Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype

Rationale

Metabolic syndrome (MetS) has consistently been identified as an adverse effect of long-term treatment with atypical antipsychotics (AAPs) such as clozapine. Elevated serum homocysteine concentration has been found to act as an independent risk factor for MetS, and catechol-O-methyltransferase (COMT) catalyzes the homocysteine metabolism. We accordingly hypothesized that COMT dysregulation may confer the susceptibility to MetS induced by AAPs, potentially in a gender-specific manner, because the interaction effects of COMT and gender have been consistently reported.

Objectives

This study aimed at determining the prevalence and influence of COMT on MetS among a population undergoing long-term clozapine treatment.

Methods

A total of 468 schizophrenia patients taking clozapine were divided into two groups, those experiencing MetS and non-MetS. We genotyped three functional variants (rs4633, rs4680, and rs4818) in COMT and measured the serum levels of fasting homocysteine, glucose, triglyceride (TG), and high-density lipoprotein cholesterol.

Results

MetS was found in 202/468 (43.2 %) of all the patients, with 40.2 % prevalence (138/343) in males and 51.2 % (64/125) in females. Patients with MetS had notably higher metabolic parameters than those without MetS. The mean levels of homocysteine in patients with MetS were significantly higher than those without MetS. We found a positive association between the rs4680 polymorphism and the serum triglyceride levels (corrected P?=?0.024). Further analysis revealed that the rs4680 Met allele was significantly associated with increased triglyceride levels among female patients (P?=?0.009), but not among males (P?=?0.07).

Conclusions

Our findings suggest a potential association between rs4680 in COMT and elevated TG levels, particularly among female patients.     

D2 and D3 dopamine receptor affinity predicts effectiveness of antipsychotic drugs in obsessive-compulsive disorders: a metaregression analysis

Rationale and objective

The relationship between clinically effective antipsychotic drugs in obsessive–compulsive disorders (OCD) and binding affinities to cloned dopamine and serotonin receptor subtypes was analyzed in an effort to clarify the contribution of individual receptor subtypes to medication response.

Methods

Meta-analysis was used to update previous meta-analyses of effectiveness data of add-on antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) in OCD. Twelve previously analyzed randomized controlled trials (RCTs) and one new RCT were included. We performed a metaregression using a mixed-effect model to examine the association between antipsychotic’s effectiveness and receptor affinity.

Results

A total of 5 treatment arms obtained from 13 RCTs (431 patients) were included in our study. The results of our metaregression showed a significant association between D2 and D3 dopamine receptor affinities and effectiveness in OCD (respectively, slope?=??0.36, p?=?0.01; and slope?=??0.50, p?=?0.01) whereas other dopamine receptors and serotonin receptors were not significantly associated.

Conclusions

These observations suggest that increasing D2 and D3 dopamine receptor binding affinities enhances antipsychotics’ effectiveness in obsessive–compulsive disorders.     

Functional Screening of Drug Target Genes

Background and objectives: A number of recent studies surveying single nucleotide polymorphisms within the exonic regions of human genes have revealed a significant number of such variants, including many non-synonymous variants. This highlights the need to directly identify, within individual clinically well-defined patients, those variants that alter protein function as well as structure. We report on the development of a novel phenotypic screening process that combines high-throughput molecular cloning techniques with functional expression utilizing the cell-based assay R-SAT. Methods: We applied the phenotypic screening process to an analysis of the m1 muscarinic acetylcholine receptor (CHRM1) gene in a cohort of 74 individuals, including 48 diagnosed with neurodegenerative disease, primarily Alzheimer disease, who have been stratified according to their clinical response to the acetylcholinesterase inhibitor donepezil. Phenotypic screening of the CHRM1 gene involved PCR-based amplification from genomic DNA and heterologous expression in mammalian cells. Results: Phenotypic screening yielded functional responses to the agonist carbachol displaying a mean potency (?pEC50 ± standard deviation) of 5.8 ± 0.2, which did not differ from that observed with expression of the wild-type receptor gene (6.0 ± 0.3). No altered levels of constitutive receptor activity were observed. Dideoxy sequencing did not reveal any non-synonymous variants in the coding exon of this gene within this clinical cohort, while detecting three synonymous variants. Conclusion: The results confirm that the m1 receptor gene (CHRM1) is not highly polymorphic in the human population, suggesting that genetic variation within the coding exon of this gene is not a contributing factor to the clinical variability observed during treatment of dementia with cholinergic enhancement therapies.     

Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment

Rationale

The endocannabinoid system has been implicated in the pathogenesis of major depression (MD) as well as in the mediation of antidepressant drug effects.

Objectives

To analyze CNR1 gene variants in MD and clinical response to citalopram (selective serotonin re-uptake inhibitors [SSRI]).

