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Objective: Obsessive-compulsive disorder (OCD) is common and debilitating with patients exhibiting persistent intrusive thoughts (obsessions), repetitive ritualistic behaviours (compulsions) and anxiety. While it is known that OCD is highly heritable, the specific genetic risk factors for OCD are still largely unknown. The etiology of OCD has also not been fully elucidated but there is growing evidence that glutamate signaling dysfunction in the cortico-striatal-thalamo-cortical (CSTC) circuitry plays a role in its pathogenesis., Methods: We conducted a focused review of recent literature on the role of glutamate genes in OCD., Results: There have been several recent discoveries in the SAPAP (DLGAP) family, SLC1A1, and GRIN/GRIK families of proteins related to OCD., Conclusion: There is growing evidence supporting a role for genetic variation leading to dysfunctional glutamate signaling in OCD. Based on this new evidence we hypothesize that sustained glutamatergic neurotransmission in key areas of the brain may be contributing to the etiology of OCD.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The neonatal Fc receptor (FcRn) is a major histocompatibility complex class I type molecule that binds to, transports, and recycles immunoglobulin G (IgG) and albumin, thereby protecting them from lysosomal degradation. Therefore, besides the knowledge of FcRn affinity, FcRn protein expression is critical in understanding the pharmacokinetic behavior of Fc-containing biotherapeutics such as monoclonal antibodies. The goal of this investigation was to achieve for the first time a comparative assessment of FcRn distribution across a variety of tissues and species. FcRn was mapped in about 20 tissues including placenta from human and the most frequently used species in non-clinical safety testing of monoclonal antibodies (mouse, rat, cynomolgus monkey). In addition, the FcRn expression pattern was characterized in two humanized transgenic mouse lines (Tg32 and Tg276) expressing human FcRn under different promoters, and in the severe combined immunodeficient (SCID) mouse. Consecutive sections were stained with specific markers, namely, anti-CD68 for macrophages and anti-von Willebrand Factor for endothelial cells. Overall, the FcRn expression pattern was comparable across species and tissues with consistent expression of FcRn in endothelial cells and interstitial macrophages, Kupffer cells, alveolar macrophages, enterocytes, and choroid plexus epithelium. The human FcRn transgenic mouse Tg276 showed a different and much more widespread staining pattern of FcRn. In addition, immunodeficiency and lack of IgG in SCID mice had no negative effect on FcRn expression compared with wild-type mice.

Pharmacogenetic approach to antidepressant (AD) response is a promising avenue toward individualizing AD treatment. This is particularly relevant in pediatric populations because of concerns about the suicide risk of serotonin selective reuptake inhibitors (SSRIs), resulting in a black-box warning. However, to date, no specific gene or polymorphism has been consistently implicated as a marker of AD side effect (SE) in the pediatric population. The aim of this study was to examine the association between polymorphisms in genes related to the serotonergic system and citalopram SE's in children and adolescents with major depressive disorder (MDD)/dysthymia and/or anxiety disorders. Outpatients (N = 87, 44 % males), aged 7-18 years with a DSM-IV-TR diagnosis of MDD/dysthymia and/or an anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. SE's were rated using a questionnaire devised specifically for this study. Association analysis between known/candidate genetic variants in three genes (5-HTR2A, 5-HTR1Dβ, 5-HTR2C) and SE's was conducted. Agitation was more common in boys than girls (male:female 42.1 vs. 18.7 %, χ 2  = 5.61, df = 1, p = 0.018). Subjects with 5-HTR1Dβ CC genotype showed more agitation vs. both CG and GG genotypes (CC:CG:GG 71.4 vs. 33.3 vs. 18.1 %, χ 2  = 8.99, df = 2, p = 0.011). The 5-HTR1Dβ CC genotype was associated with more reports of agitation. It has been suggested that agitation may be an intermediate phenotype to suicidal behavior. Thus, it seems that 5-HTR1Dβ polymorphism may be involved in citalopram-related agitation in children and adolescents treated for depression and/or anxiety.

