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Bipolar disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent mania and depression episodes and requiring lifelong treatment with mood stabilizing drugs. Several lines of evidence, including with BD patient iPSC-derived neurons, suggest that neuronal hyperexcitability may underlie the key clinical symptoms of BD. Indeed, higher mRNA levels of SCN11A, coding for the voltage-gated sodium channel NaV 1.9 implicated in nociception, were detected in iPSC-derived neurons from BD patients, and were normalized by in vitro lithium. Here we studied SCN11A expression in peripheral blood mononuclear cells (PBMCs) from well-phenotyped female BD patients and controls and evaluated their association with several clinical sub-phenotypes. We observed higher mRNA levels of SCN11A in PBMCs from female BD patients with no records of alcohol dependence (p = .0050), no records of psychosis (p = .0097), or no records of suicide attempts (p = .0409). A trend was observed for higher SCN11A expression (FD = 1.91; p = .052) in BD PBMCs compared with controls. Datamining of published postmortem gene expression datasets indicated higher SCN11A expression in dorsolateral prefrontal cortex and orbitofrontal cortex tissues from BD patients compared with controls. Higher phenotype-associated expression levels in PBMC from BD patients were also observed for ID2 (alcohol dependence, suicide attempts) and HDGFRP3 (seasonal BD pattern). Our findings suggest that higher PBMC SCN11A expression levels may be associated with certain behavioral BD sub-phenotypes, including lack of alcohol dependence and psychosis, among BD patients. The NaV 1.9 voltage-gated sodium channel thus deserves consideration as a tentative phenotype modifier in BD.

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment. This study aimed to elucidate the transcriptional differences in peripheral blood mononuclear cells (PBMC) between individuals with TRD and a control group without a psychiatric illness; and between patients with TRD, treated with either standard antidepressant drugs alone, or in combination with ECT or ketamine. Additionally, PBMC transcriptomics were compared between treatment responders, following completion of their treatment protocols. Total RNA was extracted from PBMC of the TRD group at two time points, and RNA and miRNA expression were profiled. Multiple mRNAs and miRNAs were found to be modified, with two protein coding genes, FKBP5 and ITGA2B, which are up- and downregulated, respectively; and several miRNAs have shown changes following successful ECT treatment. Further analysis demonstrated the direct functional regulation of ITGA2B by miR-24-3p. Our findings suggest that PBMC expression levels of FKBP5, ITGA2B, and miR-24-3p should be further explored as tentative ECT response biomarkers.

Infection rates, severity, and fatalities due to COVID‐19, the pandemic mediated by SARS‐CoV‐2, vary greatly between countries. With few exceptions, these are lower in East and Southeast Asian and Sub‐Saharan African countries compared with other regions. Epidemiological differences may reflect differences in border closures, lockdowns, and social distancing measures taken by each county, and by cultural differences, such as common use of face masks in East and Southeast Asian countries. The plasma serine protease inhibitor alpha‐1 antitrypsin was suggested to protect from COVID‐19 by inhibiting TMPRSS2, a cell surface serine protease essential for the SARS‐CoV‐2 cell entry. Here, we present evidence that population differences in alpha‐1 antitrypsin deficiency allele frequencies may partially explain national differences in the COVID‐19 epidemiology. Our study compared reported national estimates for the major alpha‐1 antitrypsin deficiency alleles PiZ and PiS (SERPINA1 rs28929474 and rs17580, respectively) with the Johns Hopkins University Coronavirus Resource Center dataset. We found a significant positive correlation (R = .54, P = 1.98e−6) between the combined frequencies of the alpha‐1 antitrypsin PiZ and PiS deficiency alleles in 67 countries and their reported COVID‐19 mortality rates. Our observations suggest that alpha‐1 antitrypsin deficiency alleles may contribute to national differences in COVID‐19 infection, severity, and mortality rates. Population‐wide screening for carriers of alpha‐1 antitrypsin deficiency alleles should be considered for prioritizing individuals for stricter social distancing measures and for receiving a SARS‐CoV‐2 vaccine once it becomes available.

Uncertainties remain concerning the pathophysiology, epidemiology, and potential therapeutics for COVID‐19. Among unsettled controversies is whether tobacco smoking increases or protects from severe COVID‐19. Several epidemiological studies reported reduced COVID‐19 hospitalizations among smokers, while other studies reported the opposite trend. Some authors assumed that smokers have elevated airway expression of ACE2, the cell recognition site of the SARS‐Cov‐2 spike protein, but this suggestion remains unverified. We therefore performed data mining of two independent NCBI GEO genome‐wide RNA expression files (GSE7894 and GSE994) and report that in both data sets, current smokers and never smokers have, on average, closely similar bronchial epithelial cell mRNA levels of ACE2, as well as TMPRSS2, coding for a serine protease priming SARS‐Cov‐2 for cell entry, and ADAM17, coding for a protease implicated in ACE2 membrane shedding. In contrast, the expression levels of TMPRSS4, coding for a protease that primes SARS‐CoV‐2 for cell entry similarly to TMPRSS2, were elevated in bronchial epithelial cells from current smokers compared with never smokers, suggesting that higher bronchial TMPRSS4 levels in smokers might put them at higher SARS‐Cov‐2 infection risk. The effects of smoking on COVID‐19 severity need clarification with larger studies. Additionally, the postulated protective effects of nicotine and nitric oxide, which may presumably reduce the risk of a “cytokine storm” in infected individuals, deserve assessment by controlled clinical trials.

