Sialorrhea is a common and uncomfortable adverse effect of clozapine, and its severity varies between patients. The aim of the study was to select broadly genes related to the regulation of salivation and study associations between sialorrhea and dry mouth and polymorphisms in the selected genes.

The study population consists of 237 clozapine-treated patients, of which 172 were genotyped. Associations between sialorrhea and dry mouth with age, sex, BMI, smoking, clozapine dose, clozapine and norclozapine serum levels, and other comedication were studied. Genetic associations were analyzed with linear and logistic regression models explaining sialorrhea and dry mouth with each SNP added separately to the model as coefficients.

Clozapine dose, clozapine or norclozapine concentration and their ratio were not associated with sialorrhea or dryness of mouth. Valproate use (p = 0.013) and use of other antipsychotics (p = 0.015) combined with clozapine were associated with excessive salivation. No associations were found between studied polymorphisms and sialorrhea. In analyses explaining dry mouth with logistic regression with age and sex as coefficients, two proxy-SNPs were associated with dry mouth: epidermal growth factor receptor 4 (ERBB4) rs3942465 (adjusted p = 0.025) and tachykinin receptor 1 (TACR1) rs58933792 (adjusted p = 0.029).

Use of valproate or antipsychotic polypharmacy may increase the risk of sialorrhea. Genetic variations in ERBB4 and TACR1 might contribute to experienced dryness of mouth among patients treated with clozapine.

In Alzheimer’s disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators.

Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy–Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Depression in pregnancy is common and often requires treatment with antidepressant drugs. Most antidepressants are metabolized by the cytochrome P450 system (CYP), in particular CYP2C19 and -2D6, both of which are genetically polymorphic. Additionally, the activity of these enzymes is altered during pregnancy.

To investigate pharmacogenetic variability regarding CYP2C19 and -2D6 in pregnant users of antidepressants and treatment outcomes.

The study population comprises all women born between 1981-1999, who gave birth to at least one child before December 2015 identified from the large Danish population-based iPSYCH2012 case-cohort study sample linked to information on genetic variants, prescription drug use and outcome data. Pharmacogenetic genotypes and phenotypes of CYP2C19 and CYP2D6 will be categorized into poor, (PM), intermediate, (IM), extensive, (EM), rapid (RM) and ultra-rapid metabolizers (RM) using array-based SNP information. Antidepressant drug use and comedication during pregnancy will be assessed based on prescription data. Outcomes include treatment discontinuation, switching and psychiatric hospitalizations. Cox regression analysis will be performed to estimate the hazard ratios comparing the rates of the different outcomes in people with different phenotypes, compared with EM adjusted for a number of confounding factors.

Based on previous research we will be able to identify approximately 6531 pregnant women with a psychiatric history. Among those, we estimate to find 14 PM, 161 IM, 285 EM, 168 RM and 25 UM of CYP2C19, and 27 PM, 218 IM and 408 EM of CYP2D6. Exposure to antidepressants is estimated at 10%.

We expect to be able to present the results at the conference.

No significant relationships.

There are relatively fewer pharmacogenetic studies of antipsychotics in adolescents than in adult patients. The development of personalized pharmacotherapy is promising.

Identify the most significant pharmacogenetic predictors of antipsychotic safety in adolescents experiencing acute psychotic episodes

The study included 101 adolescents diagnosed with acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients were taking an antipsychotic as their main treatment for 14 days. Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I), UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS) were used. All study participants underwent pharmacogenetic testing of pharmacokinetic and pharmacodynamic factors.

CYP2D6 “intermediate” metabolism increased the risk of developing an adverse reaction by a trend of significance (OR=2.616 (95% CI 0.950-7.203); p=0.063). Carriage of HTR2A rs6313 was associated with a lower score on the UKU SERS “Other Symptoms” subscale (Beta=(-0.289); p=0.003) and an objective score on the BARS akathisia severity scale (Beta=(-0.217); p=0.029). DRD3 rs324026 carriers had a lower BARS akathisia scale score (Beta=(-0.349); p=0.004); DRD3 rs6280 carriers had a lower SAS extrapyramidal symptom severity scale score (Beta=(-0.351); p=0.003). Carriers of ANKS1B rs7968606 were associated with a higher SAS scale score (Beta=0.237; p=0.017).

