TY  - JOUR
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
AU  - Bråten, Line Skute
AU  - Kringen, Marianne Kristiansen
AU  - Molden, Espen
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5300
AB  - We   read   with   great   interest   the  paper  by  Zubiaur  et  al.1  on  the   analysis   of   a   genotype–phenotype  relationship  of  the  CYP2C:TG haplotype. This study, including 225 patients receiving one  of  6  different  drugs  and  liver  pieces  from  135  children  (median   age   7   years),   is   in   contrast to 2 studies by Bråten et al. using in vivo data from 875 escitalopram-treated2  and  840  sertraline-treated3    Norwegian    patients,  respectively,  in  which  significantly increased rate (+20 to 25%) of CYP2C19-dependent metabolism    of    these    drugs    was   found   for   the   CYP2C:TGhaplotype.
PB  - John Wiley and Sons Inc
T2  - Clinical Pharmacology and Therapeutics
T1  - What is the Current Clinical Impact of the CYP2CTG Haplotype?
VL  - 115
IS  - 2
SP  - 183
EP  - 183
DO  - 10.1002/cpt.3094
ER  - 

@article{
author = "Ingelman-Sundberg, Magnus and Jukić, Marin and Bråten, Line Skute and Kringen, Marianne Kristiansen and Molden, Espen",
year = "2024",
abstract = "We   read   with   great   interest   the  paper  by  Zubiaur  et  al.1  on  the   analysis   of   a   genotype–phenotype  relationship  of  the  CYP2C:TG haplotype. This study, including 225 patients receiving one  of  6  different  drugs  and  liver  pieces  from  135  children  (median   age   7   years),   is   in   contrast to 2 studies by Bråten et al. using in vivo data from 875 escitalopram-treated2  and  840  sertraline-treated3    Norwegian    patients,  respectively,  in  which  significantly increased rate (+20 to 25%) of CYP2C19-dependent metabolism    of    these    drugs    was   found   for   the   CYP2C:TGhaplotype.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical Pharmacology and Therapeutics",
title = "What is the Current Clinical Impact of the CYP2CTG Haplotype?",
volume = "115",
number = "2",
pages = "183-183",
doi = "10.1002/cpt.3094"
}

Ingelman-Sundberg, M., Jukić, M., Bråten, L. S., Kringen, M. K.,& Molden, E.. (2024). What is the Current Clinical Impact of the CYP2CTG Haplotype?. in Clinical Pharmacology and Therapeutics
John Wiley and Sons Inc., 115(2), 183-183.
https://doi.org/10.1002/cpt.3094

Ingelman-Sundberg M, Jukić M, Bråten LS, Kringen MK, Molden E. What is the Current Clinical Impact of the CYP2CTG Haplotype?. in Clinical Pharmacology and Therapeutics. 2024;115(2):183-183.
doi:10.1002/cpt.3094 .

Ingelman-Sundberg, Magnus, Jukić, Marin, Bråten, Line Skute, Kringen, Marianne Kristiansen, Molden, Espen, "What is the Current Clinical Impact of the CYP2CTG Haplotype?" in Clinical Pharmacology and Therapeutics, 115, no. 2 (2024):183-183,
https://doi.org/10.1002/cpt.3094 . .

TY  - JOUR
AU  - Milosavljević, Filip
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5593
AB  - The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.
PB  - Elsevier B.V.
T2  - European Neuropsychopharmacology
T1  - 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
VL  - 81
SP  - 43
EP  - 52
DO  - 10.1016/j.euroneuro.2024.01.005
ER  - 

@article{
author = "Milosavljević, Filip and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2024",
abstract = "The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.",
publisher = "Elsevier B.V.",
journal = "European Neuropsychopharmacology",
title = "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",
volume = "81",
pages = "43-52",
doi = "10.1016/j.euroneuro.2024.01.005"
}

Milosavljević, F., Molden, E., Ingelman-Sundberg, M.,& Jukić, 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. in European Neuropsychopharmacology
Elsevier B.V.., 81, 43-52.
https://doi.org/10.1016/j.euroneuro.2024.01.005

Milosavljević F, Molden E, Ingelman-Sundberg M, Jukić M. 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. in European Neuropsychopharmacology. 2024;81:43-52.
doi:10.1016/j.euroneuro.2024.01.005 .