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH–IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine–cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH–IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development.

Dr David Gurwitz has been a Director of The National Laboratory for the Genetics of Israeli Populations at the Sackler Faculty of Medicine, Tel-Aviv University, since its establishment in 1995. His research and teaching interests are focused on pharmacogenomics and its implications for personalized medicine, mainly in the context of neurology and psychiatry.

The Human Genome Project, the most celebrated human consortium effort in biomedicine and one of the greatest scientific achievements of modern time, has yet to deliver the anticipated improvements in healthcare [1] . The blueprint of a human being, the complete 3.2 billion nucleotides of the human DNA sequence, has been available since April 2002. Up to the present day, however, we still understand very little about the biology of common complex disorders, such as diabetes, hypertension, osteoarthritis, osteoporosis, Alzheimer’s disease, schizophrenia, and depression, despite the fact that the genetic determination of each of these conditions is reliably established.

This study aimed to critically appraise the current level of economic evidence available for thiopurine S-methyltransferase (TPMT) testing of thiopurine drugs, such as azathioprine. Six economic evaluations of testing were identified, which all recommended that TPMT testing is a cost-effective use of healthcare resources. Critical appraisal, using published guidelines, showed potential limitations in model structures, approaches to data analysis and input parameters, which were mainly based on expert opinion. Where data did exist these were from retrospective studies. To conduct economic evaluations with more robust findings, decision analysts need good quality data for the following key parameters: current prevalence of profound neutropenia among patients prescribed thiopurine drugs; mean length of related hospitalization and clinical outcome; impact of introducing the test on clinical pathways in terms of resource use; and clinical effectiveness data in terms of number of cases of neutropenia averted and subsequent impact on mortality and health-related quality of life. An iterative approach may be used to stimulate the production of a sufficient evidence base for innovative technologies, such as pharmacogenetic testing. Such an iterative approach involves starting with simple models using available existing clinical and resource use data, as in the case of TPMT testing. The use of formal value of information methods may guide the decision whether prospective studies are required to address uncertainties in the key parameters driving the model results. The results from well-designed prospective studies can then be used to populate more complex economic models.

Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly. Centenarians – reaching the age of >100 years while maintaining good cognitive skills – seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56–82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.

Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50-60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder.

The progressing discovery of genetic variants associated with drug-related adverse events has raised expectations for pharmacogenetic tests to improve drug efficacy and safety. To further the use of pharmacogenetics in health care, tests with sufficient potential to improve efficacy and safety, as reflected by good clinical validity and population impact, need to be identified. The potential benefit of pharmacogenetic tests is often concluded from the strength of the association between the variant and the adverse event; measures of clinical validity are generally not reported. This paper describes measures of clinical validity and potential population health impact that can be calculated from association studies. We explain how these measures are influenced by the strength of the association and by the frequencies of the variant and the adverse event. The measures are illustrated using examples of testing for HLA-B∗5701 associated with abacavir-induced hypersensitivity and SLCO1B1 c.521T>C (∗5) associated with simvastatin-induced adverse events.

ECNP Workshop for Junior Scientists in Europe 9-12 March 2017 • Nice, France Behavioural and Systems Posters

Pharmacogenomics, personalized medicine and global health are hot topics. They represent enormously active areas of research and development (R&D) and are situated at the epicenter of the genomics innovation and investment agenda, both in developed and resource-limited countries [3]. The theme of “personalization” is taking on global significance in healthcare, not only in the case of drug therapy but also for other interventions such as vaccines and nutrition as well as targeted diagnostics and screening programs for early disease detection and preventive medicine. A fine example of the latter includes testing for deleterious mutations in

Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) reduces the risk and severity of cardiovascular diseases. SSRIs block the serotonin transporter, thereby inhibiting serotonin (5-HT) uptake into presynaptic neurons as well as into platelets where 5-HT is stored in dense granules. When 5-HT is released in response to agonists it enhances platelet aggregation induced by injury-related signals. Chronic administration of SSRIs may thus reduce platelet aggregability secondary to depletion of platelets' serotonin stores.The study included ten DSM-IV-TR major depression (MDD) and four obsessive compulsive disorder (OCD) patients and fourteen healthy untreated age- and sex-matched controls. The patients were chronically medicated (6-108 months) with various SSRIs. Platelet serotonin content was assessed in fresh samples of platelet rich plasma (PRP) using radioimmunoassay. ADP, collagen, arachidonic acid and epinephrine were used as inducers of platelet aggregation measured in PRP by turbometric method in a microplate reader.Lower platelet serotonin content (66%; p0.05) and lower ADP, collagen or epinephrine-induced platelet aggregation (10-52%; p0.05) were detected in PRP of SSRI-medicated patients, while no such effect was obtained with arachidonic acid.The small sample size and the co-treatment with non-SSRI drugs such as benzodiazepines.Patients chronically medicated with SSRIs exhibit lower platelet 5-HT content and reduced platelet aggregation induced by ADP, collagen and epinephrine, but not by arachidonic acid. Our observations may explain the increased bleeding risk associated with chronic SSRI treatment as well as the reported beneficial effect of SSRIs in prevention of recurrent myocardial infarction.