We proposed that genotyping of CYP2D6*4, *10, DRD3 rs324026 (C allele), DRD3 rs6280 (C allele), HTR2A rs6313 (TT genotype) and ANKS1B rs7968606 (T allele) will predict the high risk of intolerance to antipsychotics in adolescents with acute psychotic episodes.

No significant relationships.

Pharmacogenetic (PGx) targets to optimize drug therapy, but its implementation is rare.

We evaluate the clinical utility of PGx testing in psychiatry by investigating the one-year risks of clinical outcomes in patients with depression taking sertraline, (es)citalopram or fluoxetine by their Cytochrome P450 (CYP) 2C19/2D6 phenotypes.

We investigated 17,297 individuals born between 1981-2005 with a depression diagnosis between 1996-2012 from the iPsych2012 case-cohort. Based on array-based single-nucleotide-polymorphism genotype data, individuals were phenotyped as CYP2C19/CYP2D6 normal (NM, reference group), ultra-rapid- (UM), rapid- (RM), intermediate- (IM), or poor-metabolizer (PM). Outcomes were treatment switching or discontinuation, psychiatric in-, out-, and emergency room contacts (ER), and suicide attempt/self-harm. Incidence rate ratios (IRR) by age groups were estimated using Poisson regression analysis with 95% confidence intervals, adjusted for potential confounders.

Risks of switching (IRR=1.89[1.22-2.93]), ERs (1.69 [1.01-2.81]) and suicide attempt/self-harm (2.73 [1.49-5.01]) were higher in CYP2C19 PMs <19 years taking (es)citalopram. Fluoxetine users <19 years had a decreased risk of discontinuation in CYP2D6 PMs (0.5 [0.27-0.95]) and decreased risk of out-patient contacts in CYP2D6 PMs and IMs (IRRIM=0.83 [0.68-1.00] and IRRPM=0.59 [ 0.37-0.96]). We observed an increased risk for ERs in CYP2D6 PMs aged 19-25 years taking fluoxetine (4.53 [1.54-13.35]). In CYP2C19 UMs >25 years taking (es)citalopram the risk of suicide attempt/self-harm was more than three-fold increased (3.64 [ 1.01-13.19]). We found no significant results in users of sertraline.

PGx variability was associated with treatment outcomes in depression in patients with CYP2C19 PM or UM status taking (es)citalopram, or CYP2D6 PM or IM status taking fluoxetine.

No significant relationships.

Pharmacogenetics (PGx) studies genetic variance and related differences in drug outcomes. PGx guidelines for psychotropic drugs are available (PGx drugs). By executing PGx testing in a prospective or pre-emptive setting, dose adjustments or even change of treatment type can be applied prior to start of therapy to patients who carry a specific geno- or phenotype (i.e. actionable geno- or phenotypes). By doing so, increased efficacy of therapy or reduced risk of adverse events of treatment can be accomplished. In Denmark, broad implementation of PGx is currently still low.

The aim of this study is to classify the PGx profiles of Danish individuals with and without severe mental disorders (SMD), to be used in follow-up studies investigating PGx and drug outcomes.

This study made use of imputed genotyping data of the Danish iPSYCH sample, which includes 77,639 young individuals born between 1981-2005, with or without a diagnosis of one or more of five selected SMD (i.e. depression, attention-deficit/hyperactivity disorder, autism, bipolar disorder and schizophrenia). We investigated a panel of 48 genetic variants with known PGx applications (part of the U-PGx consortium, a Horizon2020 funded project on clinical relevant PGx in the EU).