Non-clinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these often innovative and complex drugs. Hot Topics in this field were discussed recently at the 4th Annual European Biosafe General Membership meeting. In this feature article, the presentations and subsequent discussions from the main sessions are summarized. The topics covered include: (i) wanted versus unwanted immune activation, (ii) bi-specific protein scaffolds, (iii) use of Pharmacokinetic (PK)/Pharmacodynamic (PD) data to impact/optimize toxicology study design, (iv) cytokine release and challenges to human translation (v) safety testing of cell and gene therapies including chimeric antigen receptor T (CAR-T) cells and retroviral vectors and (vi) biopharmaceutical development strategies encompassing a range of diverse topics including optimizing entry of monoclonal antibodies (mAbs) into the brain, safety testing of therapeutic vaccines, non-clinical testing of biosimilars, infection in toxicology studies with immunomodulators and challenges to human risk assessment, maternal and infant anti-drug antibody (ADA) development and impact in non-human primate (NHP) developmental toxicity studies, and a summary of an NC3Rs workshop on the future vision for non-clinical safety assessment of biopharmaceuticals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The objective of this study was to determine the long-term hematological and biochemical side effects of valproic acid (VPA) in psychiatric adolescent inpatients. A retrospective naturalistic study design was used. Participants were psychiatric inpatients treated with VPA, alone or in combination with other medications. Electronic medical files were reviewed for changes in hematological and biochemical parameters following a course of VPA treatment. One hundred and four adolescents aged 12-18 (mean 15.76±1.58) years fulfilled the study criteria. The mean blood level and duration of VPA treatment were 65.81±22.18 mcg/ml and 98.57±135.94 days, respectively. The mean levels of thyroid-stimulating hormones and triglyceride levels increased significantly from the first to the last measurement. Platelet count decreased significantly following VPA treatment. No correlation was observed between these parameters and age, duration of treatment, or VPA levels. No serious adverse events were reported. Long-term VPA treatment in adolescents with psychiatric disorders is associated with significant increases in triglyceride levels. Moreover, VPA-treated adolescent psychiatric inpatients may be at risk of developing pituitary-thyroid axis dysregulation and decreased platelet count. Therefore, baseline measurement of thyroid functions and metabolic and hematological parameters and monitoring throughout the treatment are recommended.

The impacts of the Holocaust on children of survivors have been widely investigated. However, consensus is limited, and no validated measures have been tailored with or to them. We aimed to develop and validate a scale that measures these specific impacts (Part II of the Danieli Inventory of Multigenerational Legacies of Trauma). We studied 484 adult children of survivors who participated in a cross-sectional web-based survey in English or Hebrew; of these, 191 participated in a clinical interview. Exploratory factor analyses of 58 items to reduce and refine the measure yielded a 36-item scale, Reparative Adaptational Impacts, that had excellent internal consistency (α = .91) and congruence between English and Hebrew versions (φ ≥ .95). Associations between impacts and SCID-based diagnoses of major depressive episode, posttraumatic stress disorder, and generalized anxiety disorder were moderate to strong (ds = 0.48-0.89). Strong associations also emerged between severity of offspring's reparative adaptational impacts and intensity of their parents' posttrauma adaptational styles (Multiple R = .72), with intensity of victim style, especially the mother's, having the strongest effect (β = .31-.33). Having both research and clinical relevance for assessing Holocaust survivors' offspring, future studies might investigate the scale's generalizability to other populations affected by mass trauma., ((c) 2015 APA, all rights reserved).)