Background Lithium remains one of the oldest and most effective treatments for mood stabilization in bipolar disorder (BD), and is still the first-line BD treatment even that individual response is variable. Indeed, at least 30% of patients are only partially responsive, and more than 30% do not respond to lithium therapy. Biomarker predictors for lithium response have been studied by using electroencephalography, neuroimaging and molecular genetics reporting findings that mostly remain modest and unconfirmed. Human lymphoblastoid cell lines (LCLs) and, recently, also iPS cell-derived neurons from BD patients have been employed for searching genes and non-coding RNAs whose expression is modulated by lithium using gene candidate approaches and microarray gene expression technologies. RNA-sequencing (RNA-seq) provides advantages over microarray technologies; it allows detecting transcript differences with low background noise avoiding cross-hybridization issues and allows a large dynamic range of expression level evaluation. Methods This study aimed to identify biomarkers predictive for lithium response, based on comparing RNA-seq information derived from LCLs of lithium responsive (LR) vs. lithium non-responsive (LNR) BD patients, for assessing the patients’ genomic variability related to their therapeutic response to lithium. RNA-seq was carried out on 24 LCLs from female BD patients collected at UCSD classified as 12 LR and 12 LNR (according to combined Alda scale) and followed by a RT-PCR validation in an independent cohort of 41 BD patients (25 LR and 16 LNR) collected at JHMI. Results Our RNA-seq study found few genes with borderline significance differential expression (p=0.06) comparing LR and LNR BD LCLs after correcting for multiple-testing. After filtering for p FC Discussion HDGFRP3 is a protein coding gene found to have growth promoting activity for neurons as well as inducing differentiation of endothelial cells. HDGFRP3 is the only HDGF family member whose expression is almost restricted to the CNS. It is strongly expressed in the adult mice bulbus olfactorius, piriform cortex and amygdala and in cultured cells is predominantly expressed in neurons and slightly in glial cells. In mouse cortical neurons it promotes neuritogenesis via its interaction with microtubules and soluble HRP-3 acts a neurotrophic factor. Thus, we found an upregulation of HRP-3 in LCLs from lithium responder BD patients, suggesting its involvement in lithium response likely via its neurotrophic activity.

Biological drugs are gradually becoming the treatment of choice for chronic autoimmune diseases. However, their high costs are a key healthcare concern limiting their attractiveness for payers. This can, in part, be offset by implementing drug response biomarkers so that payers will only cover the drugs for patients who are most likely to benefit from them. Identifying such biomarkers in turn depends on the availability of well-characterized clinical samples. Research collaboration between the pharmaceutical industry, clinicians, and academia is paramount for achieving this goal. Drug Dev Res 72:549–552, 2011. © 2011 Wiley Periodicals, Inc.

Thiopurine S-methyltransferase (TPMT) is the rate-limiting step in the conversion of thiopurine drugs including azathioprine (AZA) to inactive metabolites. Heritable deficiency of TPMT activity increases risk for adverse events, most notably, myelosuppression leading to leukopenia and neutropenic sepsis. The reported European Commission study was undertaken to identify current evidence for the clinical utility of testing for TPMT status and extent of uptake, by either genotyping or phenotyping, in the clinical setting. Data presented here for the UK and Spain indicate that there has been a considerable increase in the uptake of TPMT testing in recent years. There are some data that support routine TPMT testing before AZA prescribing for reducing AZA-related adverse events. Key data include evidence in favor of TPMT testing in addition to the current practice of routine monitoring for reducing the number of AZA-related episodes of myelosuppression, averting deaths from neutropenic sepsis and improving health-related quality of life. Further data are needed for determining the cost-effectiveness of routine TPMT testing.

Pharmacogenetic tests allow medications to be tailored to individual patients to improve efficacy and reduce drug toxicity. In 2005, the International Society of Pharmacogenomics (ISP) made recommendations for undergraduate medical teaching in pharmacogenetics. We aimed to establish the quantity and scope of this in British medical schools. An electronic survey was sent to all British medical schools. Nineteen out of 34 (56%) medical schools responded. Sixteen of the 19 (84%) respondents provided pharmacogenetics teaching, usually 1–2 h in total. Only four (21%) medical schools offered the four or more hours of teaching recommended by the ISP. However, 10 of 16 (63%) schools felt the amount of pharmacogenetic teaching offered was sufficient. The quantity of undergraduate teaching of pharmacogenetics is low. However, a majority of UK medical schools teach it, covering a broad scope of elements. It is encouraging that future clinicians are being provided with the knowledge to deliver pharmacogenetics into clinical practice.

