Espen Molden

• Koch, Elise; Parker, Nadine; Mohammad, Helin; Lenk, Hasan Cagin; Ystaas, Lars Andreas Rømo & Jaholkowski, Piotr Pawel [Show all 13 contributors for this article] (2026). Genetic overlap between treatment-resistant schizophrenia and smoking initiation. International Journal of Neuropsychopharmacology. ISSN 1461-1457. 29(7). doi: 10.1093/ijnp/pyag035. Full text in Research Archive Show summary

  Background Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Objective Here, we aim to identify genetic variants associated with TRS by leveraging overlapping genetic variants with smoking initiation to increase statistical power. Methods We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes. Results We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 P = .0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. Mendelian randomization indicates putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses suggest that alpha-1-adrenergic receptors may be involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs. Conclusion In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.

• Park, Yoomi; Lenk, Hasan Cagin; Zhou, Yitian; Lauschke, Volker M. & Molden, Espen (2026). Association between CYP2D6 and CYP2C19 genotypes and venlafaxine treatment failure: a retrospective study on two cohorts from Norway and the UK. The Lancet Psychiatry. ISSN 2215-0374. 13(10), p. 852–860. doi: 10.1016/S2215-0366(26)00238-5.
• Voloshyna, Tetyana; Svendsen, Øyvind Veel; Szafranska, Karolina; Pospíšil, Jakub; Struck, Eike Christopher & Størset, Elisabet [Show all 12 contributors for this article] (2026). Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells. Translational Psychiatry. doi: 10.1038/s41398-026-04328-4. Full text in Research Archive Show summary

  Abstract Clozapine is the most effective antipsychotic drug, while also causing the most severe metabolic side effects. The underlying mechanisms of these side effects appear multifactorial and are not entirely understood. We hypothesized that liver sinusoidal endothelial cells (LSEC) dysfunction is linked to the metabolic side effects of clozapine, based on known association between reduced LSEC porosity, hypertriglyceridemia and insulin resistance. Accordingly, we conducted a translational study by assessing the porosity of murine LSECs following clozapine exposure in vitro and correlating serum clozapine concentrations with metabolic parameters in routine human blood samples. The patient data showed a correlation for clozapine serum concentrations with both triglycerides (Spearman’s ρ = 0.47, P  = 0.00024) and glucose levels (ρ = 0.24, P  = 0.034), but no correlation with LDL cholesterol (ρ = −0.04, P  = 0.82) or HDL cholesterol (ρ = −0.22, P  = 0.088). The in vitro experiments showed a concentration-dependent reduction in murine LSEC porosity (P for trend = 0.00036). Together, these findings support a link between clozapine exposure and reduced LSEC porosity. This represents a promising point of intervention that potentially could expand safe access to clozapine as a highly effective antipsychotic treatment for a broader population, also in individuals at high risk for metabolic and cardiovascular side effects.

• Bråten, Line Skute; Wollmann, Birgit Malene Tovik; Molden, Espen & Kringen, Marianne Kristiansen (2026). Metabolite Profiles of Sertraline in Relation to Genotype-Predicted Phenotypes of CYP2B6 and CYP2C19—A Study on 470 Patients. Therapeutic Drug Monitoring. ISSN 0163-4356. Publish Ahead of Print. doi: 10.1097/FTD.0000000000001435. Full text in Research Archive
• Krebs, Kristine; Luitva, Laura Birgit; Kõre, Anette Caroline; Kokasaar, Raul; Jõeloo, Maarja & Hudjashov, Georgi [Show all 19 contributors for this article] (2026). Pharmacokinetic recall study of Estonian Biobank participants with novel genetic variants in CYP2C19 and CYP2D6. NPJ GENOMIC MEDICINE. 11(1). doi: 10.1038/s41525-025-00549-6. Full text in Research Archive Show summary

  CYP2C19 and CYP2D6 are involved in the hepatic metabolism of approximately 35–40% of clinically used drugs. We conducted an in vivo phenotyping study encompassing 114 Estonian Biobank participants to evaluate the functional impact of rare or novel single-nucleotide and structural variants in the CYP2C19 and CYP2D6 genes using omeprazole and metoprolol as respective probe drugs. Plasma concentrations of these drugs and their metabolites were measured at 10 time points, and parent drug-to-metabolite ratios were calculated to determine enzymatic activity. Long-read sequencing enabled high-resolution star allele calling. Our results provide the first in vivo confirmation that partial gene and intragenic deletions in CYP2C19 (CYP2C19*37 and CYP2C19*42), enriched in Estonians and Finns, are associated with poor metaboliser phenotypes (P < 1.2 × 10−7). Additionally, we offer in vivo evidence of reduced metabolic activity of the CYP2D6*124 allele and a novel missense variant (c.940C>A) in exon 6 of CYP2D6. Furthermore, we observed that inhibitor exposure was significantly associated with higher metabolic ratios for both CYP2C19 (P = 3.0 × 10−6) and CYP2D6 (P = 0.02). Our findings emphasise the importance of identifying genetic variants in CYP2C19 and CYP2D6 beyond commonly assessed star alleles and that profiling for drug interactions can provide more precise assignments of metabolic phenotypes and improve personalised treatment.

• Bruun, Lina Dorthea; Andersen, Geir Øystein; Myhre, Peder Langeland; Halvorsen, Sigrun; Kringen, Marianne Kristiansen & Hansen, Charlotte Holst [Show all 8 contributors for this article] (2026). Prognostic relevance of β1-adrenergic receptor polymorphisms on cardiovascular outcome in patients treated with metoprolol after acute myocardial infarction - an observational study. European Journal of Clinical Pharmacology. ISSN 0031-6970. 82(7). doi: 10.1007/s00228-026-04091-x. Full text in Research Archive
• Schaik, Ron H.N. van; Swen, Jesse J.; Llerena, Adrián; Koch, Birgit C.P.; Coenen, Marieke J.H. & Molden, Espen [Show all 21 contributors for this article] (2026). The 8th European Society of Pharmacogenomics and Personalized Therapy (ESPT) congress. Pharmacogenomics (London). ISSN 1462-2416. 27(1-2), p. 5–8. doi: 10.1080/14622416.2026.2648608. Full text in Research Archive
• Leon, Jose de; Schoretsanitis, Georgios; Smith, Robert Løvsletten; Molden, Espen; Solismaa, Anssi & Seppälä, Niko [Show all 104 contributors for this article] (2026). An international adult guideline for making Clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and Clozapine levels. Chinese Journal of Psychiatry. ISSN 1006-7884. 59(2), p. 87–113. doi: 10.3760/cma.j.cn113661-20250402-00157. Full text in Research Archive
• Schoretsanitis, Georgios; Laaboub, Nermine; Crettol, Séverine; Lenk, Hasan Çağın; Bråten, Line Skute & Ranjbar, Setareh [Show all 17 contributors for this article] (2025). CYP2D6 Genotypes Do Not Affect Clozapine Levels in a Large, Multicenter Cohort: Time Has Come to Revise Food and Drug Administration’s Clozapine Packet Insert. Schizophrenia Bulletin. ISSN 0586-7614. doi: 10.1093/schbul/sbaf160. Full text in Research Archive Show summary

  Abstract Background and Hypothesis The US Food and Drug Administration (FDA) package insert for clozapine states that cytochrome P450 (CYP) 2D6 is important in clozapine metabolism, implying that CYP2D6 genotypes should be considered in clozapine dosing. We investigated differences for clozapine concentration-to-dose (C/D) ratios, as a pharmacokinetic measure, in relation to CYP2D6 phenotype. Study Design Linear mixed-effect regression models were applied to investigate the association between genotype-predicted CYP2D6 metabolizer phenotypes and C/D ratios including the effects of age, sex, smoking, and sampling time in a pooled sample of three cohorts, both without and with adjusting for the interaction between cohort and CYP2D6 phenotype, as well as in separate models stratified by cohort. Study Results We included 897 patients from three cohorts with a total of 10 428 clozapine and norclozapine measurements. We found no association between CYP2D6 phenotypes and clozapine or norclozapine C/D ratios or clozapine-to-norclozapine ratios in the pooled sample with or without adjustment for the interaction between cohort and CYP2D6 phenotype nor when analyzing three cohorts separately (P&gt;.05 in all cases). Older patients and females had higher C/D ratios of clozapine and norclozapine (P&lt;.001, P&lt;.001, P&lt;.001 and P=.02), whereas smokers had lower C/D ratios of clozapine and norclozapine as well as clozapine-to-norclozapine ratios (P&lt;.001 for all three). Conclusions We reported no association between CYP2D6 genotype-predicted phenotypes and clozapine pharmacokinetics. Dose adjustment based on CYP2D6 genotyping is unlikely to be helpful in managing clozapine-treated patients. We propose that the current FDA package insert should be updated to avoid misleading prescribers.