Objective: The purpose of this study was to determine if the known side effects of lithium in adults may be generalized to younger patients with psychiatric disorders., Methods: A retrospective naturalistic study design was used. Data were collected from the database of a tertiary pediatric medical center covering the years 1994-2010. Included were patients hospitalized for bipolar and non-bipolar disorders and treated with lithium, alone or in combination with other medications. The electronic medical files were reviewed for changes in thyroid and kidney function and for hematological parameters during the course of treatment., Results: Sixty-one patients 12.5-20.4 years of age (mean 16.94±1.66) met the study criteria: 33 with bipolar disorder and 28 with a non-bipolar disorder. Mean duration of lithium treatment (mean lithium blood level, 0.73±0.24 mEq/L) was 193.68±254.35 days. Mean levels of thyroid-stimulating hormones (TSH) rose significantly from baseline to last measurement (3.16±2.68 vs. 1.52±0.92 mU/L; paired t=-5.19, df=50, p<0.001); in 25% of patients, TSH levels at the last measurement were above normal (≥4 mU/L). Only one patient developed TSH values >10 mU/L (the threshold considered clinically significant). Positive correlation was found between pre- and posttreatment TSH levels (Pearson's r=0.60; n=51, p<0.05). White blood cell count (WBC) also increased significantly following lithium treatment (7195±2151 vs. 7944±2096 cells/mm(3); t=2.83, df=60, p=0.006). No significant changes were noted in serum creatinine levels. There was no difference in these parameters between patients treated with lithium alone or in combination with other medications., Conclusions: Lithium treatment in adolescents with bipolar or non-bipolar disorders is associated with a significant increase in blood TSH levels and WBC count. Lithium-treated adolescent inpatients with a high basal TSH level may be at risk of developing pituitary-thyroid axis dysregulation. Therefore, baseline measurement of thyroid functions and serial monitoring throughout treatment are recommended.

Background and Objective: Elevated levels of platelet-leukocyte aggregates (PLAs) have been reported in several cardiovascular diseases and suggested to contribute to disease pathology. Our aim was to characterize the effects of inclacumab, a novel human anti-P-selectin antibody, on the interactions between leukocytes and platelets in preclinical and clinical studies., Experimental Approaches: Dual-label flow cytometry was used to detect the effect of inclacumab on agonist-induced platelet-leukocyte/platelet-monocyte aggregates in cynomolgus monkeys and humans, following ex vivo and in vivo administration. Platelet-dependent leukocyte activation and leukocyte adhesion to a platelet monolayer were also investigated after ex vivo administration of inclacumab to human blood., Results: Treatment of cynomolgus monkeys with inclacumab profoundly inhibited thrombin receptor-activating peptide (TRAP) or adenosine diphosphate (ADP)-induced PLAs with an IC50 (<2 μg/mL) similar to the in vitro spiking experiments. Maximal inhibition of PLAs persisted for ≥28 days following single dose of inclacumab. In human blood, inclacumab was about 2-fold more potent in inhibiting TRAP-induced PLAs (IC50: 0.7 μg/mL) compared to monkeys. PLA formation was suppressed independently of the inducing platelet agonist. Inclacumab also inhibited the activation of the leukocyte integrin Mac-1 and leukocyte adhesion to a platelet monolayer under flow conditions. In clinical studies, inclacumab inhibited TRAP-induced PLA formation in a dose-dependent manner following single and multiple dose administration to healthy volunteers. It also reduced elevated circulating PLA levels in patients with peripheral arterial disease., Conclusion: By inhibiting platelet-leukocyte interactions, demonstrated in multiple preclinical and clinical studies, inclacumab may provide an effective treatment for cardiovascular diseases., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The purpose of this study was to evaluate the association between polymorphisms in two serotonin pathway genes and the clinical response to citalopram among children and adolescents with depression and/or anxiety disorders., Methods: Eighty-three children and adolescents with depression and/or anxiety disorders were treated with citalopram for 8 weeks. We assessed the association between the response to citalopram and polymorphisms in the tryptophan hydroxylase-2 (TPH2) and the serotonin transporter gene. The polymorphisms included single nucleotide polymorphisms (SNPs) in the transcriptional control region (G-703T) of the TPH2 gene and the serotonin transporter gene-linked promoter region (5-HTTLPR)., Results: Fifty patients of the 83 (60.2%) achieved satisfactory response (Clinical Global Impressions - Improvement ≤2). We observed an additive effect of the two genes on the clinical response to citalopram. Patients carrying the combination of TPH2 -703G and the 5-HTTLPR L alleles were the most likely to respond (80%). In contrast, patients carrying the combination of TPH2 -703T and the 5-HTTLPR S alleles were least likely to respond (31%). The other patients (with -703G/5-HTTLPR S and -703T/5-HTTLPR L alleles) showed intermediate response (67%)., Conclusions: This finding suggests that 5-HTTLPR and TPH2 genes may act in concert to modulate the clinical response to citalopram among children and adolescents with depression and/or anxiety disorders.