Methods

The role of CNR1 gene (rs806368, rs1049353, rs806371, rs806377 and rs1535255) was investigated in 319 outpatients with MD and 150 healthy individuals. A subsample of 155 depressive patients were treated with citalopram and evaluated for response (fourth week) and remission (12th week) by the 21-item Hamilton Depression Rating Scale (HDRS).

Results

We observed a higher frequency of rs806371 G carriers in MD patients with both presence of melancholia (p?=?0.018) and psychotic symptoms (p?=?0.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368–rs1049353–rs806371) (p?=?0.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p?=?0.0009) and psychotic symptoms (p?=?0.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p?=?0.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p?=?0.032). Also, we observed significant effect of time–sex–genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group (p?=?0.026).

Conclusions

These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram.     

Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia

Rationale

Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine.

Objective

The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS).

Methods

We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables.

Results

T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p?=?0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8?% variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38?% variability.

Conclusions

We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.     

Risk for antipsychotic-induced extrapyramidal symptoms: influence of family history and genetic susceptibility

Objectives

This study aims to further evaluate the impact of family history of primary movement disorders (FHpMD) and a candidate genetic variant on risk of antipsychotic-induced extrapyramidal symptoms (EPS).

Methods

We examined 156 (76 men) inpatients receiving antipsychotics for EPS and FHpMD stratified by patient characteristics. The genetic analysis included genotyping of a multiallelic dinucleotide polymorphism in the ATP1A3 gene.

Results

EPS lifetime prevalence was 69% and more frequent in the presence of FHpMD (p?=?0.052), particularly in patients younger than 60?years (p?=?0.012) and with acute dystonic reactions. The ATP1A3 polymorphism showed an allele length-dependent association with parkinsonism (p=0.019 uncorrected, p=0.057 corrected) exclusively. Carriers of the shortest allele had a 7.7-fold increased risk for parkinsonism.

Conclusions

The association of FHpMD and EPS may be linked to the EPS subtype and age of the patient. A common ATP1A3 genomic variation may represent a susceptibility factor for the risk for antipsychotic-induced parkinsonism in an allele-dependent manner.     

Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive–compulsive symptoms

Rationale

Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive–compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology.

Objectives

This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms.

Methods

A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped.

Results

Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene–gene interaction model (p?=?0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F _{6, 137}?=?7.650, p?<?0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT.

Conclusions

These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.     

A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression

Rationale

In clinical practice, ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR (GRIN2B) is considered a promising candidate gene for MDD susceptibility.

Objectives

The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients.

Methods

We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls.

Results

Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G–T haplotype between the TRD and control groups (corrected P?=?0.007), and the frequency of the G–T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR?=?1.55, 95 % CI?=?1.18–2.05, corrected P?=?0.008).

Conclusions

These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients.     

Antidepressant use and glycemic control

Rationale

Past research on the association of antidepressant medication use with glycemic control abnormalities has produced mixed results.

Objective

To examine the association of antidepressant use with glycemic control abnormalities and screen-positive diabetes in a representative population sample of US adults without a diagnosis of diabetes.

Methods

Using data from adult participants of the National Health and Nutrition Examination Survey (NHANES, 2005–2010), the association of antidepressant use with continuous measures of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, insulin sensitivity and screen-positive diabetes according to HbA1c, fasting blood sugar and 2-h oral glucose tolerance test were assessed.

Results

Antidepressant use was not associated with increased levels of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, reduced insulin sensitivity or increased prevalence of screen-positive diabetes. Results were mostly consistent across sociodemographic groups and across different lengths of exposure, different classes of antidepressants and levels of body mass index.

Conclusions

In this representative population sample, antidepressant use was not associated with an increased risk of abnormalities in glycemic control or undetected diabetes. Positive findings from past research may be attributable to detection bias, in that individuals prescribed antidepressants may be more likely to be tested and diagnosed with diabetes.     

Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage

Purpose

ORM1 is a plasma drug binding protein. Its polymorphism rs17650 (*S>*F) has been reported to be an important factor affecting the binding ability and effect of antiretroviral protease inhibitors. The aim of this study was to determine whether the ORM1 rs17650 polymorphism also influences warfarin therapy.

Methods

A total of 191 Chinese patients with steady-dose warfarin therapy were enrolled in this study. The patients were studied for warfarin maintenance dose, the ORM1 rs17650 polymorphism, and two polymorphisms previously demonstrated to affect warfarin response [CYP2C9 rs1057910 (*3) and VKORC1 rs7294 (?1639 G>A)].

Results

Warfarin dose was partially correlated with the VKORC1 rs7294, CYP2C9 rs1057910 and ORM1 rs17650 polymorphisms. Patients carrying the wild-type of these three genes (n = 96) took a mean dose of 3.0?±?1.1 mg warfarin, which was significantly higher than that taken by the 52 *S patients (2.7?±?0.7) and 11 *S*S patients (2.5?±?0.6 mg) (p =?0.048).