• Nordby, Karoline L; Faraj, Pari; Molden, Espen & Hole, Kristine (2025). Impact of CYP2D6 genotype on fluoxetine exposure and treatment switch in adults and children/adolescents. European Journal of Clinical Pharmacology. ISSN 0031-6970. 81(11), p. 1623–1632. doi: 10.1007/s00228-025-03893-9. Full text in Research Archive
• Thorén, Linda; Lindh, Jonatan D.; Molden, Espen; Kringen, Marianne Kristiansen; Bergh, Jonas & Eliasson, Erik [Show all 7 contributors for this article] (2025). CYP2D6 genotype and outcome in tamoxifen treated early breast cancer. Acta Oncologica. ISSN 0284-186X. 64, p. 848–856. doi: 10.2340/1651-226X.2025.43208. Full text in Research Archive
• Rask, Susanna Maria; Solismaa, Anssi; Ahola-Olli, Ari; Molden, Espen; O'Connell, Kevin Sean & Lyytikäinen, Leo Pekka [Show all 9 contributors for this article] (2025). Meta-analyses of clozapine, norclozapine levels and their ratio across three genome wide association studies. Translational Psychiatry. 15(1). doi: 10.1038/s41398-025-03649-0. Full text in Research Archive
• Mellingsæter, Trude Cecilie; Molden, Espen & Steihaug, Ole Martin (2025). Serum Concentration of Apixaban in Relation to Renal Function in Older Hospitalized Patients. Drugs & Aging. ISSN 1170-229X. 42(9), p. 879–886. doi: 10.1007/s40266-025-01232-2. Full text in Research Archive
• Solhaug, Vigdis; Waade, Ragnhild Birkeland; Jansrud, Lene; Molden, Espen; Størset, Elisabet & Høiseth, Gudrun [Show all 7 contributors for this article] (2025). Antipsychotic load during olanzapine mono- versus polytherapy and in relation to age. European Journal of Clinical Pharmacology. ISSN 0031-6970. 82(1). doi: 10.1007/s00228-025-03947-y. Full text in Research Archive
• Lenk, Hasan Cagin; Bråten, Line Skute; Andreassen, Ole & Molden, Espen (2025). Impact of CYP1A, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NFIB genotypes on clozapine serum concentration in smokers and nonsmokers. Therapeutic Advances in Psychopharmacology. ISSN 2045-1253. 15, p. 1–14. doi: 10.1177/20451253251377183. Full text in Research Archive Show summary

  Background: Clozapine is the most effective drug for schizophrenia and is the only drug indicated for use in patients with treatment resistance. The therapeutic range of clozapine is narrow with extensive interindividual differences in serum levels at similar dosing, mainly due to variability in hepatic metabolism mediated by several cytochrome P450 (CYP) enzymes. Tobacco smoking is the most important environmental factor determining clozapine metabolism, while the effect of pharmacogenetic variability is unclear. Objectives: To investigate the impact of CYP1A, CYP2C19, CYP2D6, CYP3A4, CYP3A5 , and NFIB alleles on clozapine levels stratified by smoking status in a large patient population. Design: This is a retrospective naturalistic/observational study. Methods: The study population was included from the therapeutic drug monitoring/pharmacogenetics service at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, during January 2005–November 2024. We assessed the influence of CYP1A rs247229 T , CYP1A2*1F , CYP2C19 , CYP2D6 , CYP3A4*22 and CYP3A5*3 , and NFIB rs28379954 C genetic variants on clozapine dose-adjusted serum concentrations (CD) in both smokers and nonsmokers. Results: The study comprised 663 participants (55% smokers). CYP1A T variant was significantly associated with reduced clozapine serum levels, compared to CYP1A CC genotype, both among smokers (–15%, p  = 0.010) and nonsmokers (–16%; p  = 0.011). Moreover, among smokers, participants with NFIB C variant had 40% reduced clozapine CD compared to participants with NFIB TT ( p  < 0.001), whereas carriers of the CYP3A5*1/*1 genotype exhibited a 37% lower clozapine CD compared to CYP3A5*3/*3 carriers ( p  = 0.024) among nonsmokers. CYP1A2*1F , CYP2C19 , CYP2D6 , and CYP3A4*22 variants did not have any significant impact on clozapine CD, regardless of smoking habits. Conclusion: The CYP1A T , NFIB C , and CYP3A5*1 alleles have significant impact on clozapine serum levels. Incorporating genotype information for these variants, together with patient smoking status, would improve algorithms for precision dosing of clozapine.

• Smith, Robert Løvsletten; Andreassen, Ole; Kane, John M.; Schoretsanitis, Georgios & Molden, Espen (2025). Correlation Between Clozapine and CRP Levels in Relation to Smoking Status. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 152(1), p. 69–76. doi: 10.1111/acps.13801. Full text in Research Archive
• Koch, Elise; Shadrin, Alexey; Parker, Nadine; Lock, Siobhan K.; Smith, Robert Løvsletten & Frei, Oleksandr [Show all 11 contributors for this article] (2025). Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis. Neuropsychopharmacology. ISSN 0893-133X. 50, p. 947–955. doi: 10.1038/s41386-025-02054-x. Full text in Research Archive Show summary

  While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci. We used the largest available GWAS summary statistics of clozapine metabolism (clozapine-to-norclozapine ratio) and clozapine-induced agranulocytosis, applying the conditional false discovery rate (condFDR) method to increase power for genetic discovery by conditioning on granulocyte counts variants. To investigate potential causal effects of shared loci, we performed Mendelian Randomization analyses. After conditioning on granulocyte counts, we identified two novel loci associated with clozapine-to-norclozapine ratio. These loci were significantly associated with clozapine metabolism in a validation sample of 392 clozapine-treated individuals. For clozapine-induced agranulocytosis, five loci were identified after conditioning on granulocyte counts. These five loci were significantly associated with reduced granulocyte counts in a small independent sample of clozapine-treated individuals. Genetic liability to slow clozapine metabolism (high clozapine-to-norclozapine ratio) showed evidence of a causal effect on reduced neutrophil counts, and genetic liability to low neutrophil counts exhibited weak evidence of a causal effect on clozapine-induced agranulocytosis. Our findings of shared genetic variants associated with clozapine metabolism and granulocyte counts may form the basis for developing prediction models for clozapine-induced agranulocytosis.

• Johansson, Inger; Xanthopoulou, Emmanouella M.; Zhou, Yitian; Sanchez-Spitman, Anabel; Lee, Maaike van der & Wollmann, Birgit Malene Tovik [Show all 12 contributors for this article] (2025). Improved Prediction of CYP2D6 Catalyzed Drug Metabolism by Taking Variant Substrate Specificities and Novel Polymorphic Haplotypes into Account. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 118(1), p. 218–231. doi: 10.1002/cpt.3680. Full text in Research Archive Show summary

  The polymorphic CYP2D6 enzyme plays a pivotal role in the metabolism of approximately 25% of clinically prescribed drugs. However, the impact of specific genetic variants on the interindividual variability in CYP2D6-mediated drug metabolism remains insufficiently quantified. This translational study sought to address this gap by analyzing the genotypes and phenotypes of patients in two large clinical cohorts, focusing on the metabolism of the CYP2D6 substrates risperidone and desmethyltamoxifen. The analysis incorporated novel polymorphic haplotypes and substrate-specific differences among the CYP2D6.1, CYP2D6.2, and CYP2D6.35 enzyme variants. The study revealed that CYP2D6.2 and CYP2D6.35 exhibit reduced metabolic capacity for these substrates, both in vivo and in an in vitro expression model. This was evidenced by decreased catalytic turnover (Kcat), decreased substrate affinity, and altered substrate docking. Furthermore, novel polymorphic haplotypes on the CYP2D6*1, CYP2D6*2, and CYP2D6*35 backgrounds were identified, each associated with a 30–40% increase in CYP2D6 activity. Incorporating these findings into prediction equations significantly improved the genetic prediction accuracy (R2) for CYP2D6-mediated metabolism of desmethyltamoxifen from 59% to 71% and risperidone, also metabolized by CYP3A4, from 42% to 46%. These results highlight the importance of accounting for drug-specific interactions with enzyme variants and integrating distinct polymorphic haplotypes into CYP pharmacogenomic models and guidelines for better translation into clinical practice.

• Koch, Elise; Smart, Sophie; Einarsson, Guðmundur; Kämpe, Anders; Jonsson, Lina & Alver, Maris [Show all 30 contributors for this article] (2025). Recommendations for defining treatment outcomes in major psychiatric disorders using real-world data. The Lancet Psychiatry. ISSN 2215-0374. 12, p. 457–468. doi: 10.1016/S2215-0366(25)00061-6. Full text in Research Archive
• Hole, Kristine & Molden, Espen (2025). Association Between CYP2D6 Genotypes and Serum Concentrations of Mirtazapine and Mianserin. Basic & Clinical Pharmacology & Toxicology. ISSN 1742-7835. 136(4). doi: 10.1111/bcpt.70013. Full text in Research Archive Show summary

  The aim of the present study was to investigate the effect of CYP2D6 genotypes on mirtazapine and mianserin serum concentrations. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on mirtazapine and mianserin concentration-to-dose (C/D) ratio. The study included 2315 mirtazapine patients and 474 mianserin patients who were assigned to the genotype-predicted phenotype groups of CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs) and ultrarapid metabolizers (UMs). Multiple linear regression analysis revealed 18% and 14% higher mirtazapine C/D ratio in CYP2D6 PMs and IMs, respectively, compared with NMs (p ≤ 0.004). For mianserin, the C/D ratio was 80% and 45% higher in PMs and IMs, respectively, compared with NMs (p < 0.001). The C/D ratio in UMs did not differ from NMs for either drug (p ≥ 0.3). In conclusion, CYP2D6 genotype was only associated with a minor change in mirtazapine serum concentration. The association between CYP2D6 genotype and mianserin serum concentration was greater, with 80% higher mianserin C/D ratio in CYP2D6 PMs compared with NMs.