In the United States, duloxetine has been approved for the treatment of major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia in the adult population. Data regarding the use of duloxetine in the pediatric population, however, are very limited. Femoral nerve injury is a rare complication of cardiac catheterization. In the case described, duloxetine contributed to a successful multimodal treatment program for peripheral neuropathic pain due to femoral neuropathy in an adolescent with 'reactive depression' and conversion symptoms. To the best of the authors' knowledge, the present article is only the third such report on this dual use of duloxetine in children and adolescents, and the first report of such treatment following femoral neuropathy induced by cardiac catheterization.

Large studies examining remission rates obtained by antidepressants have yielded somewhat dismal results. In the well-reported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 36.8% of patients exhibited remission with the selective serotonin-reuptake inhibitor (SSRI) citalopram and the cumulative remission rate was 67% after multiple treatments were attempted. Warner-Schmidt et al. recently published an interesting paper that suggests specific mechanisms by which anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. They employed well-established mouse models of depression: the tail suspension test and the forced swim test. In their experiment, ibuprofen significantly attenuated the antidepressant-like effects of SSRIs in both tests. The authors also presented data from the STAR*D study itself. These data - demonstrating higher remission rates for depressed patients receiving citalopram without concomitant NSAIDs (55.2%) than those receiving citalopram with NSAIDs (44.5%) - serve to illustrate the potential hindering effects of anti-inflammatory drugs.

To assess the effectiveness and tolerability of citalopram for the acute treatment of children and adolescents suffering from depression and/or anxiety disorders. As much as 78 outpatients, aged 7-18 years with a diagnosis of depressive and/or anxiety disorder, completed an 8-week open trial with citalopram (20-40 mg/day). Outcome, side effects and suicidality were assessed weekly to bi-weekly using appropriate rating scales. At endpoint 56% of subjects were found to be responders (Clinical Global Impression-Improvement [CGI-I] Scale

Selective serotonin reuptake inhibitors (SSRIs) are now an accepted and widely used first-line treatment for pediatric depression and anxiety. However, the data indicate that SSRI treatment achieves a clinical response in only 55-60% of children, and some may develop drug-induced suicidal behavior. Clinicians have no reliable tools to help them identify in advance those youths who are not likely to respond to an SSRI, or who are likely to develop SSRI-induced suicidality. Pharmacogenetic research attempts to identify genetic markers that are associated with response and side-effect profile. This review covers all the pharmacogenetic studies conducted as yet on pediatric samples and compares them with available data on adult samples. An emphasis is put on serotonergic genes such as the serotonin transporter (5-HTT) and additional genes known to be active in the CNS.

Objective: The aim of this study was to examine the association between polymorphism in the serotonin transporter gene and citalopram effectiveness and side effects in children and adolescents with major depressive disorder (MDD) and/or anxiety disorders., Methods: Outpatients, aged 7- 18 years with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) MDD and/or anxiety disorder were treated in an 8-week open trial with 20-40 mg/day of citalopram. Subjects were genotyped with respect to short (s) versus long (l) forms of the 5-HTTLPR polymorphism of the serotonin transporter, and the relationship between genotype and outcome and side effects was assessed., Results: Subjects with 5-HTTLPR ss genotype showed a less vigorous response with regard to depressive symptoms measured by the Children's Depression Rating Scale-Revised (CDRS-R) scores over time compared to subjects with sl/ll genotypes (beta = 0.67, z = 2.02, p = 0.04). In addition, the 5-HTTLPR ss group exhibited lower rates of agitation compared to those with sl/ll genotype (6.3% vs. 32.8%, p = 0.05). Also, subjects with 5-HTTLPR ss genotype had consistently higher scores of suicidality at each week compared to the sl/ll group (beta = 0.76, z = 2.04, p = 0.04) as measured by item number 13 of the CDRS-R., Conclusions: The 5-HTTLPR ss genotype was associated with a poorer clinical response with regard to depressive symptoms as well with fewer reports of agitation. The 5-HTTLPR polymorphism may be a genetic marker of response to citalopram in children and adolescents with depression and/or anxiety.

