with AD and HFA. The majority of the studies reported weight gain as a potentially concerning adverse effect. There is a lack of robustly conducted trials on the use of SGAs in the management of AD and HFA. More research in pharmacological and psychosocial treatments is warranted. Clinicians are cautioned to approach pharmacological treatment prudently balancing benefit with potential cardiometabolic risk.

A Population-Based Study of Antipsychotic Prescription Trends in Children and Adolescents in British Columbia, from 1996 to 2011

To establish prevalence rates of antipsychotic (AP) prescriptions for children 18 years of age or younger in British Columbia (BC) from 1996 to 2011 by age, sex, AP type, and primary diagnosis; and to identify the predominant AP prescribers for children by specialty training. BC Ministry of Health administrative data were used to describe AP prescriptions for youth aged 18 years or younger. Comparisons were made using population prevalence based on sex; age group; AP; International Classification of Diseases, Ninth Revision, diagnosis; and prescriber specialty. From 1996 to 2011, overall AP (both first and second generation) prescription prevalence rate increased 3.8-fold (1.66 to 6.37 per 1000 population); second-generation AP (SGA) prescriptions increased 18.1-fold (0.33 to 5.98 per 1000 population). The highest increase in all AP prescriptions occurred in males aged 13 to 18 years (3.3 to 14.4 per 1000 population; 4.4-fold), followed by similar increases in males aged 6 to 12 years (2.3 to 8.6 per 1000 population; 3.7-fold) and in females aged 13 to 18 years (2.8 to 10.7 per 1000 population; 3.8-fold). Overall, the 3 most common diagnoses associated with all AP prescriptions were depressive disorders (12.8%), hyperkinetic syndrome of childhood (11.7%), and neurotic disorders (11.1%); however, variation was observed by prescriber specialty training. Among all new AP prescriptions in 2010/11, 38.6%, 34.3%, and 15.6% were provided by psychiatrists, family physicians, and pediatricians, respectively. There has been an exponential rise in SGA prescriptions in BC secondary to extensive off-label use, not only by psychiatrists but also by family physicians and pediatricians. Knowledge translation initiatives promoting evidence-based prescribing and monitoring practices related to SGA treatment need to target all 3 prescriber groups and be tailored for age subgroups.

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

COMT rs4680 variant and cardiometabolic side‐effects in children treated with second‐generation antipsychotics

Second‐generation antipsychotics (SGA) are used to treat children for a wide‐range of mental health conditions but are associated with side effects such as rapid weight gain; increased waist circumference; and elevated fasting plasma glucose, blood pressure, and metabolic syndrome (MetS). The aim of this study is to investigate the interaction of the rs4680 variant in the catechol‐ O‐methyltransferase gene (COMT) and SGA treatment on cardiometabolic side‐effects in a cross‐sectional population of SGA‐treated (n=99) and SGA–naïve (n=114) children. SGA‐treated children had higher (P&lt;0.05) BMI z‐scores, systolic blood pressure (SBP) z‐scores, and fasting plasma glucose and total and LDL‐cholesterol concentrations than SGA‐naïve children. Fifteen percent of SGA‐treated children had MetS compared to 2% of SGA‐naïve children (P=0.001). The COMT rs4680 variant genotype frequencies were not different between SGA‐treated (AA 24.2%, AG 50.5%, GG 25.3%) and SGA‐naïve (AA 24.6%, GA 45.6%, GG 29.8%) children. An interaction between SGA‐treatment and COMT rs4680 genotype was observed such that SGA‐treated children with the AA genotype had higher SBP, fasting plasma insulin, and HOMA‐IR than those with the GG genotype. The opposite effect was observed in SGA‐naïve children. These findings suggest that the COMT rs4680 variant may interact with SGAs and contribute to cardiometabolic side‐effects in children.

Type 2 Diabetes in Children and Adolescents.