• Solhaug, Vigdis; Waade, Ragnhild Birkeland; Molden, Espen; Størset, Elisabet; Høiseth, Gudrun & Tveito, Marit (2025). The Effect of Age on Antipsychotic Serum Concentration in Males and Females: A Study Based on Therapeutic Drug Monitoring Data From 19,926 Patients. Therapeutic Drug Monitoring. ISSN 0163-4356. 47(5), p. 662–668. doi: 10.1097/FTD.0000000000001309. Full text in Research Archive
• Solbakk, Maria; Smith, Robert Løvsletten; Wollmann, Birgit Malene Tovik; Bråten, Line Skute; Johansson, Inger & Ingelman-Sundberg, Magnus [Show all 8 contributors for this article] (2025). Impact of the transcription factor nuclear factor 1 B T>C polymorphism on clozapine metabolism in vivo and expression of intestinal transporters in vitro. Drug Metabolism And Disposition. ISSN 0090-9556. 53(7). doi: 10.1016/j.dmd.2025.100100. Full text in Research Archive
• Bruun, Lina Dorthea; Andersen, Geir Øystein; Kringen, Marianne K.; Myhre, Peder Langeland; Halvorsen, Sigrun & Hansen, Charlotte Holst [Show all 8 contributors for this article] (2025). Effect of metoprolol exposure following myocardial infarction on future cardiovascular events: a Mendelian randomization study. European Journal of Clinical Pharmacology. ISSN 0031-6970. 81(4), p. 551–560. doi: 10.1007/s00228-025-03806-w. Full text in Research Archive Show summary

  Purpose The clinical benefit of up-titration of metoprolol to a guideline-recommended target dose after myocardial infarction (MI) is unknown. Our aim was to investigate whether variation in metoprolol exposure determined by cytochrome p450 enzyme 2D6 (CYP2D6) influences the occurrence of major adverse cardiovascular events (MACE) and cardiovascular death (CV death) among patients treated with metoprolol after MI. Method This Mendelian randomization study was performed using individual-level data from 1554 patients treated with metoprolol after an acute MI. CYPD26 genotype was applied as a binary genetic instrument assigning patients into two metoprolol exposure groups: CYP2D6 normal metabolizers (NM) (low exposure) and CYP2D6 intermediate and poor metabolizers (IM + PM) (high exposure). The null hypothesis of no association between the CYP2D6 metabolizer subgroup and MACE or CV death was tested using the Cox proportional hazards model. All-cause mortality and individual components of MACE were included as secondary outcomes. Results In total, 879 (56.6%) patients were classified as NM and 675 (43.4%) as IM + PM. During the 3-year follow-up, 56 patients (6.4%) in the NM group had an outcome of MACE, and 24 (2.7%) patients died from CV disease. Corresponding frequency in the IM + PM group was 47 (7.0%) and 22 (3.3%), respectively. There was no association between genotype and MACE [unadjusted HR 1.12 (CI 0.76, 1.65)] or CV death [unadjusted HR 1.20 (CI 0.67, 2.14)], or between the CYP2D6 group and any of the secondary outcomes. Conclusion In patients treated with metoprolol after MI, variation in metoprolol exposure determined by CYP2D6 did not impact the occurrence of cardiovascular events.

• Lenk, Hasan Cagin; Smith, Robert Løvsletten; O'Connell, Kevin Sean; Andreassen, Ole A. & Molden, Espen (2024). Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data. CNS Drugs. ISSN 1172-7047. 38, p. 473–480. doi: 10.1007/s40263-024-01079-y. Full text in Research Archive Show summary

  Introduction Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. Methods Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. Results Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). Conclusion LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

• Røed-Undlien, Henriette; Schultz, Nina Haagenrud; Amundsen, Erik Koldberg; Wollmann, Birgit Malene Tovik; Molden, Espen & Akerkar, Rupali Rajendra [Show all 7 contributors for this article] (2024). Does in vitro hemolysis affect measurements of plasma apixaban concentration by UPLC-MS and anti-Xa assay? International Journal of Laboratory Hematology (IJLH). ISSN 1751-5521. 46(5), p. 946–952. doi: 10.1111/ijlh.14311. Full text in Research Archive Show summary

  Introduction: Hemolytic interference may impact various laboratory tests, including coagulation analyses. Apixaban is the most commonly used direct oral anticoagulant in Norway, and there is lacking knowledge on how apixaban concentration measure- ments might be influenced by hemolysis. Moreover, hemolysis-induced alterations in apixaban levels could potentially impact the risk of bleeding in specific clinical scenar- ios. We wanted to study whether hemolysis would increase apixaban concentration and investigate the impact of hemolytic interference on apixaban concentration measurements. Methods: Blood samples from 20 apixaban-treated patients and 8 healthy controls were hemolyzed in vitro by a freeze method. The degree of hemolysis was measured with plasma free hemoglobin (PfHb) at baseline and two levels of hemolysis. Apixa- ban concentration was measured in plasma using both the chromogenic anti-Xa method and the ultraperformance liquid chromatography mass spectrometry (UPLC-MS). Thrombin generation assay was performed to assess coagulability. Results: UPLC-MS measurements showed a mean concentration change of 1.66% (±3.2%, p = 0.005) and anti-Xa assay showed a mean concentration change of 3.37% (±6.5%, p = 0.09) with increasing hemolysis. Thrombin generation lagtime decreased, and endogenous thrombin potential and peak thrombin increased with increasing hemolysis in both the control group and the apixaban group. Conclusion: Apixaban concentration measurements by anti-Xa assay and UPLC-MS were not affected by hemolysis to a clinically relevant extent. Furthermore, hemolysis did not lead to hypocoagulability when assessed by thrombin generation.

• Smith, Robert Løvsletten; Wollmann, Birgit Malene Tovik; Størset, Elisabet; Lenk, Hasan Cagin; O'Connell, Kevin Sean & Kringen, Marianne K. [Show all 8 contributors for this article] (2024). Effect of the NFIB rs28379954 T>C polymorphism on CYP2D6-catalyzed metabolism of solanidine. Clinical and Translational Science (CTS). ISSN 1752-8054. 17(2). doi: 10.1111/cts.13743. Full text in Research Archive Show summary

  Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%–25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra-high performance liquid chromatography-high-resolution mass spectrometry in a cohort of 463 CYP2D6-genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83- and 3.38-fold higher M416-to-solanidine (p = 0.039) and M444-to-solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6-mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans.

• Mathiesen, Liv; Blix, Hege Salvesen; Molden, Espen; Kersten, Hege; Trapnes, Elin & Bergan, Stein [Show all 7 contributors for this article] (2024). Erfaringsbasert master i klinisk farmasi – en kartleggingsstudie. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. p. 32–36. Full text in Research Archive Show summary

  Hensikt Kartlegge bakgrunn for farmasøyter som har gjennomført minst halve det erfaringsbaserte masterprogrammet i klinisk farmasi ved Farmasøytisk institutt, Universitetet i Oslo. Kartlegge i hvilken grad arbeidsoppgavene har endret seg for de som har fullført utdanningen. Materiale og metode Deskriptiv nettbasert spørreskjemaundersøkelse med spørsmål knyttet til demografi, grunnutdanningen i farmasi, det erfaringsbaserte masterprogrammet og arbeidsoppgaver. Farmasøyter som hadde fullført minst tre av seks emner i masterprogrammet, kunne inkluderes, og 92 farmasøyter ble invitert til å delta. Resultater 82 farmasøyter (88 %) besvarte undersøkelsen, hvorav 53 hadde gjennomført hele utdanningen, og 29 farmasøyter hadde gjennomført minst halve utdanningen. Blant respondentene som hadde fullført masterprogrammet, hadde en signifikant høyere andel 5-årig farmasiutdanning (master i farmasi eller cand.pharm.) (p < 0,01) og jobbet i sykehus med klinisk farmasøytiske oppgaver før de startet på masterprogrammet (p = 0,04), sammenliknet med de som var underveis i utdanningen. Blant de som hadde fullført masterprogrammet, svarte 93 % at de hadde jobbet med klinisk farmasøytiske oppgaver etter utdanningen. Det var 70 % som for tiden utførte klinisk farmasøytiske arbeidsoppgaver, sammenliknet med 62 % før oppstart. 43 % hadde vært involvert i kliniske forskningsprosjekter etter endt utdanning. Konklusjon Blant de som var i ferd med å gjennomføre videreutdanningen var det flere med bachelorgrad og færre med erfaring som klinisk farmasøyt enn i gruppen som hadde fullført. Ni av ti farmasøyter som hadde gjennomført hele videreutdanningen, har hatt klinisk arbeidsoppgaver etterpå, mens seks av ti hadde slike oppgaver før utdanningen. Nesten halvparten hadde vært involvert i kliniske forskningsprosjekter.

• Milosavljević, Filip; Molden, Espen; Ingelman-Sundberg, Magnus & Jukić, Marin M (2024). Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials. European Neuropsychopharmacology. ISSN 0924-977X. 81, p. 43–52. doi: 10.1016/j.euroneuro.2024.01.005. Full text in Research Archive
• Ingelman-Sundberg, Magnus & Molden, Espen (2024). Therapeutic drug monitoring, liquid biopsies or pharmacogenomics for prediction of human drug metabolism and response. British Journal of Clinical Pharmacology. ISSN 0306-5251. doi: 10.1111/bcp.16048. Full text in Research Archive
• Koch, Elise Mirjam; Pardiñas, Antonio F.; O'Connell, Kevin Sean; Selvaggi, Pierluigi; Camacho-Collados, Jose & Babic, Aleksandar [Show all 26 contributors for this article] (2024). How real-world data can facilitate the development of precision medicine treatment in psychiatry. Biological Psychiatry. ISSN 0006-3223. 96, p. 543–551. doi: 10.1016/j.biopsych.2024.01.001. Full text in Research Archive Show summary

  Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements—well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms—to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.

• Røed-Undlien, Henriette; Schultz, Nina Haagenrud; Husebråten, Inger; Wollmann, Birgit Malene Tovik; Akerkar, Rupali Rajendra & Molden, Espen [Show all 8 contributors for this article] (2024). Apixaban removal during emergency surgery for type A acute aortic dissection: a prospective cohort study. International Journal of Surgery (IJS). ISSN 1743-9191. 110(12), p. 7782–7790. doi: 10.1097/JS9.0000000000002137. Full text in Research Archive Show summary

  Background: Acute type A aortic dissection (ATAAD) has a high mortality, and acute aortic repair is the only curative treatment. In patients treated with factor Xa (FXa) inhibitors, the risk of severe disease-related complications such as cardiac tamponade and hemodynamic shock must be balanced against the potential for severe perioperative bleeding. The aim was to study intraoperative changes in plasma levels of the FXa inhibitor apixaban when using hemoadsorption during acute thoracic aortic repair. Materials and methods: This is a single-center prospective cohort study. Eight apixaban-treated patients presenting with ATAAD underwent acute thoracic aortic repair with intraoperative hemoadsorption with CytoSorb. Apixaban concentrations were measured at the start of cardiopulmonary bypass (CPB) and after 5, 15, 30, 60, and 90 min of CPB, at CPB weaning, 30 min after CPB weaning and 24 h postoperatively, using ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). Results: After 30 min of CPB with hemoadsorption, mean apixaban concentration ( ± SD) was reduced by 59% from 108 ( ± 69) μg/l to 44 ( ± 20) μg/l (P = 0.009). There was a further reduction to 37 ( ± 17) μg/l at CPB weaning (P = 0.008). Apixaban concentration displayed an increase to 56 ( ± 29) μg/l 24 h postoperatively (P = 0.01). In-hospital mortality was 25%. The mean 24H chest tube drainage volume was 621 ( ± 136) ml. Conclusion: Intraoperative hemoadsorption lowers apixaban levels in patients undergoing emergency surgery for ATAAD. Further research is needed to determine its impact on perioperative bleeding complications and mortality.