Conclusion

We identified ORM1 as another polymorphic gene affecting warfarin dose requirements. ORM1 *S carriers require lower maintenance doses to achieve and maintain an optimal level of anticoagulation.     

The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

Rationale

Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence.

Objectives

We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI.

Methods

We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured.

Results

Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation.

Conclusions

The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.     

CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients

Purpose

Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice.

Methods

Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n?=?21) or in combination with metformin (n?=?135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110.

Results

The average duration of diabetes in the study group was 10.6?±?7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0?±?0.9). In total, 76 hypoglycemia events were observed (mean 0.48?±?1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n?=?103). Among them, carriers of two wild-type alleles suffered 0.36?±?0.98 events, while patients with one or two polymorphic alleles had 0.79?±?1.7 or 2.67?±?4.6 events, respectively (p?=?0.014).

Conclusions

Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.     

The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype

Rationale

Oxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults?? responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single-nucleotide polymorphism of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype.

Objectives

The present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults?? preferences for infant faces.

Methods

A double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants?? and adults?? faces showing neutral expressions and assessed how appealing they found each face.

Results

Infants?? faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults?? faces.

Conclusions

The present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results are also consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.     

Exploring Variation in Known Pharmacogenetic Variants and its Association with Drug Response in Different Mexican Populations

Purpose

Information on genetic variants that affect the pharmacokinetics and pharmacodynamics (PK/PD) of drugs in different populations from Mexico is still an ongoing endeavor. Here, we investigate allele frequencies on pharmacogenetic targets in Mexican Mestizos and Natives from three different States and its association with drug efficacy in individuals receiving either anticoagulants or antipsychotic drugs.

Methods

Natives from three different states and Mestizo patients receiving acenocoumarol or antipsychotics were genotyped using the DMET microarray (Affymetrix).

Results

We provide a collection of genetic variants that indicate that there are 3-times more variation than similarities between populations from Mexico and major continental groups. These differences were observed in several relevant targets including ABCB1, SLCO1A1, NAT2, UGTs, TYMS, VKORC1, and NR1I3. Moreover, Mexican Mestizos also showed allele frequency differences when compared to Natives for variants on DPYD, ADH1A, CYP3A4, SLC28A3, and SLC28A1. Significant allele differences also arose among the three Native groups here studied, mostly for transporters of the ABC-binding cassette and the solute carrier gene family. Finally, we explored genotype-drug response associations and pinpointed variants on FMOs (coumarins), and GSTM1 (haloperidol).

Conclusions

These findings confirm previous results and further delve into the pharmacogenetics of Mexican populations including different Native groups.

     

Role of cannabis and endocannabinoids in the genesis of schizophrenia

Rationale

Cannabis abuse and endocannabinoids are associated to schizophrenia.

Objectives

It is important to discern the association between schizophrenia and exogenous Cannabis sativa, on one hand, and the endogenous cannabinoid system, on the other hand.

Results

On one hand, there is substantial evidence that cannabis abuse is a risk factor for psychosis in genetically predisposed people, may lead to a worse outcome of the disease, or it can affect normal brain development during adolescence, increasing the risk for schizophrenia in adulthood. Regarding genetic predisposition, alterations affecting the cannabinoid CNR1 gene could be related to schizophrenia. On the other hand, the endogenous cannabinoid system is altered in schizophrenia (i.e., increased density of cannabinoid CB1 receptor binding in corticolimbic regions, enhanced cerebrospinal fluid anandamide levels), and dysregulation of this system can interact with neurotransmitter systems in such a way that a “cannabinoid hypothesis” can be integrated in the neurobiological hypotheses of schizophrenia. Finally, there is also evidence that some genetic alterations of the CNR1 gene can act as a protectant factor against schizophrenia or can induce a better pharmacological response to atypical antipsychotics.

Conclusions

Cannabis abuse is a risk factor for psychosis in predisposed people, it can affect neurodevelopment during adolescence leading to schizophrenia, and a dysregulation of the endocannabinoid system can participate in schizophrenia. It is also worth noting that some specific cannabinoid alterations can act as neuroprotectant for schizophrenia or can be a psychopharmacogenetic rather than a vulnerability factor.     

The association between CYP2D6 genotype and switching antipsychotic medication to clozapine

Purpose

Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics.

Methods

CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics.

Results

A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively).

Conclusions

Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes.     

Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders

Rationale

Autism and related pervasive developmental disorders (PDD) are characterized by impairments in social interaction and communication, restricted interests, and repetitive and stereotyped patterns of behavior. Individuals with PDD frequently display irritability and disruptive behaviors including tantrums, self-injurious behavior, and aggression. Atypical antipsychotics are currently the most efficacious pharmacological interventions available for treatment of irritability associated with PDD.