Objectives: Vitamin K epoxide reductase (VKORC1) is the drug target for inhibition by coumarin-based anticoagulant drugs such as warfarin. Warfarin therapy has been reported as a leading cause of drug-related hospitalization and there is therefore an urgent need to develop tests for better warfarin prescription. We report here the distribution of the intron 1 -136 T>C (1173 T>C intron) polymorphism of VKORC1, previously reported to be associated with warfarin maintenance dose in Caucasians and Japanese, in several ethnic populations from Japan and Israel, and describe its significance for warfarin dosage in Japanese cardiovascular surgery patients. Methods: Subjects consisted of 132 Japanese individuals and 341 Israeli individuals from four Jewish ethnic groups (86 Ashkenazi Jews, 95 Yemenite Jews, 73 Moroccan Jews and 87 Libyan Jews). In addition, 31 Japanese patients receiving warfarin therapy after cardiovascular surgery, maintained with a target International Normalized Ratio, were studied. The genotyping for the 1173 T>C intron polymorphism of VKORC1 was determined using rapid real-time PCR. Results: The allele frequency of the combined VKORC1 1173 CT and CC genotypes varied among the four Israeli ethnic groups and was, on average, much higher in the Israeli (0.728) than in the Japanese population (0.152). For the Japanese cardiovascular surgery patients, the maintenance dose of warfarin was significantly larger in the combined VKORC1 1173 TC and CC genotype group than in the 1173 TT genotype group (3.6 ± 0.5 mg vs 2.8 ± 0.7 mg, respectively; p = 0.02). Conclusion: The frequencies of the intron 1 VKORC1 1173 T>C SNP show significant differences between ethnic groups and are associated with warfarin dose requirements for achieving a recommended International Normalized Ratio range in Japanese cardiovascular surgery patients. This study supports the example of warfarin as an appropriate model for applying personalized medicine for anticoagulant drugs, and highlights the importance of ethnicity in pharmacogenetics.

David Gurwitz1† & Howard L McLeod2† †Author for correspondence 1Department of Human Genetics and Molecular Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel Tel.: +97 236 407 611; Fax: +97 236 407 611; E-mail: gurwitz@ post.tau.ac.il 2Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599-7360, USA Tel.: +1 919 966 0512; E-mail: hmcleod@unc.edu

Metabolic Syndrome, already affecting over 40% of the US population over the age of 60, is fast becoming "the plague of the 21 st century" in developed nations. The time has come for health system policymakers to prioritize the fight against Metabolic Syndrome and its associated morbidity. We need an aggressive effort and funding for better early diagnosis, educational programs and assistance for lifestyle changes, basic research, as well as novel drug development programs. Failing in this effort, we are doomed to witness further increases in morbidity from associated diseases, ranging from type 2 diabetes to coronary heart disease and stroke, with these events taking place at younger ages. The cost to society is projected to be so high that it justifies an effort at least similar in magnitude to past and current drives for fighting cancer, drug abuse, and AIDS. Sadly, it seems that so far we have fallen behind in our battle against Metabolic Syndrome. We call upon government and industry leaders to wake up and engage the fight against Metabolic Syndrome and its associated diseases. The clock is ticking and the cost to society is escalating.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS). Activated coagulation factors are associated with inflammation and are elevated in the plasma of animals with EAE. Thrombin is a key coagulation factor and its major endogenous inhibitors are antithrombin III (ATIII) in the plasma and protease nexin 1 (PN-1) in the brain. We measured the capacity of brain homogenates to inhibit exogenous thrombin and the CNS levels of ATIII and PN-1 during the course of EAE. Acute EAE was induced in SJL/J mice by immunization with mouse spinal cord homogenates. On Days 8, 13, and 22 post-immunization, inhibition of exogenous thrombin activity was measured by a recently developed fluorimetric assay. PN-1 and ATIII were assayed both by immunohistochemistry and by immunoblots in the brain and spinal cord. Total brain thrombin inhibitory activity increased (32%) in EAE mice at the peak of clinical disease (Day 13, P = 0.04 compared to controls). Brain ATIII also increased at the peak of disease (2.5-fold higher than controls, P = 0.0001), and correlated significantly with clinical scores at all stages of disease (r = 0.72, P = 0.0068). In contrast, PN-1 elevations were more pronounced at the preclinical stage on Day 8 (3-fold higher than controls, P = 0.01) than on Day 13 (1.4-fold higher, P = 0.005). Increased brain thrombin inhibition at the clinical peak of EAE probably reflects increased influx of plasma thrombin inhibitors. Early PN-1 changes represent a potential target for thrombin modulating drugs in EAE and MS. © 2004 Wiley-Liss, Inc.

In spite of new therapeutics and diagnostics, thrombosis-related diseases including heart failure and stroke remain the leading cause of death globally and a major healthcare burden. Pharmacogenomic studies may reduce the burden of thrombotic diseases by aiding treatment individualization with the most appropriate anti-coagulant and anti-platelet therapeutics. Discovering and validating biomarkers for improved personalized treatment of thrombotic diseases will require massive investment. A concerted dedicated effort built upon a public-private partnership is warranted for addressing this foremost public health concern.

Psychiatry is among the primary medical disciplines to focus on the potential benefits from the cloning of the human genome and the subsequent implementation of personalized medicine. This viewpoint reflects the evident difficulties of current psychiatric practice compared with other disciplines, most notably the limited understanding of disease etiologies, the lack of reliable and objective diagnostic tools, and the paucity of relevant animal models. These aspects of psychiatry face major changes as a consequence of the recent identification of several schizophrenia risk genes. The reviews presented in this issue illustrate the potential for innovative drug discovery and personalized pharmacotherapy for schizophrenia. Drug Dev. Res. 60:71–74, 2003. © 2003 Wiley-Liss, Inc.