• Hole, Kristine; Lorentsen, Silje K.; Nordby, Karoline L; Slettvik, Marie; Sørum, Ida T. G. & Molden, Espen [Show all 7 contributors for this article] (2024). Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets. European Journal of Clinical Pharmacology. ISSN 0031-6970. doi: 10.1007/s00228-024-03655-z. Full text in Research Archive
• Wollmann, Birgit Malene Tovik; Haugen, Aina Gaustad; Smith, Robert Løvsletten & Molden, Espen (2024). Novel Identification of Cysteinyl Derivatives of Toxic Clozapine Nitrenium Ions and the Effect of Valproic Acid on Metabolite Formation: A Study Using Reprocessed High-Resolution Mass Spectra of Analyzed Therapeutic Drug Monitoring Samples. Therapeutic Drug Monitoring. ISSN 0163-4356. 46(2), p. 265–269. doi: 10.1097/FTD.0000000000001177. Full text in Research Archive
• Tveit, Kristine; Hermann, Monica; Nilsen, Roy Miodini; Wallerstedt, Susanna M.; Rongve, Arvid & Molden, Espen [Show all 7 contributors for this article] (2024). Age of onset for increased dose-adjusted serum concentrations of antidepressants and association with sex and genotype: An observational study of 34,777 individuals. European Journal of Clinical Pharmacology. ISSN 0031-6970. 80, p. 435–444. doi: 10.1007/s00228-023-03611-3. Full text in Research Archive Show summary

  Purpose The aim of this study was to examine the age of onset for increased dose-adjusted serum concentrations (C/D ratio) of common antidepressant drugs and to explore the potential association with sex and CYP2C19/CYP2D6 genotype. Methods Serum concentrations and prescribed daily doses for citalopram, escitalopram, sertraline, venlafaxine and mirtazapine, and CYP genotypes, were obtained from a therapeutic drug monitoring (TDM) service. Segmented linear regression analysis was used to examine the relationship between age and antidepressant log C/D ratio in (i) all individuals, (ii) men and women, and (iii) CYP2D6/CYP2C19 normal metabolizers (NMs) and CYP2D6/CYP2C19 intermediate or poor metabolizers (IMs/PMs). Results A total of 34,777 individuals were included in the study; CYP genotype was available for 21.3%. An increase in C/D ratio started at 44‒55 years of age. Thereafter, the increase progressed more rapidly for citalopram and escitalopram than for venlafaxine and mirtazapine. A doubled C/D ratio was estimated to occur at 79 (citalopram), 81 (escitalopram), 86 (venlafaxine), and 90 years (mirtazapine). For sertraline, only modest changes in C/D ratio were observed. For escitalopram and venlafaxine, the observed increase in C/D ratio started earlier in women than in men. The results regarding CYP genotype were inconclusive. Conclusion The age-related increase in C/D ratio starts in middle-aged adults and progresses up to more than twofold higher C/D ratio in the oldest old. Sertraline seems to be less prone to age-related changes in C/D ratio than the other antidepressants.

• Schoretsanitis, Georgios; Yağcıoğlu, A. Elif Anıl; Ruan, Can-Jun; Eap, Chin B.; Molden, Espen & Baptista, Trino [Show all 24 contributors for this article] (2024). Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition. Schizophrenia Research. ISSN 0920-9964. doi: 10.1016/j.schres.2023.05.010. Full text in Research Archive
• Faraj, Pari; Haslemo, Tore; Tran, Jenny Phung; Stingl, Julia; Molden, Espen & Hole, Kristine (2024). Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population. British Journal of Clinical Pharmacology. ISSN 0306-5251. doi: 10.1111/bcp.16156. Full text in Research Archive
• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Show all 50 contributors for this article] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), p. 1310–1318. doi: 10.1038/s41588-024-01771-1. Full text in Research Archive
• Koch, Elise Mirjam; Kämpe, Anders; Alver, Maris; Sigurðarson, Sindri; Einarsson, Guðmundur & Partanen, Juulia [Show all 21 contributors for this article] (2024). Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study. Neuropsychopharmacology. ISSN 0893-133X. 49, p. 1113–1119. doi: 10.1038/s41386-023-01792-0. Full text in Research Archive
• Ruan, Can-Jun; Olmos, Ismael; Ricciardi, Carina; Schoretsanitis, Georgios; Vincent, Philippe D. & Yağcıoğlu, A. Elif Anıl [Show all 27 contributors for this article] (2024). Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies. Schizophrenia Research. ISSN 0920-9964. doi: 10.1016/j.schres.2023.07.002. Full text in Research Archive
• Hernandez, Marta H.; Cohen, Jacqueline Mallory; Skåra, Karoline Hansen; Grindstad, Thea Karoline Walstad; Lee, Yunsung & Magnus, Per [Show all 14 contributors for this article] (2024). Placental efflux transporters and antiseizure or antidepressant medication use impact birth weight in MoBa cohort. iScience. 27(3). doi: 10.1016/j.isci.2024.109285. Full text in Research Archive Show summary

  Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2-ABCC2 and MDR1-ABCB1) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2-ABCC2 and MDR1-ABCB1 variants and antiseizure medication may impact neonatal birth weight.

• Milosavljevic, Filip; Manojlovic, Marina; Matkovic, Lena; Molden, Espen; Ingelman-Sundberg, Magnus & Leucht, Stefan [Show all 7 contributors for this article] (2024). Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis. JAMA Network Open. 7(8). doi: 10.1001/jamanetworkopen.2024.25593. Full text in Research Archive
• Rognan, Stine; Mathiesen, Liv; Lea, Marianne; Mowe, Morten; Molden, Espen & Skovlund, Eva (2024). Development and external validation of a prognostic model for time to readmission or death in multimorbid patients. Research in Social and Administrative Pharmacy. ISSN 1551-7411. 20(9), p. 926–933. doi: 10.1016/j.sapharm.2024.06.007. Full text in Research Archive Show summary

  Objective To develop and externally validate a prognostic model built on important factors predisposing multimorbid patients to all-cause readmission and/or death. In addition to identify patients who may benefit most from a comprehensive clinical pharmacist intervention. Methods A multivariable prognostic model was developed based on data from a randomised controlled trial investigating the effect of pharmacist-led medicines management on readmission rate in multimorbid, hospitalised patients. The derivation set comprised 386 patients randomised in a 1:1 manner to the intervention group, i.e. with a pharmacist included in their multidisciplinary treatment team, or the control group receiving standard care at the ward. External validation of the model was performed using data from an independent cohort, in which 100 patients were randomised to the same intervention, or standard care. The setting was an internal medicines ward at a university hospital in Norway. Results The number of patients who were readmitted or had died within 18 months after discharge was 297 (76.9 %) in the derivation set, i.e. the randomized controlled trial, and 69 (71.1 %) in the validation set, i.e. the independent cohort. Charlson comorbidity index (CCI; low, moderate or high), previous hospital admissions within the previous six months and heart failure were the strongest prognostic factors and were included in the final model. The efficacy of the pharmaceutical intervention did not prove significant in the model. A prognostic index (PI) was constructed to estimate the hazard of readmission or death (low, intermediate or high-risk groups). Overall, the external validation replicated the result. We were unable to identify a subgroup of the multimorbid patients with better efficacy of the intervention. Conclusions A prognostic model including CCI, previous admissions and heart failure can be used to obtain valid estimates of risk of readmission and death in patients with multimorbidity.

• Cuevas, Carlos De las; Sanz, Emilio J.; Gross, Jason A.; Correll, Christoph U.; Verdoux, Hélène & Lally, John [Show all 14 contributors for this article] (2024). Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK. Schizophrenia Research. ISSN 0920-9964. doi: 10.1016/j.schres.2023.11.010. Full text in Research Archive
• Lenk, Hasan Cagin; Koch, Elise Mirjam; O'Connell, Kevin Sean; Smith, Robert Løvsletten; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Show all 8 contributors for this article] (2024). Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment. Human Genomics. ISSN 1473-9542. 18(1). doi: 10.1186/s40246-024-00673-x. Full text in Research Archive Show summary

  Background Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively. Results We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively. Conclusions We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

• Størset, Elisabet; Bråten, Line Skute; Ingelman-Sundberg, Magnus; Johansson, Inger; Molden, Espen & Kringen, Marianne K. (2024). Impact of CYP2D6*2, CYP2D6*35, rs5758550, and related haplotypes on risperidone clearance in vivo. European Journal of Clinical Pharmacology. ISSN 0031-6970. 80, p. 1531–1541. doi: 10.1007/s00228-024-03721-6. Full text in Research Archive
• Schaik, Ron Hn van; Manolopoulos, Vangelis G.; Daly, Ann K.; Niemi, Mikko; Zukic, Branka & Patrinos, George P. [Show all 24 contributors for this article] (2023). The Sixth European Society of Pharmacogenomics and Personalised Therapy Congress. Pharmacogenomics (London). ISSN 1462-2416. 24(5), p. 243–246. doi: 10.2217/pgs-2023-0013. Full text in Research Archive
• Hole, Kristine; Gangsø, Sofie; Jensstuen, Åse Tonette; Ormøy, Hanne Holte; Paulsen, Maren & Molden, Espen [Show all 7 contributors for this article] (2023). Effect of CYP2D6 genotype on duloxetine serum concentration. Basic & Clinical Pharmacology & Toxicology. ISSN 1742-7835. 134(1), p. 186–192. doi: 10.1111/bcpt.13954. Full text in Research Archive Show summary

  Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 geno- type, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n = 23), intermediate metabolizers (IMs, n = 121), normal metabolizers (NMs, n = 120) and ultrara- pid metabolizers (UMs, n = 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p = 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p = 0.01), while women had a 46% higher C/D ratio than men (p = 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.