Imputed data contains over 11 million SNPs of 77,639 individuals.

We expect results in the end of 2020.

We thank the iPSYCH consortium, in specific the iPSYCH PI’s (Merete Nordentoft, Anders Børglum, Preben B. Mortensen, Ole Mors, Thomas Werge and David M. Hougaard). The iPSYCH project is funded by the Lundbeck Foundation Denmark and the universities and un

Pharmacogenetics (PGx) studies genetic variance and related differences in drug outcomes. The aim of PGx testing is to increase therapy efficacy and safety, by applying e.g. dose adjustments in patients with a specific geno- or phenotype. PGx guidelines for psychotropic drugs are available (PGx drugs), including atomoxetine used in the treatment of attention deficit hyperactivity disorder (ADHD). In Denmark, broad implementation of PGx is currently still low, possibly due to the lack of population-based studies investigating the real-world impact of PGx variability.

The aim of this study is to investigate the association of PGx variability (patients’ genotype/phenotype) in users of atomoxetine and different treatment outcomes in a large population-based sample of individuals with ADHD.

This study will use data of the large Danish population-based iPSYCH case-cohort study sample including information on genetic variants, prescription drug use and outcome data, e.g. psychiatric and somatic hospitalizations and death. The study population comprises all individuals diagnosed with ADHD born 1981-2005 with at least one prescription for atomoxetine between 1995 and 2016. All individuals will be categorized according to their CYP2D6 phenotypes. We will perform Cox regression analysis to estimate the hazard ratios comparing the rates of the different outcomes in people with different phenotypes adjusted for a number of confounding factors.

We have identified approximately 20,000 individuals with ADHD, of whom an estimated 10-20% have filled at least one prescription of atomoxetine.

We expect results in the beginning of 2021.

We thank the iPSYCH consortium, in specific the iPSYCH PI’s (Merete Nordentoft, Anders Børglum, Preben B. Mortensen, Ole Mors, Thomas Werge and David M. Hougaard). The iPSYCH project is funded by the Lundbeck Foundation Denmark and the universities and un

Schizophrenia is one of the most severe mental disorders. Haloperidol and other first-generation antipsychotics are widely used for schizophrenia treatment, but have prominent side effects, primarily extrapyramidal symptoms (EPS). The EPS severity is highly variable and may be underlied by genetic factors.

We performed a prospective study to test the association of DRD2/ANKK1 Taq1A polymorphism (rs18000497) and CYP2D6 phenotype, predicted from genotypes using 8 CYP2D6 alleles (*3, *4, *5, *6,*9, *10,*41, xN) with EPS severity during haloperidol treatment in schizophrenia spectrum disorders patients.

57 inpatients with schizophrenia spectrum disorders (42,1% females; mean age - 46,7±11,8 y.o (M±SD) of European ancestry were enrolled in the study. Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) were used to assess EPS on two timepoints: day 1 and day 21 of haloperidol treatment.

TaqIA T-allele carriers in contrast to wild-type allele homozygous patients had higher scores of BARS (p=0.029) and SAS (p=0.024) on day 21. After stratification by CYP2D6 phenotype, these differences were observed only in extensive metabolizers (p=0.006 and p=0.001 respectively), although the CYP2D6 phenotype itself was not associated with EPS severity. The combined effect of TaqIA T allele with CYP2D6 extensive phenotype on BARS score on day 21 was confirmed by General Linear Model (p=0.013).

Our results show that minor TaqIA T-allele is associated with the severity of EPS after 3 weeks of haloperidol treatment only in CYP2D6 extensive metabolizers. That highlights the importance of using both pharmacokinetic and pharmacodynamic genetic markers in pharmacogenetic EPS risk assessment.

No significant relationships.

Pharmacogenetics (PGx) studies genetic variance and related differences in drug outcomes. PGx guidelines for psychotropic drugs are available (PGx drugs), but PGx testing is used only limitedly in psychiatric clinical practice.

