F189. PERSONALIZED MEDICINE: ESTIMATING THE IMPACT OF GENOTYPES ON ANTIPSYCHOTIC EFFICACY USING A QUANTITATIVE SYSTEMS PHARMACOLOGY APPROACH

Abstract Background CNS disorders are lagging behind other indications such as oncology in implementing genotype-dependent treatment algorithms for personalized medicine. This is due to the limited knowledge about the interaction of the relevant biology and the drug’s pharmacology Methods We applied a mechanism-based computer model of a cortico-striatal-thalamocortical loop of the dorsal motor circuit that has been calibrated with clinical data on antipsychotic treatment in schizophrenia patients (Spiros, Roberts et al. 2017). The Quantitative Systems Pharmacology (QSP) model is based on the appropriate connections between basal ganglia regions and consists of 220 neurons (8 different cell types), 3500 synapses and implementations of 32 CNS active targets, based on their unique locations and coupling with intracellular pathways. COMTVal156Met, 5-HTTLPR rs 23351 s/L and D2DRTaq1A1 genotypes are implemented using human imaging data in non-medicated human volunteers Results The dose-dependent antipsychotic effect for risperidone, aripiprazole and paliperidone is sensitive to the COMT genotype with the MM genotype having the greatest difference with the wild-type. Interestingly the 5-HTTLPR genotype interacts with the COMT genotype: this difference is positive for 5-HTTLPRss and negative for 5-HTTLPR LL. Olanzapine, quetiapine, clozapine and haloperidol are affected much less. The D2DRTaq1A allele interacts in a complex way with the COMT genotype with haloperidol, aripiprazole and risperidone and with the 5-HTLLPR genotype for haloperidol, aripiprazole, risperidone and paliperidone. These effects are anticipated to be detectable in clinical settings. Discussion The QSP platform predicts strong and complex genotype-dependent interactions with aripiprazole, risperidone, haloperidol and paliperidone and to a much smaller degree with olanzapine, quetiapine and clozapine. These predictions could in principle be verified in clinical setting and could lead to rational personalized treatment guidance


F188. THALAMIC MICROSTRUCTURE IN UNAFFECTED RELATIVES OF SCHIZOPHRENIA
Wu Jeong Hwang* ,1 , Kang Ik Cho 2 , Yoo Bin Kwak 1 , Tae Young Lee 3 , Jun Soo Kwon 3 1 Seoul National University; 2 Seoul National University, Medical Research Center; 3 Seoul National University College of Medicine Background: Family, twin, adoption and candidate gene studies all support a genetic component for psychotic disorders. A considerable evidence suggests that the thalamus is abnormal in schizophrenia. The thalamus has a heterogeneous structure with its nucleus having distinct inputs and outputs. Disrupted thalamo-cortical connectivity, in particular, is considered as a core psychopathology in patients with schizophrenia. The disruption is also observed in subjects at clinical-high risk for psychosis. However, using the conventional magnetic resonance imaging methods, it had been difficult to investigate the subtle structural changes that may be present in the thalamus. Furthermore, despite the numerous reports of thalamic abnormalities in schizophrenia, the genetic aspect of the thalamic microstructure has not been thoroughly investigated. Methods: To examine the microstructure of the thalamus, a total of 34 unaffected relatives of schizophrenia (UR) and 33 healthy control subjects underwent diffusion-weighted and diffusion kurtosis magnetic resonance imaging. Using the probabilistic tractography the projections from the thalamus to the lateral and medial prefrontal cortices, lateral and medial temporal cortices, occipital cortex, somatosensory cortex, parietal cortex and orbitofrontal cortex were analyzed. Then, the thalamus was segmented by the projections and the microstructures of those segmented regions were compared between the groups. The mean kurtosis values of the segmented regions were analyzed by analysis of covariance with age and sex as covariates and the results were adjusted with Bonferroni correction. Results: There was no statistical difference in the mean kurtosis values of the left and right thalamic regions projecting to any of the investigated regions between the UR and healthy controls. Discussion: Our findings, via diffusion kurtosis imaging, show preserved microstructural integrity of the thalamus in UR and that this imaging technique may be less well suited to detect thalamic abnormalities in them.

F189. PERSONALIZED MEDICINE: ESTIMATING THE IMPACT OF GENOTYPES ON ANTIPSYCHOTIC EFFICACY USING A QUANTITATIVE SYSTEMS PHARMACOLOGY APPROACH
Hugo Geerts* ,1 , Athan Spiros 1 1 In Silico Biosciences Background: CNS disorders are lagging behind other indications such as oncology in implementing genotype-dependent treatment algorithms for personalized medicine. This is due to the limited knowledge about the interaction of the relevant biology and the drug's pharmacology Methods: We applied a mechanism-based computer model of a cortico-striatal-thalamocortical loop of the dorsal motor circuit that has been calibrated with clinical data on antipsychotic treatment in schizophrenia patients (Spiros, Roberts et al. 2017). The Quantitative Systems Pharmacology (QSP) model is based on the appropriate connections between basal ganglia regions and consists of 220 neurons (8 different cell types), 3500 synapses and implementations of 32 CNS active targets, based on their unique locations and coupling with intracellular pathways. COMTVal156Met, 5-HTTLPR rs 23351 s/L and D2DRTaq1A1 genotypes are implemented using human imaging data in non-medicated human volunteers Results: The dose-dependent antipsychotic effect for risperidone, aripiprazole and paliperidone is sensitive to the COMT genotype with the MM genotype having the greatest difference with the wild-type. Interestingly the 5-HTTLPR genotype interacts with the COMT genotype: this difference is positive for 5-HTTLPRss and negative for 5-HTTLPR LL. Olanzapine, quetiapine, clozapine and haloperidol are affected much less. The D2DRTaq1A allele interacts in a complex way with the COMT genotype with haloperidol, aripiprazole and risperidone and with the 5-HTLLPR genotype for haloperidol, aripiprazole, risperidone and paliperidone. These effects are anticipated to be detectable in clinical settings.