• Hole, Kristine; Haslemo, Tore & Molden, Espen (2023). Impact of CYP2D6 Genotype on Paroxetine Serum Concentration. Therapeutic Drug Monitoring. ISSN 0163-4356. 45(5), p. 683–688. doi: 10.1097/FTD.0000000000001096. Full text in Research Archive
• Solhaug, Vigdis; Tveito, Marit; Waade, Ragnhild Birkeland; Høiseth, Gudrun; Molden, Espen & Smith, Robert Løvsletten (2023). Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients. British Journal of Clinical Pharmacology. ISSN 0306-5251. doi: 10.1111/bcp.15849. Full text in Research Archive Show summary

  Aims To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N ‐desalkylquetiapine (NDQ). Methods Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. Results The average age of the included population ( n  = 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged &gt;50 years compared to those aged 18–30 years, with 28 and 29% increase, respectively, for patients aged &gt;70 years ( P  &lt; .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P  &lt; .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males ( P  &lt; .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males &lt;65 years ( P  &lt; .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P  = .012) and poor (+17%, P  = .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. Conclusion This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose‐dependent side effects of NDQ during QUE treatment.

• Wollmann, Birgit Malene Tovik; Smith, Robert Løvsletten; Kringen, Marianne K.; Ingelman-Sundberg, Magnus; Molden, Espen & Størset, Elisabet (2023). Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism. British Journal of Clinical Pharmacology. ISSN 0306-5251. doi: 10.1111/bcp.15721. Full text in Research Archive Show summary

  Aims: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. Methods: The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio. Results: A total of 229 patients were included. Highly significant, positive correla- tionswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to- risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72–0.77, P < .0001). Conclusion: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

• Hjemås, Bodil Jahren; Bøvre, Katrine; Bjerknes, Kathrin; Mathiesen, Liv; Mellingsæter, Marte & Molden, Espen (2023). Implementation of pharmacogenetic testing in medication reviews in a hospital setting. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(10), p. 3116–3125. doi: 10.1111/bcp.15815. Full text in Research Archive Show summary

  Abstract Aim To investigate whether it is feasible to perform pharmacogenetic testing and implement the test results as part of medication reviews during hospitalization of multimorbid patients. Methods Patients with ≥2 chronic conditions and ≥5 regular drugs with at least one potential gene‐drug interaction (GDI) were included from one geriatric and one cardiology ward for pharmacogenetic testing. After inclusion by the study pharmacist, blood samples were collected and shipped to the laboratory for analysis. For patients still hospitalized at the time when the pharmacogenetic test results were available, the information was used in medication reviews. Recommendations from the pharmacist on actionable GDIs were communicated to the hospital physicians, who subsequently decided on potential immediate changes or forwarded suggestions in referrals to general practitioners. Results The pharmacogenetic test results were available for medication review in 18 of the 46 patients (39.1%), where median length of hospital stay was 4.7 days (1.6‐18.3). The pharmacist recommended medication changes for 21 of 49 detected GDIs (42.9%). The hospital physicians accepted 19 (90.5%) of the recommendations. The most commonly detected GDIs involved metoprolol ( CYP2D6 genotype), clopidogrel ( CYP2C19 genotype) and atorvastatin ( CYP3A4/5 and SLCOB1B1 genotype). Conclusions The study shows that implementation of pharmacogenetic testing for medication review of hospitalized patients has the potential to improve drug treatment before being transferred to primary care. However, the logistics workflow needs to be further optimized, as test results were available during hospitalization for less than half of the patients included in the study.

• Leon, Jose de; Schoretsanitis, Georgios; Smith, Robert Løvsletten; Molden, Espen; Solismaa, Anssi & Seppälä, Niko [Show all 104 contributors for this article] (2023). An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Psiquiatría Biológica. ISSN 1696-9138. 30(3). doi: 10.1016/j.psiq.2023.100415. Full text in Research Archive
• Faraj, Pari; Størset, Elisabet; Hole, Kristine; Smith, Godfrey L; Molden, Espen & Dietrichs, Erik Sveberg (2023). Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients – a study based on a cohort of 19,742 patients. EBioMedicine. 95. doi: 10.1016/j.ebiom.2023.104779. Full text in Research Archive Show summary

  Background - For a decade, patients have been advised against using high citalopram- and escitalopram-doses due to risk for ventricular arrhythmia and cardiac arrest. Still, these drugs are widely used to treat depression and anxiety especially in older patients. It is unclear why they are cardiotoxic and at what serum concentrations patients are at risk for arrhythmias. Thus, how many patients that are at risk for iatrogenic cardiac arrest is unknown.<p> <p>Methods - We studied the arrhythmogenic effects of citalopram, escitalopram and their metabolites on human cardiomyocytes. Concentrations showing pro-arrhythmic activity were compared with observed drug and metabolite serum concentrations in a cohort of 19,742 patients (age 12–105 years) using escitalopram or citalopram in Norway (2010–2019). As arrhythmia-risk is related to maximum serum concentration, this was simulated for different age-groups from the escitalopram patient material.<p> <p>Findings - Therapeutic concentrations of both citalopram and escitalopram but not their metabolites showed pro-arrhythmic changes in the human cardiac action potential. Due to age-dependent reduction of drug clearance, the proportion of patients above threshold for arrhythmia-risk increased with age. 20% of patients >65 years were predicted to reach potentially pro-arrhythmic concentrations, following intake of 10 mg escitalopram.<p> <p>Interpretation - All patients that are using escitalopram or citalopram and have genetic disposition for acquired long-QT syndrome, are >65 years, are using additional pro-arrhythmic drugs or have predisposition for arrhythmias, should be monitored with therapeutic drug monitoring (TDM) to avoid exposure to potentially cardiotoxic concentrations. Serum concentrations should be kept below 100 nM, to reduce arrhythmia-risk.

• O'Connell, Kevin Sean; Koch, Elise; Lenk, Hasan Cagin; Akkouh, Ibrahim Ahmed; Hindley, Guy Frederick Lanyon & Jaholkowski, Piotr Pawel [Show all 16 contributors for this article] (2023). Polygenic overlap with body-mass index improves prediction of treatment-resistant schizophrenia. Psychiatry Research. ISSN 0165-1781. 325. doi: 10.1016/j.psychres.2023.115217. Full text in Research Archive Show summary

  Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

• Wollmann, Birgit Malene Tovik; Størset, Elisabet; Kringen, Marianne K.; Molden, Espen & Smith, Robert Løvsletten (2023). Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype. European Journal of Clinical Pharmacology. ISSN 0031-6970. 79(4), p. 523–531. doi: 10.1007/s00228-023-03462-y. Full text in Research Archive Show summary

  Purpose Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing. Methods The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts. Full-scan high-resolution mass spectrometry data files of previously analyzed serum samples were reprocessed for identification and quantification of solanidine and seven metabolites. Metabolite-to-solanidine ratios (MRs) of the vari- ous solanidine metabolites were calculated prior to performing receiver operator characteristic (ROC) and multiple linear regression analyses on the test cohort. The MR thresholds obtained from the ROC analyses were tested for the prediction of CYP2D6 PMs in the validation cohort. Results In the test cohort, the M414-to-solanidine MR attained the highest sensitivity and specificity parameters from the ROC analyses (0.98 and 1.00) and highest explained variance from the linear models (R2 = 0.68). Below these thresholds, CYP2D6 PM predictions were tested in the validation cohort providing positive and negative predictive values of 100% for the MR of M414, while similar values for the other MRs ranged from 20.5 to 73.3% and 96.7 to 99.3%, respectively. Conclusion The M414-to-solanidine MR is an excellent predictor of the CYP2D6 PM phenotype. By measuring solanidine and metabolites using liquid chromatography-mass spectrometry in patient serum samples, CYP2D6 PMs can easily be identified, hence facilitating the implementation of precision dosing in clinical practice.