The clinical uptake of pharmacogenomic (PGx) testing and genotype-based prescribing has been disappointingly slow even though research on PGx is thriving. A recent survey on the adoption of PGx testing by US physicians suggests that this trend may start changing for the better. 1 Acquiring more knowledge of PGx tests and their clinical significance during graduate and postgraduate education will enable physicians to make better use of the available and upcoming PGx diagnostics in clinical practice. © 2012 american Society for clinical Pharmacology and Therapeutics.

The prevalence of Alzheimer's disease (AD) is on the rise in developed nations as a consequence of longer human lifespan. Current costs to society are alarming, and are projected to become even more demanding on future health budgets. Considering the relative success of Parkinson's disease pharmacotherapy, the success of AD therapy has been disappointing. Quite a few novel and promising AD drug targets are presented in this special issue of Drug Development Research. These are built on countless research studies, by many bright minds, carried out over the last several decades. However, the answer to the growing AD threat must include reliable and accurate tools, presently lacking, for its early diagnosis in at-risk individuals. Drug Dev. Res. 56:45–48, 2002. © 2002 Wiley-Liss, Inc.

Migraine is among the most common chronic disorders in the developed countries, affecting up to 17% of adult women and 6% of adult men. It is also among the chronic disorders most commonly associated with recurring absence from work. It has been estimated that in the United States the indirect annual societal cost of migraine, mostly as lost work, is US$12 billion. Migraine diagnosis and treatment is hindered by the lack of reliable serum or genetic biomarkers that could potentially improve treatment choices. Research programs focused on identifying and developing migraine biomarkers for both prevention and treatment must be included in the national biomedical research agenda. Drug Dev Res 68:267–269, 2007. © 2007 Wiley-Liss, Inc.

Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal cortex, significantly declines with advanced age. We have previously demonstrated that DHEA prevents the reduction in non-amyloidogenic APP processing, following prolonged stimulation of the muscarinic receptor, in PC12 cells that express the ml acetylcholine-receptor. The present study examined whether this effect may be mediated via modulation of APP metabolism. It was found that DHEA treatment increases the content of membrane-associated APP holoprotein by 24%, and the accumulation of secreted APP in the medium by 63%. No increase in viable cell number nor in nonspecific protein production was observed in DHEA-treated cells. Thus, DHEA seems to increase specifically both APP synthesis and secretion. We propose that the age-associated decline in DHEA levels may be related to the pathological APP metabolism observed in Alzheimer's disease.

Processing of beta-amyloid precursor protein (APP) is coupled to several neurotransmitter receptors, including m1 muscarinic (m1AChR), and is associated with decreased amyloid deposition. Muscarinic agonist-stimulated APP secretion and membrane APP were measured in control and in NGF-differentiated PC12 cells stably transfected with m1AChR. This secretion was markedly enhanced following treatment with 50 ng/ml NGF for 3 days, and was observed using either carbachol or the M1-selective agonist AF102B. The effects of NGF were reflected by larger reductions in membrane-associated APP levels following muscarinic stimulation. These observations imply that M1 muscarinic receptors may act in concert with NGF to boost APP processing, and M1-selective agonists may thus be beneficial for reducing amyloid deposition by NGF-responsive neurons.

Aim: Over 30% of patients with major depression do not respond well to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Using genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) CHL1 was identified as a tentative SSRI sensitivity biomarker. This study reports on miRNAs implicated in SSRI sensitivity of LCLs. Methods: Eighty LCLs were screened from healthy adult female individuals for growth inhibition by paroxetine. Eight LCLs exhibiting high or low sensitivities to paroxetine were chosen for genome-wide expression profiling with miRNA microarrays. Results: The miRNA miR-151-3p had 6.7-fold higher basal expression in paroxetine-sensitive LCLs. This corresponds with lower expression of CHL1, a target of miR-151-3p. The additional miRNAs miR-212, miR-132, miR-30b*, let-7b and let-7c also differed by >1.5-fold (p < 0.05) between the two LCL groups. Conclusion: The potential value of these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients. Original submitted 28 March 2012; Revision submitted 21 May 2012

Adverse drug reactions (ADRs) are a major concern in pharmacotherapy and are more common among women. Immortalized human lymphoblastoid cell lines (LCLs) are emerging as a novel tool for studying interindividual variability in drug response, including ADRs. In the present study, we compared sensitivities of LCLs from unrelated healthy male and female donors to growth inhibition by a panel of common drugs. We observed large interindividual drug sensitivity variations with similar mean sensitivities recorded for LCLs from male and female donors for most tested drugs. A notable exception was observed for the typical antipsychotic haloperidol and the atypical antipsychotic risperidone, which exhibited, on average, more robust in vitro growth inhibition in male as compared with female LCLs. An opposite finding was observed for the antidepressant paroxetine, which was more potent for inhibiting the growth of female as compared with male LCLs. These observations are discussed in the context of the higher incidence of dystonia reported for male schizophrenia patients treated with haloperidol and the higher efficacy of paroxetine in female major depression patients.

