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Negative symptoms often inhibit the social integration of people suffering from schizophrenia. Reducing severe negative symptoms (SNS) in a clinically relevant way is a major unmet need. The aim of this study was to investigate whether Integrated Neurocognitive Therapy (INT), a group cognitive remediation therapy (CRT), reduces SNS in schizophrenia outpatients. INT was compared with Treatment As Usual (TAU) in a randomized-controlled trial (RCT). A total of 61 SNS outpatients participated in the study, 28 were allocated to the INT group and 33 to the TAU group. A test-battery was used at baseline, post-treatment at 15weeks, and 1-year-follow-up. Remission rates of SNS after therapy were significantly higher for INT compared to TAU. A trend favoring INT was obtained at follow-up. Furthermore, INT showed significantly higher functional outcome during follow-up compared to TAU. Regarding cognition, the strongest significant effect was found in attention post-treatment. No effects between groups on more complex neurocognition and social cognition were evident. SNS outpatients seem to accept INT group intervention as suggested by the high attendance rate. [ABSTRACT FROM AUTHOR]

Purpose: Several risk factors and causes of adjacent segment disease have been debated; however, no quantitative relationship to spino-pelvic parameters has been established so far. A retrospective case-control study was carried out to investigate spino-pelvic alignment in patients with adjacent segment disease compared to a control group. Methods: 45 patients (ASDis) were identified that underwent revision surgery for adjacent segment disease after on average 49 months (7-125), 39 patients were selected as control group (CTRL) similar in the distribution of the matching variables, such as age, gender, preoperative degenerative changes, and numbers of segments fused with a mean follow-up of 84 months (61-142) (total n = 84). Several radiographic parameters were measured on pre- and postoperative radiographs, including lumbar lordosis measured (LL), sacral slope, pelvic incidence (PI), and tilt. Results: Significant differences between ASDis and CTRL groups on preoperative radiographs were seen for PI (60.9 ± 10.0° vs. 51.7 ± 10.4°, p = 0.001) and LL (48.1 ± 12.5° vs. 53.8 ± 10.8°, p = 0.012). Pelvic incidence was put into relation to lumbar lordosis by calculating the difference between pelvic incidence and lumbar lordosis (∆PILL = PI−LL, ASDis 12.5 ± 16.7° vs. CTRL 3.4 ± 12.1°, p = 0.001). A cutoff value of 9.8° was determined by logistic regression and ROC analysis and patients classified into a type A (∆PILL <10°) and a type B (∆PILL ≥10°) alignment according to pelvic incidence-lumbar lordosis mismatch. In type A spino-pelvic alignment, 25.5 % of patients underwent revision surgery for adjacent segment disease, whereas 78.3 % of patients classified as type B alignment had revision surgery. Classification of patients into type A and B alignments yields a sensitivity for predicting adjacent segment disease of 71 %, a specificity of 81 % and an odds ratio of 10.6. Conclusion: In degenerative disease of the lumbar spine a high pelvic incidence with diminished lumbar lordosis seems to predispose to adjacent segment disease. Patients with such pelvic incidence-lumbar lordosis mismatch exhibit a 10-times higher risk for undergoing revision surgery than controls if sagittal malalignment is maintained after lumbar fusion surgery. [ABSTRACT FROM AUTHOR]

Since bone morphogenetic proteins (BMPs) play an important role in melanoma progression, we aimed to determine the molecular mechanisms leading to overexpression of BMP4 in melanoma cells compared to normal melanocytes. With our experimental approach we revealed that loss of expression of a microRNA represents the starting point for a signaling cascade finally resulting in overexpression of BMP4 in melanoma cells. In detail, strongly reduced expression of the microRNA miR-196a in melanoma cells compared to healthy melanocytes leads to enhanced HOX-B7 mRNA and protein levels, which subsequently raise Ets-1 activity by inducing basic fibroblast growth factor (bFGF). Ets-1 finally accounts for induction of BMP4 expression. We were furthermore able to demonstrate that bFGF-mediated induction of migration is achieved via activation of BMP4, thus determining BMP4 as major modulator of migration in melanoma. In summary, our study provides insights into the early steps of melanoma progression and might thereby harbor therapeutic relevance. [ABSTRACT FROM AUTHOR]

Highlights from the article: Genome-wide analyses of remission on venlafaxine treatment in older adults with late-life depression The objective of this investigation was to conduct a genome-wide association study (GWAS) of late-life depression (LLD) remission after treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Discussion: Our post-GWAS analyses support the involvement of known processes in synaptic plasticity, as well as, intracellular signaling pathways including MAPK and neutrophins (e.g., BDNF) as being involved in LLD remission on venlafaxine.

