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.

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.

Atomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark.

We investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability.

We analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates.

Over two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35).

This is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing.

No significant relationships.

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

Involuntary electroconvulsive therapy (ECT) can be a life-saving intervention for patients suffering from potentially lethal conditions who are unable to give informed consent. However, its use is not widespread, probably partly due to the scarce data on hard outcomes following involuntary ECT. In Denmark, involuntary ECT is only used when patients are at imminent/potential risk of dying if not receiving ECT.

We aimed to assess the effectiveness of involuntary ECT by estimating the 1-year survival following its administration.

We conducted a register-based cohort study involving i) all patients receiving involuntary ECT in Denmark between 2008 and 2019, ii) age and sex-matched patients receiving voluntary ECT, and iii) age and sex-matched individuals from the general population. 1-year survival rates were compared via mortality rate ratios.

We identified 618 patients receiving involuntary ECT, 547 patients receiving voluntary ECT, and 3,080 population-based controls. The survival rate in the year after involuntary ECT was 90%. For patients receiving involuntary ECT, the 1-year mortality rate ratios were 3.1 (95% confidence interval (CI)= 1.9-5.2) and 5.8 (95%CI = 4.0-8.2) compared to those receiving voluntarily ECT and to the population-based controls, respectively. Risk factors for early death among patients receiving involuntary ECT were male sex, being ≥70 years old and having organic mental disorder as the treatment indication.

Treatment with involuntary ECT is associated with a high survival rate, suggesting that the intervention is effective. However, patients receiving involuntary ECT constitute a high-risk population that should be monitored closely after this treatment.

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