Informing patients about risks and benefits of alternative treatment options and choosing between them is becoming a bigger challenge as knowledge about the relationship between the individual's genetic profile and the efficacy and safety of available medications accumulates. Putting personalized medicine into practice requires new modes of information sharing and decision making by patient and physician. This is illustrated by a case study on treatment choices of breast cancer patients following genotyping for CYP2D6, recently published in Genome Medicine.See research article: http://genomemedicine.com/content/3/10/64.

In order to ascertain data availability and feasibility for conducting cost–effectiveness studies in pharmacogenetics, and as part of a European Commission Joint Research Center, Institute for Prospective Technological Studies (JRC-IPTS) study, data concerning risperidone use and cytochrome P450 (CYP2D6) genotyping in medical care was collected in Germany, Spain and the USA, and are summarized in this perspective. The gene coding for CYP2D6 is highly polymorphic, resulting in a significant part of the population being poor metabolizers and ultrarapid metabolizers. Individuals who are CYP2D6 poor metabolizers, have an increased risk of adverse drug reactions (ADRs) when treated with CYP2D6-metabolized drugs, suggesting that CYP2D6 genotyping might be beneficial for patient care. This might be especially important in psychiatry, where approximately 50% of the patients use at least one drug primarily metabolized by CYP2D6. In particular, ADRs and poor response to treatment are major problems for some antipsychotics, including risperidone. However, there are no published cost–effectiveness studies on CYP2D6 genotyping, and the benefit that pharmacogenetic testing might represent by identifying problematic patients is still unclear. The present European Commission study found that current clinical and economical data concerning the frequency and direct healthcare costs of risperidone-related ADRs, the relation of such ADRs with the patients CYP2D6 genotypes, and costs for CYP2D6 genotyping, are not sufficient for determining if routine CYP2D6 genotyping might be cost beneficial for patients treated with risperidone. Therefore, efforts should be put on performing prospective cost–benefit studies with randomized treatment according to the CYP2D6 genotype to establish the utility of CYP2D6 genotyping for personalizing antipsychotic treatment.

Only a few studies have addressed the cost-effectiveness of pharmacogenetics interventions in healthcare. Lack of health economics data on aspects of pharmacogenetics is perceived as one of the barriers hindering its implementation for improving drug safety. Thus, a recent Institute for Prospective Technological Studies (IPTS) study, entitled 'Pharmacogenetics and pharmacogenomics: state-of-the-art and potential socio-economic impact in the EU' included an explorative cost-effectiveness review for a pharmacogenetic treatment strategy compared with traditional medical practice. The selected case study examined the cost-effectiveness of thiopurine methyltransferase (TMPT) genotyping prior to thiopurine treatment in children with acute lymphoblastic leukemia (ALL). Information for the cost-effectiveness model parameters was collected from literature surveys and interviews with experts from four European countries (Germany, Ireland, the Netherlands and the UK). The model has established that TPMT testing in ALL patients has a favorable cost-effectiveness ratio. This conclusion was based on parameters collected for TPMT genotyping costs, estimates for frequency of TMPT deficiency, rates of thiopurine-mediated myelosuppression in TPMT-deficient individuals, and myelosuppression-related hospitalization costs in each of the four countries studied. The mean calculated cost per life-year gained by TPMT genotyping in ALL patients in the four study countries was €2100 (or €4800 after 3% discount) based on genotyping costs of €150 per patient. Cost per life-year gained is expected to further improve following the introduction of the wider use of TMPT genotyping and the availability of lower cost genotyping methods. Our analysis indicates that TPMT genotyping should be seriously considered as an integral part of healthcare prior to the initiation of therapy with thiopurine drugs. © 2006 Future Medicine Ltd. Chemicals / CAS: azathioprine, 446-86-6; mercaptopurine, 31441-78-8, 50-44-2, 6112-76-1; thiopurine methyltransferase, 67339-09-7; Antineoplastic Agents; Methyltransferases, EC 2.1.1.-; thiopurine methyltransferase, EC 2.1.1.67

It is becoming increasingly evident that the implementation of true personalized medicine will not come as rapidly and smoothly as initially hoped. In the aftermath of the drafting of the human genome in 2001, the popular and scientific media featured numerous commentaries heralding the approaching arrival of personalized medicine to the clinic, and describing its huge benefits for patients. Media coverage predicted a drastic transformation for the practice of medicine, second to the revolution brought about by the discovery of vaccines and antibiotics. From the perspective of another 3 years, during which substantial new insights were made into the enormous complexity of human genome variation, it seems that true personalized medicine may still be decades away for many aspects of medical treatment. Nonetheless, the prospects for implementation of at least certain elements of personalized medicine for one key discipline, psychiatry, might be relatively close and more realistic. With the correct focus, realization of some benefits of genetic patient profiling for psychiatric pharmacotherapy might be near, and in due course, lead the way for true personalized psychiatry.