Psychiatric medications continue to be prescribed on a 'trial-and-error' fashion, with virtually no predictive tools available allowing to select type and dose of medications for any given individual. An increasing amount of evidence support an important role for genetic markers to improve outcome to many antidepressant and antipsychotic used for depression and schizophrenia, respectively. High levels of clinical evidence in favor of genetic associations are particularly reported for drug metabolizing genes. Another example are patients of Asian ancestry who receive carbamazepine and where the HLA-B*1502 marker substantially increases risk of serious skin disorders (Stevens Johnson Syndrome and toxic epidermal necrolysis), leading to policies where genetic testing is now mandatory in some Asian countries. This presentation will begin by reviewing the state of the current research with a focus on drug metabolizing enzymes and highlight expert consensus guidelines and recommendations provided by national drug and safety administrative institutions. CYP450 enzymes, and in particular CYP2D6 and CYP2C19, are responsible for metabolizing most psychiatric medications. Data will be shown from 383 physicians (mostly psychiatrists and family general practitioners) from the greater Toronto area returning surveys following genetic testing for CYP2D6 and CYP2C19 genes (among others) of their patients treated with antidepressants and antipsychotic medications. Questionnaires where retrieved 6-8 weeks later and results indicate that whenever genetic information was considered in their treatment decisions, improvement of drug treatment was seen in 122 cases compared to only 2 cases where a slight symptom deterioration was reported (p < 0.01). Next, results from genetic analyses in noradrenergic and serotonergic genes will be shown from 350 adults diagnosed with late life depression (LLD). Participants received open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor, for up to 12 weeks. After adjusting for multiple comparisons, the norepinephrine variant rs2242446 (T-182C) was significantly associated with remission (odds ratio=1.66, 95% CI=1.13, 2.42). Individuals with the rs2242446 C/C genotype were more likely to remit (73.1%) than those with either the C/T (51.8%) or the T/T genotype (47.3%). Individuals with the C/C genotype also had a shorter time to remission than those with the C/T or T/T genotypes and had a greater percentage change in depressive symptom scores from baseline to end of treatment (up to week 12). We are currently testing selected microRNA plasma level changes at baseline and end of treatment and these results will be presented at the conference. Overall, pharmacogenomics is being recognized by many stakeholders to bear the potential to improve psychiatric medication treatments. While this notion has become increasingly supported for some important gene-drug pairs through thorough reviews provided by expert panels, more research is required to develop, improve and validate multi-gene algorithms in order to overcome the current trial-and-error approaches in psychiatric medicine. Limitations such as lack of consensus' to select for actionable gene-drug pairs, which genotypes best to select, how to assign metabolizer status and how to effectively develop algorithms to guide treatment decisions will be discussed. [ABSTRACT FROM AUTHOR]