Discussion:
The QSP platform predicts strong and complex genotypedependent interactions with aripiprazole, risperidone, haloperidol and paliperidone and to a much smaller degree with olanzapine, quetiapine and clozapine. These predictions could in principle be verified in clinical setting and could lead to rational personalized treatment guidance Background: Cannabis use, particularly regular use in adolescence, is associated with an increased risk of developing psychosis earlier.
An earlier age of onset negates the protective effects of more mature psychosocial and individual variables, thus the potential for worse outcomes. Genetic variations in this relationship are important to understand as this will allow not only a better understanding of the biological interaction of cannabis and psychosis, but would inform future genetic approaches to risk identification as well. We uniquely examined the mediation of this association (gene x cannabis associations in age of onset of psychosis (AoP)) in 3 genetic variants which, while each have been examined separately, not in combination in the same population. We examined: 1) COMT Val158Met (rs4680) 2) BDNF Val66Met (rs6265) and 3) the AKT1 variant rs2494732. Methods: 168 subjects with a diagnosis of psychosis were recruited from 2 sites in Canada, Edmonton Alberta and Halifax Nova Scotia. Cannabis use data (age at first and regular use) were collected using an electronic self-report survey (to address potential minimization of use to a researcher) and saliva samples were used for genotyping. Kaplan-Meier and Cox regression analyses were used to study the gene -cannabis effects. Results: In those who had used cannabis, first use of cannabis prior to 20 years of age was associated with earlier AoP (p = .005). In those who used cannabis before age 20, rs4680 had a trend level association with AoP (log rank test: p=0.0617). A trend effect for an rs6265 x gender interaction (HR = 2.08, p = 0.067) on AoP, controlling for regular cannabis use was also observed. No association was observed between rs2494732 and rs6265 -rs2494732 interaction, and AoP. Discussion: The trends in our associations are in keeping with previous literature, however our gender analyses underscores the importance of examining sex and gender as we further move towards risk identification for the cannabis and psychosis interaction. Our results also suggest that not all genetic variants associated with psychosis are involved with the association between cannabis and AoP. While our results offer support for future research in this area, larger sample sizes are required to test the gene-cannabis-AoP relationship.

F191. THE GENETICS OF DRUG-RELATED MOVEMENT DISORDERS AN UMBRELLA REVIEW OF META-ANALYSES
Nadine van der Burg 1 , P. Roberto Bakker* ,2 , Jim Van Os 3 , Peter Van Harten 2 , Asmar Al Hadithy 4 1 GGZ Centraal; 2 Maastricht University; 3 Maastricht University Medical Centre; 4 Parnassia Group Background: Treatment with antipsychotics can provoke drug-related movement disorders (DRMD) (also known as extrapyramidal symptoms (EPS)), i.e. tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia. DRMD remain a cause for concern in the treatment of patients with psychotic disorders, especially because the DRMD can become irreversible (Correll and Schenk, 2008). There are lower percentages in younger patients (32%) (Mentzel 2017), but the prevalence is substantial in chronic patients (68%) (Bakker 2011), with around a quarter of chronic patients showing two different types of DRMD (Bakker 2011). DRMD can cause severe impairment in quality of life (Fujimaki 2012. In addition, a meta-analysis (Ballesteros 2000) and two recent studies showed a higher mortality in patients with tardive dyskinesia (Chong 2009, Dean andThuras 2009). It is therefore important to find ways of preventing DRMD. Pharmacogenetic studies may identify genetic risk factors, which underlie individual vulnerability for DRMD in response to antipsychotics (Reynolds 2007;Ohmori 2003;Lerer 2002), in theory paving the way for individually tailored medication prescriptions (Lerer and Segman 2006). To date, many different papers have been written on the subject and they have presented inconsistent results. The aim of this umbrella review is to provide clinicians and patients with evidence-based information regarding the genes that are thought to be associated with DRMD and to use this umbrella review on the genetics of DRMD as a basis for recommendations for future prevention programs and research. Methods: To identify all relevant meta-analyses a Medline, Embase, and Psychinfo literature search was performed. Titles and abstract were screened using predetermined criteria by two independent authors. The methodological quality of included meta-analyses was assessed by two overview authors using 'assessment of multiple systematic reviews' (AMSTAR) critical appraisal checklist. Reference lists of included papers and those of reviews were cross-checked and no new publications were found. Results: The search yielded 14 meta-analysis studies and consensus was obtained. The DRD3, DRD2, CYP2D6, 5-HT2A, COMT and MnSOD genes all contain variants that increase the odds ratio of TD. However meta-analyses showed diminishing significance over time and meta-analyses on the same subject were difficult to compare due to differences in patient population and methods used. Discussion: For now it appears that TD is a complex disease with multiple genes that are involved in its phenotype and more studies (eg. Genome wide associatio studies), on a larger scale, are required to develop a genetic test kit to predict the chance of TD. To achieve this multiple research groups need to work together, a DRMD genetic database needs to be in place to overcome publication bias and results need to be stratified by patient characteristics. The result could be test that undoubtedly will be of great clinical value in treating patients and by prospectively preventing debilitating DRMD.