The serotonin transporter (5-HTT) plays a critical role in the termination of serotonin neurotransmission and represents the prime target for selective serotonin reuptake inhibitors (SSRIs). In the present study, the 5-HTT protein in human peripheral blood lymphocyte was characterized pharmacologically and biochemically. The tricyclic antidepressant drug [ 3 H]imipramine, an established ligand for the neuronal and platelet 5-HTT, bound saturably and reversibly to a single population of non-interacting binding sites in fresh human peripheral blood lymphocytes. The affinity of [ 3 H]imipramine ( K d ) to the transporter, calculated from association and dissociation kinetic experiments, was similar to that obtained from the equilibrium study. The function of the transporter was studied using high affinity [ 3 H]5-HT uptake into fresh lymphocytes. [ 3 H]Imipramine binding and [ 3 H]5-HT uptake were inhibited by tricyclic antidepressants as well as by SSRIs. Western blot analysis as well as immunoprecipitation analysis revealed labeling of a single protein band of approximately 100 kDa. The presence of the 5-HTT in easily accessible nucleated cells such as peripheral blood lymphocytes might permit molecular genetic studies in mood and anxiety disorder patients, and might enhance the understanding of the different efficacies of antidepressants in depressed patients.

It is a well-known and sad fact that there is very limited functional recovery following injury to the spinal cord. The social, psychological and financial burden of such calamities, typically involving car- and sport-related accidents, is enormous. It remains a mystery why mammals are unable to repair their damaged spinal cord to any great extent, while reptiles and amphibians are capable of an almost complete functional recovery of damaged spinal cord tissues within a few weeks of injury. In the past decade, it has become clear that the massive neuronal loss following traumatic brain and spinal cord injuries reflects not merely a lack of regeneration, but also a self-propagating spread of the damage, triggered by the primary insult. Michal Schwartz and her colleagues at The Weizmann Institute of Science have been studying this enigma meticulously, based on the principle that mammalian spinal cords [and other central nervous system (CNS) tissues] cannot be repaired because, unlike the reptilian CNS, they are immune privileged and, thus, are not readily accessible to the beneficial repair and maintenance processes involving immune interactions.Now, a new study from this laboratory[1xPassive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. Hauben, E. et al. J. Neurosci. 2000; 20: 6421–6430PubMedSee all References[1] shows that there might be hope for damaged spinal cords if the immune system is stimulated by active or passive immunization with self components of the damaged CNS, for example, myelin basic protein (MBP). Rats were subjected to spinal injury by contusion and injected systematically with anti-MBP T cells, either at the time of contusion, or a week later. Control rats underwent a similar contusion injury, but were injected with anti-ovalbumin T cells instead. The recovery of motor activity, measured by open-field behavior at intervals up to three months post-injury, was significantly better in the MBP-sensitized animals than in the control animals. Hauben et al. used magnetic resonance imaging (MRI) to show that this correlated with the levels of spinal tissue preservation. Remarkably, injection of anti-MBP T cells a week after the injury resulted in similar functional recovery, indicating that the post-traumatic therapeutic window for prevention of damage spread is relatively wide and, at least in rats, lasts for one week.As therapy with T cells requires immune compatibility between the donor and recipient, similar human therapeutic strategies would most probably require ex-vivo activation of the patient's own T cells and their re-administration. However, surprisingly, this study shows that beneficial autoimmunity was also achieved by active immunization with MBP. This is the first ever demonstration of successful vaccination-mediated neuroprotection from traumatic neuronal damage. The immune-privileged status of the mammalian brain might have been an evolutionary inevitability in order to develop its intricacy. The poor capacity to repair and protect traumatic brain tissue is the steep price for such advantages, a price also reflected in the relatively large ischaemic stroke-associated brain damage in humans compared with lower creatures. It now seems that recruiting the immune system would allow novel strategies for circumventing this evolutionary price.

Epidemiologic studies suggest that the age-related decline in dehydroepiandrosterone (DHEA) levels may be associated with Alzheimer's disease (AD). Cholinergic markers also decline with age, and are associated with AD pathology. Activation of m1AChR-transfected PC12 cells (PC12M1) with cholinergic agonists results in secretion of Alzheimer's beta-amyloid precursor protein (APP) which in turn reduces beta-amyloid production. This study examined whether DHEA affects APP processing in m1AChR-transfected PC12 cells. DHEA treatment did not significantly alter basal or m1AChR-stimulated APP secretion. However, DHEA (0.1 microM) significantly diminished the desensitization of APP secretion in cells exposed to carbachol for 24 h. The effect of DHEA on APP processing is probably not related to up-regulation of m1AChR or increased m1AChR-activated phosphoinositide hydrolysis since these parameters did not change following DHEA treatment. These findings imply a possible involvement of DHEA in APP processing. Thus, the age-associated decline in DHEA levels may contribute to decreased APP secretion and a consecutive increase in beta-amyloid deposition, which in turn may play a role in the development of AD.

The non-selective muscarinic agonist oxotremorine induces atropine-sensitive neurite outgrowth in PC12 cells stably transfected with m1 muscarinic receptors. In contrast, AF102B, an M1-selective muscarinic agonist, mediated minimal neurite outgrowth in these cells. In the presence of nerve growth factor (NGF) however, it induced atropine-sensitive neurite outgrowth in almost half the cell population. AF102B mediated phosphoinositide hydrolysis, but unlike carbachol, it did not stimulate cyclic AMP accumulation in these cells. These signals were not affected by NGF, indicating that they were not directly responsible for the cholinergic neurotrophic-like response. Our observations suggest that AF102B may improve neuronal responsiveness to neurotrophic factors, and thus may provide another beneficial aspect for treating Alzheimer's disease.