Recent genetic studies have identified variants in specific gene regions showing not only evidence of association but also biological mechanisms underlying the association. The goal of this symposium is to demonstrate how human genetic association findings can be translated into improved understanding of biological mechanism, disease prognosis, and treatment response using examples across different psychiatric disorders such as mood disorders, schizophrenia, eating disorder, and addiction. A variety of methods are used including randomized treatment trials, large genome wide association studies or meta-analyses, bioinformatics, and epigenetics. The first talk by Dr. Schulze is on genotype-phenotype relationships in bipolar and related traits. He will demonstrate how applying the friendly data sharing approach spanning five continents has helped pave the way for a better understanding of the genetic basis of response to lithium treatment, serving as an example for successful precision medicine research. The 2nd talk by Dr. Muller is on current evidence, evidence adjudication, implementation challenges of pharmacogenetics testing for antidepressants and antipsychotics use. He will present a review of the evidence that was considered in formulating that guidance, along with a summary of the main recommendations and associated ethical issues. He will also discuss the kinds of evidence still needed to incorporate genetic testing in clinical decision-making. The 3rd talk by Dr. Breen is on translation of genetic findings from large GWAS studies in Psychiatric Genomics Consortium (PGC) into druggable genomes. He will discuss how discovery of the biological pathways can not only reveal etiological pathways but also lead to drug discovery. The 4th talk by Dr. Chen demonstrates the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy. These data suggest that genetic risks may predict smoking cessation outcomes and moderate the effect of pharmacological treatments. Some pharmacogenetic findings have been replicated in meta-analyses of multiple smoking cessation trials. The variation in efficacy between smokers with different genetic markers suggests that personalized smoking cessation pharmacotherapy based upon genotype could maximize the efficiency of such treatment while minimizing side effects. As a result, these genetic markers are useful to predict clinical predictor such as the number needed to treat (NNT) and the number needed to harm. Different psychiatric disorders serve as successful examples in how genetic findings in human association studies inform biological experiments to uncover the underlying mechanisms and treatments tailored to individual genetic background. Each presentation represents unique and complementary research paradigms in understanding how genomics inform personalized medicine by linking the biology and treatment in different psychiatric disorders. 1) human genetic studies inform the biological mechanisms of psychiatric disorders, 2) pharmacogenetic studies inform personalized treatments with maximized efficacy and minimized risk of side effects. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) is a field of study and clinical tool that assesses how genetic variability influences drug response and tolerability. CYP450 enzymes are responsible for metabolizing most psychiatric medications. Based on their genetic make-up, an individual may be classified as an extensive metabolizer (EM), intermediate metabolizer (IM), poor metabolizer (PM), ultra-rapid metabolizer (UM). Given the increasing evidence for genetic influences on treatment response, we deemed it important to study physicians' opinions and patients' outcome following pharmacogenetic testing for CYP2D6, CYP2C19 among other genes. Initially, only CYP2D6 and CYP2C19 genes were genotyped and treatment recommendations for antidepressant and antipsychotic medications were provided to physicians. This initiative expanded to include additional CYP enzyme genotyping such as CYP2C9, CYP3A4, CYP2B6, CYP1A2 and serotonin-related genes SLC6A4 and HTR2A. Six to eight weeks after physicians were provided with their patients' genetic information, we sent our Pharmacogenetics in Psychiatry Follow-up Questionnaire (PIP-FQ) survey to psychiatrists and primary care physicians. From the 620 physicians who were sent PIP-FQ surveys for the PGx study, 383 returned the survey for a response rate of 61.8%. Of all respondents, 58.1% were female, 43.7% were over 50 years old, and 59.7% were general practitioners while 32.7% were psychiatrists. From all respondents, 90.6% indicated that they understood the PGx report they received, 79.1% were satisfied with it, and 75.7% would agree that PGx testing will become standard for psychotropic pharmacotherapy. Of those given treatment recommendations by the PGx report, 57.1% found the report helpful for further treatment decisions and 77.5% said they would remain interested in referring additional patients to the study. Remarkably, when physicians took treatment recommendations into consideration, 120 of 211 (56.9%) patients were reported to benefit from the recommendation compared to baseline, with only two patients worsening following the change (p < 0.01). Our results show that physicians feel favourably towards PGx testing for psychiatric medications and the information provided by the PGx report. Patients saw beneficial changes to both their symptoms and side effects, and were satisfied by outcomes resulting from the genetic tests. Although our sample size of 383 physicians is among the largest for such a survey, about 38% have not returned the questionnaire. While this represents a good response rate, the possibility of response bias may overemphasize positive opinions. However, because our sample of physicians provided uncompensated feedback to questions at no extra costs, it is arguable that the effects of these limitations are small. [ABSTRACT FROM AUTHOR]

Adenosine A2a receptor (A2aR) signaling acts as a barrier to autoimmunity by promoting anergy, inducing regulatory T cells, and inhibiting effector T cells. However, in vivo effects of A2aR signaling on polyclonal CD4 T cells during a primary response to foreign Ag has yet to be determined. To address this problem, we immunized mice with peptide Ag 2W1S coupled to PE in CFA and treated with the selective A2aR agonist CGS-21680 (CGS). 2W1S:I-Ab-specific tetramer-binding CD4 T cells did not become anergic or differentiate into Foxp3+ regulatory T cells. Additionally, CGS treatment did not inhibit Th1 or Th17 differentiation. However, CGS did abrogate germinal center T follicular helper cells, and blunted PE-specific germinal center B cell responses. The use of A2aR-deficient CD4 T cells established that this CGS effect was T cell intrinsic. Therefore, this study has identified a unique role for A2aRs in regulating CD4 T cell differentiation during vaccination. [ABSTRACT FROM AUTHOR]