• Smith, Robert Løvsletten; Molden, Espen & Bernard, Jean-Paul Anthony (2023). Effect of CYP2D6 and CYP2C19 genotypes on atomoxetine serum levels: A study based on therapeutic drug monitoring data. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(7), p. 2246–2253. doi: 10.1111/bcp.15706. Full text in Research Archive Show summary

  Aims Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced‐function CYP2C19 genotype on atomoxetine concentrations in real‐world settings. Methods Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced‐function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3 ‐ *6 , *9 ‐ *10 and *41 . For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose‐adjusted serum atomoxetine concentration was the exposure measure. Results Using a patient cohort ( n  = 315), it was found that CYP2D6 IM and PM patients had 1.9‐fold (95% confidence interval: 1.4–2.7) and 9.6‐fold (5.9–16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5‐fold (1.1–2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. Conclusion CYP2D6 genotype has a great impact on atomoxetine exposure, where our real‐world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs . NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre‐emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

• Smith, Robert Løvsletten; Wollmann, Birgit Malene Tovik; Kausberg, Marianne; Mæland, Sondre; Tveito, Marit & O'Connell, Kevin Sean [Show all 8 contributors for this article] (2022). Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo. Current drug metabolism. ISSN 1389-2002. 23(1), p. 66–72. doi: 10.2174/1389200223666220201152953. Full text in Research Archive Show summary

  Background: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear. Objective: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients’ serum after adjusting for sex, age, and smoking habits. Methods: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway. From the same patients, the following UGT variants were genotyped using Real-Time PCR: UGT2B:GA haplotype (defined as UGT2B:GA; rs1513559A>G and rs416593T>A) and UGT1A4*3 (rs2011425T>G). Serum concentrations of CLZ 5N- and N+-glucuronide were measured by UPLC high-resolution mass spectrometry. Results: None of the genotypes had significant impact on CLZ exposure (p>0.05). However, compared to UGT2B:AT/AT and UGT1A4*1/*1, the 5N-glucuronide exposure was reduced in UGT2B:GA/GA carriers (-75 %, p=0.03) while the exposure was non-significantly increased in UGT1A4*3 carriers (+100 %, p=0.14), respectively. The N+-glucuronide exposure was unchanged in UGT1A4*3 vs. noncarriers (p=0.28), but significantly reduced in heterozygous (-50 %, p=0.016) and homozygous carriers (-70 %, p=0.021) of UGT2B:GA compared to UGT2B:AT/AT carriers, respectively. Conclusion: The UGT2B:GA and UGT1A4*3 variants had no impact on CLZ exposure but were associated with differences and preferences in CLZ glucuronidation. The latter might be of potential relevance for CLZ tolerability since levels of the N+-glucuronide metabolite may reflect the generation and trapping of reactive metabolites involved in CLZ-induced toxicity

• Dietrichs, Erik Sveberg; Solhaug, Vigdis; Haslemo, Tore; Kringen, Marianne K. & Molden, Espen (2022). E.S. Dietrichs og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(17). doi: 10.4045/tidsskr.22.0695. Full text in Research Archive
• Solhaug, Vigdis; Haslemo, Tore; Kringen, Marianne Kristiansen; Molden, Espen & Dietrichs, Erik Sveberg (2022). Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(13), p. 1–10. doi: 10.4045/tidsskr.22.0017. Full text in Research Archive Show summary

  BAKGRUNN - Selektive serotoninreopptakshemmere (SSRI) brukes av over 180 000 mennesker i Norge. Enzymene CYP2D6 og CYP2C19 er sentrale i metabolismen av SSRI-antidepressiver. Serotonintransportøren kodet av SLC6A4 kan ha betydning for effekten av medikamentene.<p> <p>MATERIALE OG METODE - Alle pasienter som hadde blitt genotypet for CYP2D6, CYP2C19 og SLC6A4 ved Senter for psykofarmakologi i 2020, uavhengig av indikasjon, ble inkludert. Hos de pasientene der data var tilgjengelige, ble CYP2C19-genotype koblet til serumkonsentrasjonsmåling av escitalopram, som er det mest brukte SSRI-preparatet.<p> <p>RESULTATER - 432 av 3 492 pasienter (12,4 %) hadde en kombinasjon av genotyper av CYP2D6, CYP2C19 og SLC6A4 som anses å gi mest gunstig metabolisme og effekt av SSRI-antidepressiver. Pasienter med manglende CYP2C19-metabolisme hadde mer enn halvert dosebehov for å oppnå samme konsentrasjon av escitalopram som pasienter med normal metabolisme.<p> <p>FORTOLKNING - Våre funn viser lav forekomst av den gunstigste genotypekombinasjonen for respons av SSRI-preparater. Genotypekombinasjoner bidrar sannsynligvis til den store individuelle variasjonen i effekt av disse medikamentene og til at behandlingen ikke gir ønsket utfall hos mange pasienter.

• Kvitne, Kine Eide; Hole, Kristine; Krogstad, Veronica; Wollmann, Birgit Malene Tovik; Wegler, Christine & Johnson, Line Kristin [Show all 19 contributors for this article] (2022). Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. European Journal of Clinical Pharmacology. ISSN 0031-6970. 78(8), p. 1289–1299. doi: 10.1007/s00228-022-03336-9. Full text in Research Archive Show summary

  Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ =  − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ =  − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.

• Faraj, Pari; Hermansen, Astrid; Molden, Espen & Hole, Kristine (2022). Identification of Escitalopram Metabolic Ratios as Potential Biomarkers for Predicting CYP2C19 Poor Metabolizers. Therapeutic Drug Monitoring. ISSN 0163-4356. 44(6), p. 720–728. doi: 10.1097/FTD.0000000000000991. Full text in Research Archive
• Nymoen, Lisbeth Damlien; Flatebø, Trude Eline; Moger, Tron Anders; Øie, Erik; Molden, Espen & Viktil, Kirsten Kilvik (2022). Impact of systematic medication review in emergency department on patients’ postdischarge outcomes—A randomized controlled clinical trial. PLOS ONE. 17:e0274907(9), p. 1–19. doi: 10.1371/journal.pone.0274907. Full text in Research Archive Show summary

  Introduction The main objective of this study was to investigate whether systematic medication review conducted by clinical pharmacists can impact clinical outcomes and post-discharge outcomes for patients admitted to the emergency department. Method This parallel group, non-blinded, randomized controlled trial was conducted in the emergency department, Diakonhjemmet Hospital, Oslo, Norway. The study was registered in ClinicalTrials.gov, Identifier: NCT03123640 in April 2017. From April 2017 to May 2018, patients ≥18 years were included and randomized (1:1) to intervention- or control group. The control group received standard care from emergency department physicians and nurses. In addition to standard care, the intervention group received systematic medication review including medication reconciliation conducted by pharmacists, during the emergency department stay. The primary outcome was proportion of patients with an unplanned contact with hospital within 12 months from inclusion stay discharge. Results In total, 807 patients were included and randomized, 1:1, to intervention or control group. After excluding 8 patients dying during hospital stay and 10 patients lacking Norwegian personal identification number, the primary analysis comprised 789 patients: 394 intervention group patients and 395 control group patients. Regarding the primary outcome, there was no significant difference in proportion of patients with an unplanned contact with hospital within 12 months after inclusion stay discharge between groups (51.0% of intervention group patients vs. 53.2% of control group patients, p = 0.546). Conclusion As currently designed, emergency department pharmacist-led medication review did not significantly influence clinical- or post-discharge outcomes. This study did, however pinpoint important practical implementations, which can be used to design tailored pharmacist-led interventions and workflow regarding drug-related issues in the emergency department setting.

• Jukic, Marin; Milosavljević, Filip; Molden, Espen & Ingelman-Sundberg, Magnus (2022). Pharmacogenomics in treatment of depression and psychosis: an update. TIPS - Trends in Pharmacological Sciences. ISSN 0165-6147. 43(12), p. 1055–1069. doi: 10.1016/j.tips.2022.09.011. Full text in Research Archive
• Veddeng, Sigbjørn; Madland, Håkon; Molden, Espen; Wyller, Torgeir Bruun & Romskaug, Rita (2022). Association between statin use and physical performance in home-dwelling older patients receiving polypharmacy: cross-sectional study. BMC Geriatrics. 22(1), p. 242–242. doi: 10.1186/s12877-022-02942-7. Full text in Research Archive Show summary

  Background In older patients with polypharmacy and multiple comorbidities, even low grades of statin-associated muscle symptoms may have clinical implications. The aim of this study was therefore to investigate the potential associations between statin use and measures of physical performance and muscle function. Methods Participants were aged 70+, treated with at least seven regular systemic medications, and not expected to die or become institutionalized within 6 months. Physical performance measured as gait speed and Short Physical Performance Battery (SPPB) score, and muscle function measured as grip strength, were compared between users and non-users of statins. In the subgroup of statin users, the dose-response relationship was assessed using harmonized simvastatin equivalents adjusted for statin potency, pharmacokinetic interactions and SLCO1B1 c.521 T > C genotype. Multiple linear regression analyses were applied to investigate potential associations between stain use and exposure as independent variables, and physical performance and muscle function as outcomes, adjusted for age, gender, body mass, comorbidity, disability and dementia. Results 174 patients (87 users and 87 non-users of statins) with a mean (SD) age of 83.3 (7.3) years were included. In analyses adjusted only for gender, grip strength was significantly higher in users than in non-users of statins [regression coefficient (B) 2.7, 95% confidence interval (CI) 1.0 to 4.4]. When adjusted for confounders, the association was no longer statistically significant (B 1.1, 95% CI − 0.5 to 2.7). SPPB and gait speed was also better in statin users than in non-users, but the differences were not statistically significant. In dose-response analyses adjusted for confounders, we found a statistically significant increase in SPPB score (B 0.01, 95% CI 0.00 to 0.02) and gait speed (B 0.001, 95% CI 0.000 to 0.002) per mg increase in simvastatin equivalents. Conclusions In contrast to our hypothesis, statin use and exposure was associated with better measures of physical performance and muscle function in older patients with complex drug treatment. The unexpected findings of this cross-sectional, observational study should be further investigated by comparing physical performance before and after statin initiation or statin withdrawal in prospective studies. Trial registration ClinicalTrials.gov identifier: NCT02379455, registered March 5, 2015.