Secretion of amyloid precursor protein (APP) by cultured cells is coupled to several receptors, including m1 muscarinic (m1AChR), and is associated with decreased production of βA4 amyloid. Secreted and cell-associated APP levels were measured in m1AChR-transfected PC12 cells stimulated with the non-selective agonist carbachol or the Mi-selective agonist, AF102B. Secreted APP levels following stimulation with AF102B (5-60 min) were about half compared with carbachol. Yet, following 24 h stimulation with carbachol or AF102B, cell-associated APP levels were similarly decreased. This may be associated with a smaller reduction in APP secretion following 24 h stimulation with AF102B as compared with carbachol. AF102B may therefore have an advantage over non-selective muscarinic ligands for sustained decrease of cell-associated APP.

Disparities in health outcomes of members of different ancestral or ethnic groups can be observed in both developed and developing countries and continue to be a global concern. Genomic medicine can help toward closing this gap by expanding the knowledge on novel alleles related to disease risk and drug response, their frequencies, and their relation with disease and drug-response phenotypes, in as many countries and ethnic groups as possible. Without such knowledge, genomic medicine cannot deliver upon its promise of contributing to health for all. However, the use of ancestry or ethnicity-related genetic information as a selection criterion for assigning varying levels of access to health care is condemnable. Translational genomic medicine will allow for individualized clinical decision making - doing away with the use of race, ethnicity or ancestry as a proxy. © 2009 BioMed Central Ltd.

To the Editor: Borenstein Graves et al. point to an intriguing association between small head circumference and a substantially elevated risk of AD in carriers of the ApoE -E4 genotype.1 They conclude that smaller head circumference leads to earlier age at onset of AD, and suggest that this distinctive relationship might reflect a …

Pathogenesis of Neurodegenerative Disordersedited by M.P. Mattson. Humana Press, 2001. $135 hardback (304 pages)ISBN 0 89603 838 6Neurodegenerative disorders top the list of diseases whose prevalence is on the rise. In recent decades, better diagnostic tools and treatments have led to diminishing mortality rates from cardiovascular diseases, infectious diseases, and many types of cancer. Yet, the frequency of neurodegenerative disorders, in particular of Alzheimer's and Parkinson's diseases, and the associated morbidity and mortality rates, are rising, along with the increased human life span in industrialized countries.This book is therefore a timely and welcomed addition to the Humana Press Contemporary Neuroscience book series, launched in 1983 and already counting 32 titles. The book, skillfully edited by Mark Mattson, includes 12 chapters, written by experts on different neurodegenerative disorders and discrete aspects of neurodegeneration. Opening chapters deal with general aspects of neurodegeneration, from apoptotic control of cell death to the role of oxidative stress and excitatory amino acids in neurodegeneration. Subsequent chapters cover specific neurological disorders, from Alzheimer's and Parkinson's diseases to Down syndrome, Huntington's disease, amyotrophic lateral sclerosis (ALS), and Duchenne muscular dystrophy. Additional neurological pathologies that are rightfully included, albeit not representing neurodegenerative disorders, are ischaemic stroke and spinal cord injury.Overall, the book is an up-to-date and useful resource on neurodegeneration for researchers and clinicians alike. Many chapters include discussions of animal models, but only a few chapters discuss the genetics of the disorder concerned. A more general discussion on the genetics of neurodegenerative disorders would have been a welcome addition.Yet, some pitfalls are evident. Many chapters fail to discuss diagnosis, such as the use of modern brain imaging tools. Relatively little is mentioned on aspects of therapy, including the emerging hopeful prospects for immunization as future treatment for Alzheimer's disease and for spinal cord injury. Notable by their omission are autoimmune disorders involving neurodegeneration, such as multiple sclerosis, lupus, anti-phospholipid syndrome, and peripheral neuropathy. In a sense, this might be a wise decision: comprehensive coverage of additional disorders would have made this book too weighty.A shortcoming that is not so easily excused is the scarcity of figures: there are a mere 35 figures in the book, mostly simple line drawings – definitely not enough for a medical text describing about 10 disorders and covering about 300 pages. The most sorely missed are images of diseased brain tissues (sections, slides probed with antibodies, brain imaging figures, etc.) – only two such figures are found in the entire book. Notably, the publisher chose for the cover a color slide of silver-stained tissue from the hippocampus of an Alzheimer's disease patient, showing the typical plaques and tangles pathology. The lack of similar figures inside the book appears to be a major drawback for this otherwise informative and up-to-date book. Hopefully, future titles on neurodegeneration will include a wider scope of informative figures.Even with its shortcomings, the book is a solid and valuable resource for PhD. students and scientists working in the field of neurodegeneration. Although I would not recommend it as a general reference book for researchers outside the field, researchers in the field of neurodegeneration will find many chapters to be informative and useful reading.