In geriatric depression, antidepressant treatment response is often slow and incomplete; new biomarkers for antidepressant response could lead to precision medicine and uncover new mechanisms of illness. Therefore, we conducted a Genome-Wide Association Study (GWAS) in older adults treated with venlafaxine. Three-hundred and fifty participants (>60 years) of mixed ethnic ancestry, diagnosed with major depression (MADRS>15), were treated with venlafaxine (~12 weeks). Individuals were genotyped using the Illumina PsychArray, and genetic data was imputed to 7.5 million variants per individual. Associations with remission status (MADRS≤10) and change in MADRS score were conducted using logistic/ linear regressions, adjusted for ancestry, sex, recruitment site, length in treatment, depressive episode duration, and baseline depressive severity. We also conducted pathway enrichment analysis using DEPICT. Our top hits in association with MADRS score change were with variants near MIR1246 and in ERBB4, a schizophrenia susceptibility gene. ERBB4 has been implicated in post-ketamine treatment down regulation of GABA and glutamate levels in the rat prefrontal cortex and hippocampus, resulting in an antidepressant effect. We also observed a suggestive association between remission status and a variant in phosphodiesterase gene PDE9A, suggesting a role in synaptic neurotransmitter signaling. Our top hit pathways included processes in the metabolic pathway of amyloid precursor protein. However, no variants survived corrections for multiple testing (p<5×10-8). Our findings suggest novel gene variant associations with measures of venlafaxine remission in older adults, as well as interesting neuro-relevant genetic pathways. A new, larger study of geriatric depression treatment will confirm these novel findings. [ABSTRACT FROM AUTHOR]

Highlights from the article: F42post-gwas in silico biological characterization of variants associated with venlafaxine treatment remission in late-life depression B Background: b In geriatric depression, antidepressant treatment response is often slow and incomplete. B Discussion: b Overall, our post-GWAS analyses support the involvement of known processes in synaptic plasticity, as well as, intracellular signaling pathways including MAPK and neurotrophins (e.g., BDNF) as being potentially involved in venlafaxine treatment remission.

Controlled substance prescription use and abuse in the United States has become a public health epidemic. Specifically, benzodiazepine abuse in 2013 has increased as much 400 percent since 1996. Generalized Anxiety Disorder (GAD) was the most frequent reason these medications were given, accounting for 56% of prescriptions. Previously, GeneSight, a psychiatric pharmacogenomic decision support tool, was reported to significantly improve depression symptoms in treatment-resistant depression patients, reduce costs associated with prescriptions, and decrease polypharmacy. To evaluate the combinatorial pharmacogenomics report as a tool to treat GAD and reduce the amount of benzodiazepines used, we analyzed data from two separate studies: (1) Individualized Medicine: Pharmacogenetic Assessment and Clinical Treatment (IMPACT) study, a longitudinal pilot research program , where 315 participants with anxiety disorders (N=210 with GAD) and follow-up data on symptom severity using the GAD-7 questionnaire were identified; and (2) MEDCO dataset (Winner et al., 2015; Curr Med Res Opin.;31:1633-43) in which patients (n=660) who were prescribed at least one benzodiazepine six months pre-testing and were followed six months post-testing. The analyses in the IMPACT study sample showed that medication treatment decisions congruent with the combinatorial pharmacogenomics GeneSight test results can help guide clinician treatment of GAD and result in significantly more improvement of anxiety symptom severity (congruent: -44.9±35.9% versus non-congruent: -25.5±31.8%; t=2.19; p=0.031). In the MEDCO dataset, we found that 18% (n=116) of the patients originally taking at least one benzodiazepine pre-testing (n=660) ceased their use of benzodiazepines post-testing with a significant decrease in benzodiazepine drug counts and refills after testing (mean count 1.2 vs. 0.9; p < 0.001 and mean refill 3.3 vs 2.9; p < 0.001). The GeneSight test can lead to more effective treatment of the anxiety symptoms in GAD patients and may lead to beneficial decrease in benzodiazepine use. [ABSTRACT FROM AUTHOR]