The complex infection process of parvoviruses is not well understood so far. An important role has been attributed to a phospholipase A2 domain which is located within the unique N terminus of the capsid protein VP1. Based on the structural difference between adeno-associated virus type 2 wild-type capsids and capsids lacking VP1 or VP2, we show via electron cryomicroscopy that the N termini of VP1 and VP2 are involved in forming globules inside the capsids of empty and full particles. Upon limited heat shock, VP1 and possibly VP2 become exposed on the outsides of full but not empty capsids, which is correlated with the disappearance of the globules in the inner surfaces of the capsids. Using molecular modeling, we discuss the constraints on the release of the globularly organized VP1-unique N termini through the channels at the fivefold symmetry axes outside of the capsid.

The onset or exacerbation of psoriasis, a T-cell-dependent skin disease with autoimmune features, can be triggered by drugs such as antimalarials and beta-blockers. Xenobiotics may also play a role in idiopathic psoriasis. It has been hypothesized that different metabolic efficiencies caused by variant alleles of xenobiotic metabolizing enzymes could lead to the accumulation of xenobiotics or their reactive metabolites in target organs. Subsequently, neoantigens or cryptic peptides could be presented and initiate an aggressive T cell response. In this context, we analyzed a broad array of xenobiotic metabolizing enzymes in up to 327 Caucasian psoriasis patients and compared them to 235 control persons. Alleles tested include four phase I and three phase II enzymes. Significantly more carriers of the variant alleles of CYP1A1 (alleles *2A and *2C) were found in healthy controls than in patients, suggesting a protective role for these alleles. No significant difference between patients and controls could be found, however, for the other phase I alleles 1B1*1 and 1B1 *3, 2C19*1A and 2C19*2A, and 2E1*1A and 2E1*5B. Of the variant alleles coding for phase II enzymes only GSTM1, but not GSTT1 or NQOR, correlated with a risk to contract psoriasis. Some combinations of phase I and phase II enzymes suggested protective or risk-associated effects. Interestingly, heterozygosity for CYP2C19 alleles *1A and *2A was associated with increased risk for "late onset" psoriasis, whereas this genotype was protective for psoriatic arthritis. This is the first large-scale study on these enzymes and the results obtained support the concept that different activities of metabolizing enzymes can contribute to disease etiology and progression.

Adeno-associated virus type 2 empty capsids are composed of three proteins, VP1, VP2 and VP3, which have relative molecular masses of 87, 72 and 62 kDa, respectively, and differ in their N-terminal amino acid sequences. They have a likely molar ratio of 1:1:8 and occupy symmetrical equivalent positions in an icosahedrally arranged protein shell. We have investigated empty capsids of adeno-associated virus type 2 by electron cryo-microscopy and icosahedral image reconstruction. The three-dimensional map at 1.05 nm resolution showed sets of three elongated spikes surrounding the three-fold symmetry axes and narrow empty channels at the five-fold axes. The inside of the capsid superimposed with the previously determined structure of the canine parvovirus (Q. Xie and M.S. Chapman, 1996, J. Mol. Biol., 264, 497-520), whereas the outer surface showed clear discrepancies. Globular structures at the inner surface of the capsid at the two-fold symmetry axes were identified as possible positions for the N-terminal extensions of VP1 and VP2.