Milosavljević, Filip, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "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" in European Neuropsychopharmacology, 81 (2024):43-52,
https://doi.org/10.1016/j.euroneuro.2024.01.005 . .

TY  - JOUR
AU  - Milosavljević, Filip
AU  - Brusini, Irene
AU  - Atanasov, Andrea
AU  - Manojlović, Marina
AU  - Vučić, Marija
AU  - Oreščanin-Dušić, Zorana
AU  - Brkljačić, Jelena
AU  - Miljević, Čedo
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Wang, Chunliang
AU  - Damberg, Peter
AU  - Pešić, Vesna
AU  - Tyndale, Rachel F.
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4516
AB  - Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
PB  - John Wiley and Sons Inc
T2  - Neuropathology and Applied Neurobiology
T1  - The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia
VL  - 49
IS  - 1
DO  - 10.1111/nan.12867
ER  - 

@article{
author = "Milosavljević, Filip and Brusini, Irene and Atanasov, Andrea and Manojlović, Marina and Vučić, Marija and Oreščanin-Dušić, Zorana and Brkljačić, Jelena and Miljević, Čedo and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Wang, Chunliang and Damberg, Peter and Pešić, Vesna and Tyndale, Rachel F. and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2023",
abstract = "Aims: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. Methods: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. Results: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. Conclusions: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.",
publisher = "John Wiley and Sons Inc",
journal = "Neuropathology and Applied Neurobiology",
title = "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia",
volume = "49",
number = "1",
doi = "10.1111/nan.12867"
}

Milosavljević, F., Brusini, I., Atanasov, A., Manojlović, M., Vučić, M., Oreščanin-Dušić, Z., Brkljačić, J., Miljević, Č., Nikolić-Kokić, A., Blagojević, D., Wang, C., Damberg, P., Pešić, V., Tyndale, R. F., Ingelman-Sundberg, M.,& Jukić, M.. (2023). The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology
John Wiley and Sons Inc., 49(1).
https://doi.org/10.1111/nan.12867

Milosavljević F, Brusini I, Atanasov A, Manojlović M, Vučić M, Oreščanin-Dušić Z, Brkljačić J, Miljević Č, Nikolić-Kokić A, Blagojević D, Wang C, Damberg P, Pešić V, Tyndale RF, Ingelman-Sundberg M, Jukić M. The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia. in Neuropathology and Applied Neurobiology. 2023;49(1).
doi:10.1111/nan.12867 .

Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin-Dušić, Zorana, Brkljačić, Jelena, Miljević, Čedo, Nikolić-Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel F., Ingelman-Sundberg, Magnus, Jukić, Marin, "The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia" in Neuropathology and Applied Neurobiology, 49, no. 1 (2023),
https://doi.org/10.1111/nan.12867 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Milosavljević, Filip
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4307
AB  - Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.
PB  - Elsevier Ltd
T2  - Trends in Pharmacological Sciences
T1  - Pharmacogenomics in treatment of depression and psychosis: an update
VL  - 43
IS  - 12
SP  - 1055
EP  - 1069
DO  - 10.1016/j.tips.2022.09.011
ER  - 

@article{
author = "Jukić, Marin and Milosavljević, Filip and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation.",
publisher = "Elsevier Ltd",
journal = "Trends in Pharmacological Sciences",
title = "Pharmacogenomics in treatment of depression and psychosis: an update",
volume = "43",
number = "12",
pages = "1055-1069",
doi = "10.1016/j.tips.2022.09.011"
}

Jukić, M., Milosavljević, F., Molden, E.,& Ingelman-Sundberg, M.. (2022). Pharmacogenomics in treatment of depression and psychosis: an update. in Trends in Pharmacological Sciences
Elsevier Ltd., 43(12), 1055-1069.
https://doi.org/10.1016/j.tips.2022.09.011

Jukić M, Milosavljević F, Molden E, Ingelman-Sundberg M. Pharmacogenomics in treatment of depression and psychosis: an update. in Trends in Pharmacological Sciences. 2022;43(12):1055-1069.
doi:10.1016/j.tips.2022.09.011 .