• Lenk, Hasan Cagin; Klöditz, Katharina; Johansson, Inger; Smith, Robert Løvsletten; Jukic, Marin & Molden, Espen [Show all 7 contributors for this article] (2022). The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 111(5), p. 1165–1174. doi: 10.1002/cpt.2571. Full text in Research Archive Show summary

  The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

• Bråten, Line Skute; Ingelman-Sundberg, Magnus; Jukic, Marin M.; Molden, Espen & Kringen, Marianne K. (2022). Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population. Clinical and Translational Science (CTS). ISSN 1752-8054. 15(9), p. 2135–2145. doi: 10.1111/cts.13347. Full text in Research Archive
• Røed-Undlien, Henriette; Schultz, Nina Haagenrud; Lunnan, Asbjørn; Husebråten, Inger; Wollmann, Birgit Malene Tovik & Molden, Espen [Show all 7 contributors for this article] (2022). In Vitro Apixaban Removal By CytoSorb Whole Blood Adsorber: An Experimental Study. Journal of Cardiothoracic and Vascular Anesthesia. ISSN 1053-0770. 36(6), p. 1636–1644. doi: 10.1053/j.jvca.2022.01.038. Full text in Research Archive Show summary

  Objectives The use of unopposed oral anticoagulants while undergoing cardiothoracic surgery is associated with severe bleeding and increased morbidity. The aim of this experimental study was to examine if the apixaban concentration in reconstituted blood could be reduced in an in vitro setup by the use of CytoSorb whole blood adsorber, and to study how this affected global coagulation assays. Design and Setting An experimental study performed in a laboratory. Participants An in vitro setup with reconstituted whole blood. Interventions Reconstituted whole blood spiked with apixaban circulated in an in vitro circuit with the CytoSorb 300 mL device connected. Measurements and Main Results Blood samples were drawn at 0, 5, 15, 30, 60, and 120 minutes of adsorption. The apixaban concentration was measured at each time point. In addition, the global coagulation assays, thromboelastometry clotting time and thrombin generation, were performed, and the results were compared with baseline values obtained before spiking blood with apixaban. After 30 minutes of adsorption, the mean apixaban concentration was reduced from 414.3 (±69.1) ng/mL to 33 (±11.4) ng/mL. Thrombin generation showed maximum effect after 60 minutes, and the thromboelastometry clotting time was close to baseline values after 120 minutes. Conclusions In this in vitro study, apixaban concentrations were effectively reduced, and the clotting time and thrombin generation assays were normalized by the use of CytoSorb whole blood adsorber.

• Trubetskoy, Vassily; Pardiñas, Antonio F.; Qi, Ting; Panagiotaropoulou, Georgia; Awasthi, Swapnil & Bigdeli, Tim B. [Show all 434 contributors for this article] (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. ISSN 0028-0836. 604(7906), p. 502–508. doi: 10.1038/s41586-022-04434-5. Full text in Research Archive Show summary

  Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

• Kyllesø, Lennart; Smith, Robert Løvsletten; Wollmann, Birgit Malene Tovik; Karlstad, Øystein; Andreassen, Ole & Molden, Espen (2022). Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment: A Retrospective Pilot Study. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 42(5), p. 470–474. doi: 10.1097/JCP.0000000000001585. Full text in Research Archive Show summary

  Purpose/Background Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations. Methods/Procedures Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018–2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N-desmethylclozapine, clozapine-N-oxide, clozapine-5N-glucuronide, or clozapine-N+-glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period. Findings/Results Of the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5N-glucuronide/clozapine ratio was 69% lower (P < 0.001), while the clozapine-N+-glucuronide/clozapine-5N-glucuronide ratio was 143% higher (P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers. Implications/Conclusions The present study found a significantly reduced 5N-glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.

• Frederiksen, Trine; Smith, Robert Løvsletten; Jukic, Marin M. & Molden, Espen (2022). Association Between CYP2D6 Metabolizer Status and Vortioxetine Exposure and Treatment Switching: A Retrospective, Naturalistic Cohort Study Using Therapeutic Drug Monitoring Data From 640 Patients. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 42(4), p. 396–399. doi: 10.1097/JCP.0000000000001563. Full text in Research Archive
• Gedde-Dahl, Ane; Spigset, Olav & Molden, Espen (2022). Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway. European Journal of Clinical Pharmacology. ISSN 0031-6970. 78(10), p. 1623–1632. doi: 10.1007/s00228-022-03364-5. Full text in Research Archive Show summary

  Abstract Purpose To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. Methods The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. Results The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% ( P  &lt; 0.001) after 5 years and by 40% ( P  &lt; 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54–0.69) and OR 0.45 (95% CI 0.40–0.51), respectively, versus OR 0.84 (95% CI 0.74–0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. Conclusion The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

• Lenk, Hasan Cagin; Smith, Robert Løvsletten; O'Connell, Kevin Sean; Jukić, Marin M.; Kringen, Marianne K. & Andreassen, Ole [Show all 8 contributors for this article] (2022). Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. Clinical and Translational Science (CTS). ISSN 1752-8054. 16(1), p. 62–72. doi: 10.1111/cts.13422. Full text in Research Archive Show summary

  Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (−48%; p < 0.0001) and nonsmokers (−35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia.

• Kappel, Djenifer B.; Legge, Sophie E.; Hubbard, Leon; Willcocks, Isabella R.; O'Connell, Kevin Sean & Smith, Robert Løvsletten [Show all 15 contributors for this article] (2022). Genomic Stratification of Clozapine Prescription Patterns Using Schizophrenia Polygenic Scores. Biological Psychiatry. ISSN 0006-3223. 93(2), p. 149–156. doi: 10.1016/j.biopsych.2022.07.014. Full text in Research Archive Show summary

  Background Treatment-resistant schizophrenia affects approximately 30% of individuals with the disorder. Clozapine is the medication of choice in treatment-resistant schizophrenia, but optimizing administration and dose titration is complex. The identification of factors influencing clozapine prescription and response, including genetics, is of interest in a precision psychiatry framework. Methods We used linear regression models accounting for demographic, pharmacological, and clinical covariates to determine whether a polygenic risk score (PRS) for schizophrenia would be associated with the highest dose recorded during clozapine treatment. Analyses were performed across 2 independent multiancestry samples of individuals from a UK patient monitoring system, CLOZUK2 (n = 3133) and CLOZUK3 (n = 909), and a European sample from a Norwegian therapeutic drug monitoring service (n = 417). In a secondary analysis merging both UK cohorts, logistic regression models were used to estimate the relationship between schizophrenia PRSs and clozapine doses classified as low, standard, or high. Results After controlling for relevant covariates, the schizophrenia PRS was correlated with the highest clozapine dose on record for each individual across all samples: CLOZUK2 (β = 12.22, SE = 3.78, p = .001), CLOZUK3 (β = 12.73, SE = 5.99, p = .034), and the Norwegian cohort (β = 46.45, SE = 18.83, p = .014). In a secondary analysis, the schizophrenia PRS was associated with taking clozapine doses >600 mg/day (odds ratio = 1.279, p = .006). Conclusions The schizophrenia PRS was associated with the highest clozapine dose prescribed for an individual in records from 3 independent samples, suggesting that the genetic liability for schizophrenia might index factors associated with therapeutic decisions in cohorts of patients with treatment-resistant schizophrenia.

• Hart, Xenia M.; Hiemke, Christoph; Eichentopf, Luzie; Lense, Xenija M.; Clement, Hans Willi & Conca, Andreas [Show all 15 contributors for this article] (2022). Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis. Psychopharmacology. ISSN 0033-3158. 239(11), p. 3377–3391. doi: 10.1007/s00213-022-06233-2. Full text in Research Archive
• Smith, Robert Løvsletten; Wollmann, Birgit Malene Tovik; Kyllesø, Lennart; Tran, Thu Thuy Anh; Tveito, Marit & Molden, Espen (2022). Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 42(1), p. 43–50. doi: 10.1097/JCP.0000000000001507. Full text in Research Archive
• Cheng, Weiqiu; Frei, Oleksandr; Meer, Dennis van der; Wang, Yunpeng; O`Connell, Kevin & Chu, Yunhan [Show all 20 contributors for this article] (2021). Genetic Association Between Schizophrenia and Cortical Brain Surface Area and Thickness. JAMA psychiatry. ISSN 2168-6238. 78(9), p. 1020–1030. doi: 10.1001/jamapsychiatry.2021.1435. Full text in Research Archive Show summary

  Importance Schizophrenia is a complex heritable disorder associated with many genetic variants, each with a small effect. While cortical differences between patients with schizophrenia and healthy controls are consistently reported, the underlying molecular mechanisms remain elusive. Objective To investigate the extent of shared genetic architecture between schizophrenia and brain cortical surface area (SA) and thickness (TH) and to identify shared genomic loci. Design, Setting, and Participants Independent genome-wide association study data on schizophrenia (Psychiatric Genomics Consortium and CLOZUK: n = 105 318) and SA and TH (UK Biobank: n = 33 735) were obtained. The extent of polygenic overlap was investigated using MiXeR. The specific shared genomic loci were identified by conditional/conjunctional false discovery rate analysis and were further examined in 3 independent cohorts. Data were collected from December 2019 to February 2021, and data analysis was performed from May 2020 to February 2021. Main Outcomes and Measures The primary outcomes were estimated fractions of polygenic overlap between schizophrenia, total SA, and average TH and a list of functionally characterized shared genomic loci. Results Based on genome-wide association study data from 139 053 participants, MiXeR estimated schizophrenia to be more polygenic (9703 single-nucleotide variants [SNVs]) than total SA (2101 SNVs) and average TH (1363 SNVs). Most SNVs associated with total SA (1966 of 2101 [93.6%]) and average TH (1322 of 1363 [97.0%]) may be associated with the development of schizophrenia. Subsequent conjunctional false discovery rate analysis identified 44 and 23 schizophrenia risk loci shared with total SA and average TH, respectively. The SNV associations of shared loci between schizophrenia and total SA revealed en masse concordant association between the discovery and independent cohorts. After removing high linkage disequilibrium regions, such as the major histocompatibility complex region, the shared loci were enriched in immunologic signature gene sets. Polygenic overlap and shared loci between schizophrenia and schizophrenia-associated regions of interest for SA (superior frontal and middle temporal gyri) and for TH (superior temporal, inferior temporal, and superior frontal gyri) were also identified. Conclusions and Relevance This study demonstrated shared genetic loci between cortical morphometry and schizophrenia, among which a subset are associated with immunity. These findings provide an insight into the complex genetic architecture and associated with schizophrenia.

• Tveito, Marit; Høiseth, Gudrun; Haslemo, Tore; Molden, Espen & Smith, Robert Løvsletten (2021). Impact of age and gender on paliperidone exposure in patients after administration of long-acting injectable formulations—an observational study using blood samples from 1223 patients. European Journal of Clinical Pharmacology. ISSN 0031-6970. 77(9), p. 1201–1208. doi: 10.1007/s00228-021-03114-z. Full text in Research Archive Show summary

  Purpose Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. Methods Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15–49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. Results In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21–30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001). Conclusion The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.