The aim of this study is to pinpoint different aspects of PGx drug use in the population, to support clinical uptake of PGx.

This drug utilization study investigated prescription PGx drug use in 56,065 young individuals with different severe mental disorders (SMD) in the Danish iPSYCH sample (born 1981-2005). We investigated the number of PGx drug users (incidence, prevalence), age (at first PGx drug use), sex, multiple PGx drugs per user (in light of panel-based PGx testing) and concomitant use of PGx drugs (in light of combinatorial PGx testing).

We identified substantial PGx drug use in terms of incidence rates (e.g. 333 per 10,000 person years for the anticonvulsant lamotrigine) and prevalence (e.g. 15,260 users for the antidepressant citalopram) in patients with SMD. The age of first time PGx drug use ranged from 11.6-20 years, depending on SMD and sex. On average, more than one PGx drug was used by a single person (range 1.6-5.6 drugs, depending on SMD) or even used concomitantly (41-69%) affecting mostly two different PGx genes (84-92% of concomitant PGx drug users).

PGx drugs were frequently used in young individuals with SMD, often subsequently and concomitantly, arguing for panel-based/combinatorial PGx testing over single-gene testing. PGx testing could be applied already at a very young age.

We thank the iPSYCH consortium, in specific the iPSYCH PI’s (Merete Nordentoft, Anders Børglum, Preben B. Mortensen, Ole Mors, Thomas Werge and David M. Hougaard). The iPSYCH project is funded by the Lundbeck Foundation Denmark and the universities and un

Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set.

The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed.

GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain.

The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.

The burden of communicable and non-communicable diseases in Sub-Saharan Africa poses a challenge in achieving quality healthcare. Although therapeutic drugs have generally improved health, their efficacy differs from individual to individual. Variability in treatment response is mainly because of genetic variants that affect the pharmacokinetics and pharmacodynamics of drugs.

The intersection of disease burden and therapeutic intervention is reviewed, and the status of pharmacogenomics knowledge in African populations is explored.

The most commonly studied variants with pharmacogenomics relevance are discussed, especially in genes coding for enzymes that affect the response to drugs used for HIV, malaria, sickle cell disease and cardiovascular diseases.

The genetically diverse African population is likely to benefit from a pharmacogenomics-based healthcare approach, especially with respect to reduction of drug side effects, and separation of responders and non-responders leading to optimized drug choices and doses for each patient.

We investigated the association between clinical outcome and the recommendations of a pharmacogenetic test (Neuropharmagen) in patients with a variety of psychiatric conditions whose previous treatment regimen had failed.

This retrospective, naturalistic, multicenter study included adult psychiatric patients (depression, psychosis, anxiety, bipolar, etc.) who had been seen at 3 private clinics. All patients had received pharmacogenetic testing (Neuropharmagen) and were classified depending on whether or not their post-test treatment regimen followed the test recommendations. Clinical severity was assessed with the Clinical Global Impression of Severity (CGI-S) at baseline (pre-test) and 3-month follow-up, and adverse events were recorded.

182 patients were available for analysis. After multivariate adjustment, patients whose treatment followed the test recommendations had odds of improvement about 4 times greater than patients whose treatment did not follow the recommendations (adjusted OR=3.86, 95%CI 1.36–10.95; p=0.011). Importantly, psychiatric diagnosis did not significantly affect the odds of improvement. Also, in the subpopulation with baseline CGI-S score >3 (N=170), the rate of stabilization at follow-up (defined as CGI-S≤3) was significantly higher in patients whose treatment followed the pharmacogenetic recommendations (p=0.033). There was no apparent difference in the incidence of adverse events (6 patients in each group).

Non–drug naïve patients whose treatment followed the recommendations of pharmacogenetic testing were more likely to improve their condition than patients whose treatment did not. These results are consistent with previous clinical research on depressed patients, and this study also suggests that this benefit can be extended to psychiatric conditions other than depression.