Anticipatory guidance regarding healthy eating and active lifestyle is recommended to prevent obesity. Regular targeted screening for type 2 diabetes is recommended in children at risk. Children with type 2 diabetes should receive care in consultation with an interdisciplinary pediatric diabetes healthcare team. Early screening, intervention and optimization of glycemic control are essential, as the onset of type 2 diabetes during childhood is associated with severe and early onset of microvascular complications.

Effects of Aripiprazole, Risperidone, and Olanzapine on 5-HT1A Receptors in Patients With Schizophrenia

To investigate the impact of various antipsychotic drugs on the 5-HT1A serotoninergic system, we performed a [F]4-(2-methoxyphenyl)-1-[2-(N-2-pirydynyl)-p-luorobenzamido]-ethyl-piperazine PET study in 19 schizophrenic patients treated with either aripiprazole, which has a partial agonist activity at 5-HT1A receptors, or second-generation antipsychotics (SGA) (olanzapine or risperidone), which do not demonstrate such property. We used a simplified reference tissue model to generate parametric images of [F]MPPF-binding potential (BPND). A significant reduction of [F]MPPF BPND was found in treated schizophrenic patients compared to age- and sex-matched healthy subjects. These modifications were mainly localized in the frontal and orbitofrontal cortex and may reflect either the pathophysiology of schizophrenia or medication effects. The schizophrenic patients treated with aripiprazole showed a reduction of global [F]MPPF BPND compared with healthy subjects and schizophrenic patients with SGA treatment. In addition, compared with matched controls, the reduction of regional [F]MPPF BPND was more marked in the schizophrenic patients treated with aripiprazole compared with those receiving SGA treatment, possibly reflecting the partial agonist of aripiprazole activity at 5-HT1A receptors.

1609 – How first- and second-generation antipsychotics differentially improve anterior cingulate cortex (ACC) function in schizophrenic patients - an event-related potential study

Introduction/objectives Second-generation antipsychotics (SGAs) are a frequently and effectively used treatment in schizophrenia and psychotic disorders. Other than First-generation antipsychotics (FGAs), which mainly exert their pharmacologic effect in subcortical dopaminergic systems, SGAs additionally affect partly serotonergically innervated structures within prefrontal areas, such as the Anterior Cingulate Cortex (ACC). However, only few controlled, randomized studies have so far investigated direct and indirect effects of SGAs on the ACC. Aims The present study investigated differential effects of one SGA (quetiapine) and one FGA (flupentixol) on the human action monitoring system. Methods ACC function in 18 quetiapine-medicated patients and 13 flupentixol-treated patients suffering from schizophrenia was assessed by means of the error-related negativity (ERN), a neurophysiological marker of ACC function, in a pre-post design. Results Between-group comparisons revealed different effects of quetiapine and flupentixol on ACC function despite similar improvement in psychopathology, cognitive performance and quality of life. Whereas SGA treatment was associated with an increase in amplitudes over time, there were prolonged ERN peak latencies in patients treated with the FGA. Moreover, treatment effects depended on baseline PFC function in both groups. Conclusions We conclude that both flupentixol and quetiapine improve prefrontal function especially in patients with weak initial ACC function which might be due to their shared affinity for 5HT-receptors in frontal brain regions. However, since this affinity is more pronounced for SGAs, patients treated with quetiapine seemed to profit more evidently concerning PFC function compared to patients of the flupentixol group, who exhibited a compensatory prolongation of processes.

Diabetes Resolution Following Discontinuation of a Second-Generation Antipsychotic

Introduction Schizophrenia patients have higher rates of type 2 diabetes mellitus (T2DM) than population comparisons and, in conjunction with highly prevalent obesity and cardiovascular disease, this translates into a 20% reduced life expectancy (1). Unfortunately, despite arguably better outcomes in several psychiatric domains including symptoms, cognition and quality of life, the mortality gap for patients is not narrowing but may indeed be widening (2). Preferential use of second-generation antipsychotics (SGAs) as opposed to older (first-generation antipsychotics, FGAs) antipsychotics may account for the widening mortality gap (3). This is because research has confirmed a link between SGA use and development of T2DM and other metabolic complications (1). Conversely, very little evidence has accumulated that would support a connection between discontinuation of SGAs and diabetes resolution, although implications in the prevailing context would be important. Here, we describe three cases of diabetes onset with SGA treatment and confirmed resolution after switch to an FGA.

Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk. To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain. Pharmacogenetic association study. The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial. The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects. Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks. We conducted a genomewide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug-induced weight gain. Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P<10(-5). This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P=5.59 X 10 (-12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels. These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein

ObjectiveSevere mental disorder and cardiovascular disease (CVD) are often associated, and inflammation is implicated in both disorders. We investigated whether there is a relationship between CVD risk factors and inflammation in schizophrenia or bipolar disorder, and if second generation antipsychotics (SGA) interact. MethodsWe included 361 patients in a naturalistic cross-sectional study, 235 subjects on current SGA treatment and 126 subjects not treated with SGA as controls. Cardiovascular parameters were measured and current medication recorded. Fasting plasma levels of the following cytokines were measured: high sensitivity CRP (hsCRP), soluble tumor necrosis factor receptor 1 (sTNF-R1), osteoprotegerin (OPG), soluble CD40 ligand (sCD40L), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (vWf) and interleukin-6 (IL-6). ResultsIn this relatively young sample of patients with a mean age of 33.3years, the following CVD risk factors were associated with elevated inflammation markers after adjusting for confounders: BMI, triglycerides and glucose with hsCRP (p=0.041–0.001), HDL-cholesterol and triglycerides with sTNF-R1 (p=0.009–0.001) and triglycerides with vWf (p=0.004). In patients treated with SGA, elevated hsCRP was significantly associated with high BMI (p=0.012), and with high glucose levels (p=0.003). ConclusionSeveral CVD risk factors are associated with elevated levels of inflammation markers in young patients with severe mental illness. The interaction between SGA and CVD risk factors on hsCRP levels might indicate a specific inflammatory activation related to SGA induced overweight and hyperglycemia. This suggests that hsCRP could be a valuable marker for future cardiovascular events, particularly in patients treated with SGA.

Waist Circumference is a Sensitive Screening Tool for Assessment of Metabolic Syndrome Risk in Children Treated with Second-Generation Antipsychotics

To compare the prevalence of metabolic syndrome (MetS) and its components in second-generation antipsychotic (SGA)-treated and SGA-naive children; and to explore the utility of clinical markers, such as waist circumference (WC) and body mass index (BMI), as screening tools for MetS. Subjects were prospectively recruited from the Psychiatry Emergency Unit at British Columbia Children's Hospital. As part of a quality-assurance project, a metabolic monitoring protocol was implemented, including collection of anthropomorphic and laboratory data. From January 2008 to February 2010, there were 117 SGA-treated and 217 SGA-naive children recruited. The overall prevalence of MetS was 19.0% (16/84; median treatment duration = 14 months) in SGA-treated and 0.8% (1/127) in SGA-naive children (OR 29.7; 95% CI 3.85 to 228.40, P < 0.001), with an increased prevalence of all components except high-density lipoprotein cholesterol (HDL-C), respectively: elevated WC (40.7% and 10.1%; P < 0.001); hypertriglyceridemia (33.7% and 18.8%; P = 0.01); impaired fasting glucose (12.5% and 0.7%; P = 0.005); and elevated blood pressure (41.2% and 16.5%; P < 0.001). SGA treatment was the strongest predictor of MetS (OR 19.2; 95% CI 2.30 to 160.44, P = 0.006) followed by male sex (OR 5.7; 95% CI 1.08 to 30.62, P = 0.04). Presence of abdominal obesity was more sensitive (92.9%) than BMI (68.8%), while fasting glucose of 5.6 mmol/L or more and HDL-C of 1.03 mmol/L or less were most specific (94.1%) in correctly identifying MetS. SGA treatment confers a significantly increased risk for MetS over the long term. WC measurement is a simple and sensitive screening tool for determining MetS risk in SGA-treated children. These data highlight the dangers of SGA treatment and the importance of standardized metabolic monitoring using sex- and age-adjusted tables in this population.