• Molden, Espen & Jukić, Marin M. (2021). CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry. Frontiers in Pharmacology. 12. doi: 10.3389/fphar.2021.650750. Full text in Research Archive
• Hole, Kristine; Arnestad, Marianne; Molden, Espen & Haslemo, Tore (2021). Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients with Depression. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 41(3), p. 281–285. doi: 10.1097/JCP.0000000000001387. Full text in Research Archive
• Bråten, Line Skute; Haslemo, Tore; Jukić, Marin M.; Ivanov, Maxim; Ingelman-Sundberg, Magnus & Molden, Espen [Show all 7 contributors for this article] (2021). A Novel CYP2C-Haplotype Associated With Ultrarapid Metabolism of Escitalopram. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 110(3), p. 786–793. doi: 10.1002/cpt.2233. Full text in Research Archive
• Frederiksen, Trine; Smith, Robert L.; Wollmann, Birgit Malene Tovik; Areberg, Johan & Molden, Espen (2021). Validation of a Population Pharmacokinetic Model of Vortioxetine Using Therapeutic Drug Monitoring Data. Clinical Pharmacokinetics. ISSN 0312-5963. doi: 10.1007/s40262-021-01029-7. Full text in Research Archive
• Schoretsanitis, Georgios; Smith, Robert Løvsletten; Molden, Espen; Solismaa, Anssi; Seppälä, Niko & Kopeček, Miloslav [Show all 13 contributors for this article] (2021). European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed. Journal of Clinical Psychopharmacology. ISSN 0271-0749. 41(2), p. 140–147. doi: 10.1097/JCP.0000000000001341. Full text in Research Archive Show summary

  Purpose/background: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. Methods/procedures: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. Findings/results: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). Implications/conclusions: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

• Jukic, Marin M.; Smith, Robert Løvsletten; Molden, Espen & Ingelman-Sundberg, Magnus (2021). Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 110(3), p. 750–758. doi: 10.1002/cpt.2246. Full text in Research Archive
• Leon, Leon de; Schoretsanitis, Georgios; Smith, Robert Løvsletten; Molden, Espen; Solismaa, Anssi & Seppälä, Niko [Show all 104 contributors for this article] (2021). An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels. Pharmacopsychiatry. ISSN 0176-3679. p. 1–14. doi: 10.1055/a-1625-6388. Full text in Research Archive
• Blokland, Gabriella A. M.; Grove, Jakob; Chen, Chia-Yen; Cotsapas, Chris; Tobet, Stuart & Handa, Robert [Show all 50 contributors for this article] (2021). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. ISSN 0006-3223. 91, p. 102–117. doi: 10.1016/j.biopsych.2021.02.972. Full text in Research Archive Show summary

  Background Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• Riede, Julia; Wollmann, Birgit Malene Tovik; Molden, Espen & Ingelman-Sundberg, Magnus (2021). Primary human hepatocyte spheroids as an in vitro tool for investigating drug compounds with low hepatic clearances. Drug Metabolism And Disposition. ISSN 0090-9556. 49(7), p. 501–508. doi: 10.1124/dmd.120.000340. Full text in Research Archive
• Kyllesø, Lennart; Smith, Robert Løvsletten; Karlstad, Øystein; Andreassen, Ole A. & Molden, Espen (2021). Absolute and Dose-Adjusted Serum Concentrations of Clozapine in Patients Switching vs. Maintaining Treatment: An Observational Study of 1979 Patients. CNS Drugs. ISSN 1172-7047. 35, p. 999–1008. doi: 10.1007/s40263-021-00847-4. Full text in Research Archive Show summary

  Background Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment. Objective We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service. Methods Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005–2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included. Results In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032). Conclusions The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

• Molden, Espen (2021). Therapeutic drug monitoring of clozapine in adults with schizophrenia: a review of challenges and strategies. Expert Opinion on Drug Metabolism & Toxicology. ISSN 1742-5255. 17(10), p. 2011–2021. doi: 10.1080/17425255.2021.1974400. Full text in Research Archive
• Kyllesø, Lennart; Smith, Robert Løvsletten; Karlstad, Øystein; Andreassen, Ole Andreas & Molden, Espen (2020). Undetectable or subtherapeutic serum levels of antipsychotic drugs preceding switch to clozapine. Nature NPJ Schizophrenia. 6. doi: 10.1038/s41537-020-0107-7. Full text in Research Archive Show summary

  Abstract Adequate antipsychotic treatment intensity is required for defining treatment-resistant schizophrenia (TRS) and justifying clozapine treatment. We investigated the occurrence of undetectable or subtherapeutic serum levels of oral antipsychotics preceding switch to clozapine as an endpoint of TRS. For patients starting clozapine, 12-month retrospective reviews of antipsychotic serum concentration measurements were performed in a Norwegian therapeutic drug monitoring (TDM) database from 2005 to 2017. Undetectable levels in high-sensitive analytical assays defined ‘no drug use’, while levels &lt;50% of the lower reference range defined ‘subtherapeutic use’. Similar data were collected for patients switching to long-acting injectable (LAI) antipsychotics, as a reference of ‘no or subtherapeutic drug use’. Nineteen of 353 patients initiating clozapine (5.4%) had a recent history of undetectable antipsychotic drug levels compared to 91 of 1048 (8.7%) initiating LAI. Another 19 patients starting clozapine (5.4%) had recent events of subtherapeutic levels. In conclusion, the present retrospective study may indicate that every 10th patient starting clozapine has a recent history of undetectable or subtherapeutic serum levels of oral antipsychotics. The clinical implications of the present study for the assessment of TRS should be investigated prospectively in further studies.

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• Verdoux, Hélène; Bittner, Robert A.; Hasan, Alkomiet; Qubad, Mishal; Wagner, Elias & Lepetit, Alexis [Show all 41 contributors for this article] (2025). The time has come for revising the rules of clozapine blood monitoring in Europe. A joint expert statement from the European Clozapine Task Force. European psychiatry. ISSN 0924-9338. 68(1). doi: 10.1192/j.eurpsy.2024.1816. Full text in Research Archive
• Størset, Elisabet; Wollmann, Birgit Malene Tovik; Sverre, Gunnarsson Larne; Bråten, Line Skute; Kringen, Marianne K. & Molden, Espen (2025). Solanidine analysis during therapeutic drug monitoring revealed rare CYP2D6 poor metabolizer genotype: A case report. doi: 10.1002/bcp.70184. Full text in Research Archive
• Røed-Undlien, Henriette; Schultz, Nina Haagenrud; Lunnan, Asbjørn; Husebråten, Inger Marie; Wollmann, Birgit Malene Tovik & Molden, Espen [Show all 7 contributors for this article] (2024). Corrigendum to < IN-VITRO APIXABAN REMOVAL BY CYTOSORB® WHOLE BLOOD ADSORBER. AN EXPERIMENTAL STUDY.> <[Journal of Cardiothoracic and Vascular Anesthesia 36/6 (2024) 1636 – 1644]> (Journal of Cardiothoracic and Vascular Anesthesia (2022) 36(6) (1636–1644), (S1053077022000726), (10.1053/j.jvca.2022.01.038)). Journal of Cardiothoracic and Vascular Anesthesia. ISSN 1053-0770. doi: 10.1053/j.jvca.2024.03.039. Full text in Research Archive
• Ingelman-Sundberg, Magnus; Jukic, Marin; Bråten, Line Skute; Kringen, Marianne K. & Molden, Espen (2023). What is the Current Clinical Impact of the CYP2CTG Haplotype? Clinical Pharmacology and Therapeutics. ISSN 0009-9236. doi: 10.1002/cpt.3094. Full text in Research Archive
• Faraj, Pari; Størset, Elisabet; Hole, Kristine; Smith, Godfrey L; Molden, Espen & Dietrichs, Erik Sveberg (2023). Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in the elderly – a study based on a cohort of 19 742 patients. Full text in Research Archive
• Molden, Espen (2022). Personalized dosing of clozapine stratified by patients’ ancestry–international consensus guidelines. Nordic Journal of Psychiatry. ISSN 0803-9488. doi: 10.1080/08039488.2022.2146749. Full text in Research Archive
• Leon, Jose de; Schoretsanitis, Georgios; Smith, Robert Løvsletten; Molden, Espen; Solismaa, Anssi & Seppälä, Niko [Show all 104 contributors for this article] (2022). Erratum: Correction: An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels (Pharmacopsychiatry (2022) 55 2 (73-86)). Pharmacopsychiatry. ISSN 0176-3679. 55(2), p. e1–e1. doi: 10.1055/a-1737-1527. Full text in Research Archive
• Kvitne, Kine Eide; Hole, Kristine; Molden, Espen & Robertsen, Ida (2022). Response to: “Utility of endogenous 4β-hydroxycholesterol as a biomarker to assess cytochrome P 450 3A (CYP3A) activity: not quite ready for prime time”. European Journal of Clinical Pharmacology. ISSN 0031-6970. doi: 10.1007/s00228-022-03387-y. Full text in Research Archive
• Dietrichs, Erik Sveberg; Solhaug, Vigdis; Kringen, Marianne Kristiansen; Haslemo, Tore & Molden, Espen (2022). E. S. Dietrichs og medarbeidere svarer P. Gjerden. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. Full text in Research Archive
• Dietrichs, Erik Sveberg; Molden, Espen & Haslemo, Tore (2022). Senter for psykofarmakologi. LVS-info. Full text in Research Archive
• Dietrichs, Erik Sveberg; Haslemo, Tore; Kringen, Marianne K.; Molden, Espen & Solhaug, Vigdis (2022). E. S. Dietrichs og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(16). doi: 10.4045/tidsskr.22.0665. Full text in Research Archive

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