Objectives

This article aims to review the body of literature pertaining to the use of atypical antipsychotics in the treatment of patients with PDD.

Methods

A PubMed literature search was conducted using the following key words: autism, pervasive developmental disorders, atypical antipsychotics, risperidone, aripiprazole, quetiapine, ziprasidone, olanzapine, clozapine, paliperidone, iloperidone, asenapine, and lurasidone. Search terms were limited to English language, human subjects, and publication from 1999 to present. Relevant references from identified articles were also reviewed.

Results

The efficacy and tolerability of risperidone and aripiprazole for the treatment of irritability in autism have been established with multi-site, randomized, controlled trials. Studies supporting the use of other atypical antipsychotics are either limited in scope or less robust in their findings, though newer agents such as ziprasidone and paliperidone show promise.

Conclusions

Atypical antipsychotics are currently first-line pharmacological agents for the treatment of irritability and associated behaviors in children with PDD. Further placebo-controlled studies are warranted to characterize the efficacy and tolerability of the majority of these medications. There is also a need for the development of novel, targeted drugs with more favorable long-term side effect profiles.     

Towards the development of novel Trypanosoma brucei RNA editing ligase 1 inhibitors

Background

Trypanosoma brucei (T. brucei) is an infectious agent for which drug development has been largely neglected. We here use a recently developed computer program called AutoGrow to add interacting molecular fragments to S5, a known inhibitor of the validated T. brucei drug target RNA editing ligase 1, in order to improve its predicted binding affinity.

Results

The proposed binding modes of the resulting compounds mimic that of ATP, the native substrate, and provide insights into novel protein-ligand interactions that may be exploited in future drug-discovery projects.

Conclusions

We are hopeful that these new predicted inhibitors will aid medicinal chemists in developing novel therapeutics to fight human African trypanosomiasis.     

The Impact of Glycosylation on the Pharmacokinetics of a TNFR2:Fc Fusion Protein Expressed in Glycoengineered Pichia Pastoris

Purpose

P. pastoris has previously been genetically engineered to generate strains that are capable of producing mammalian-like glycoforms. Our objective was to investigate the correlation between sialic acid content and pharmacokinetic properties of recombinant TNFR2:Fc fusion proteins generated in glycoengineered P. pastoris strains.

Methods

TNFR2:Fc fusion proteins were generated with varying degrees of sialic acid content. The pharmacokinetic properties of these proteins were assessed by intravenous and subcutaneous routes of administration in rats. The binding of these variants to FcRn were also evaluated for possible correlations between in vitro binding and in vivo PK.

Results

The pharmacokinetic profiles of recombinant TNFR2:Fc produced in P. pastoris demonstrated a direct positive correlation between the extent of glycoprotein sialylation and in vivo pharmacokinetic properties. Furthermore, recombinant TNFR2:Fc produced in glycoengineered Pichia, with a similar sialic acid content to CHO-produced etanercept, demonstrated similar in vivo pharmacokinetic properties to the commercial material. In vitro surface plasmon resonance FcRn binding at pH6.0 showed an inverse relationship between sialic acid content and receptor binding affinity, with the higher affinity binders having poorer in vivo PK profiles.

Conclusions

Sialic acid content is a critical attribute for modulating the pharmacokinetics of recombinant TNFR2:Fc produced in glycoengineered P. pastoris.     

The d-amphetamine-treated Göttingen miniature pig: an animal model for assessing behavioral effects of antipsychotics

Rationale

Rodents are usually used to assess the ability of antipsychotic drugs to antagonize hyperlocomotion induced by dopamine agonists, such as the psychostimulant d-amphetamine. However, the substantial differences between rodents and humans may hinder extrapolation of experimental results to humans. For this reason, we speculated that Göttingen miniature pigs, which show strong physiological and genetic homology with humans, might be a better model for investigating the effects of antipsychotics. To investigate this, we determined whether d-amphetamine induced hyperlocomotion in miniature pigs and whether this effect was reversible by antipsychotics.

Materials and methods

d-Amphetamine was tested in the dose range of 0.2 to 2.0 mg kg^?1 for its ability to induce hyperactivity in the open field, and the effects of two antipsychotics, haloperidol and risperidone, on amphetamine-induced hyperactivity were examined.

Results

d-Amphetamine increased open-field activity at 0.2, 0.4, and 0.7 mg kg^?1 s.c. but not at higher doses. The stimulation of open-field activity induced by 0.4 mg kg^?1 s.c. d-Amphetamine was antagonized by haloperidol and risperidone (0.01 and 0.04 mg kg^?1 s.c.).

Conclusion

d-Amphetamine-induced hyperlocomotion in miniature pigs may be a useful model for studying the effect of putative antipsychotics.