Jukić, Marin, Milosavljević, Filip, Molden, Espen, Ingelman-Sundberg, Magnus, "Pharmacogenomics in treatment of depression and psychosis: an update" in Trends in Pharmacological Sciences, 43, no. 12 (2022):1055-1069,
https://doi.org/10.1016/j.tips.2022.09.011 . .

TY  - JOUR
AU  - Lenk, Hasan Çağın
AU  - Løvsletten Smith, Robert
AU  - O'Connell, Kevin
AU  - Jukić, Marin
AU  - Kringen, Marianne Kristiansen
AU  - Andreassen, Ole
AU  - Ingelman-Sundberg, Magnus
AU  - Molden, Espen
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4290
AB  - 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. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PB  - John Wiley and Sons Inc
T2  - Clinical and Translational Science
T1  - Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits
DO  - 10.1111/cts.13422
ER  - 

@article{
author = "Lenk, Hasan Çağın and Løvsletten Smith, Robert and O'Connell, Kevin and Jukić, Marin and Kringen, Marianne Kristiansen and Andreassen, Ole and Ingelman-Sundberg, Magnus and Molden, Espen",
year = "2022",
abstract = "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. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical and Translational Science",
title = "Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits",
doi = "10.1111/cts.13422"
}

Lenk, H. Ç., Løvsletten Smith, R., O'Connell, K., Jukić, M., Kringen, M. K., Andreassen, O., Ingelman-Sundberg, M.,& Molden, E.. (2022). Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science
John Wiley and Sons Inc..
https://doi.org/10.1111/cts.13422

Lenk HÇ, Løvsletten Smith R, O'Connell K, Jukić M, Kringen MK, Andreassen O, Ingelman-Sundberg M, Molden E. Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits. in Clinical and Translational Science. 2022;.
doi:10.1111/cts.13422 .

Lenk, Hasan Çağın, Løvsletten Smith, Robert, O'Connell, Kevin, Jukić, Marin, Kringen, Marianne Kristiansen, Andreassen, Ole, Ingelman-Sundberg, Magnus, Molden, Espen, "Impact of NFIB and CYP1A variants on clozapine serum concentration—A retrospective naturalistic cohort study on 526 patients with known smoking habits" in Clinical and Translational Science (2022),
https://doi.org/10.1111/cts.13422 . .

TY  - JOUR
AU  - Bråten, Line Skute
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
AU  - Molden, Espen
AU  - Kringen, Marianne Kristiansen
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4181
AB  - Sertraline is a commonly used SSRI antidepressant drug, metabolized by CYP2C19 and CYP2B6, that exhibits a substantial interindividual variation in clinical response, of which only a part can be attributed to known genetic variants. In the current study we have examined the role of a newly discovered ultrarapid CYP2C:TG haplotype and CYP2B6 variants in order to identify the possible missing heritability for such variation in sertraline response in a large patient population (n = 840). Compared to the reference group (CYP2C19*1/*1, n = 160), sertraline exposure was increased by 128% in CYP2C19 PMs (n = 29, p < 0.001) and decreased by about 20% in CYP2C19 ultrarapid metabolizers (UMs) (homozygous carriers of CYP2C19*17 and/or CYP2C:TG haplotype) with the diplotypes CYP2C19*17/*17, CYP2C:TG/TG, or CYP2C19*17/CYP2C:TG (n = 135, p < 0.003, p = 0.022, p < 0.003, respectively). Interestingly, in patients carrying the increased function CYP2B6*4 allele, and also carrying the CYP2C19*17 and CYP2C:TG alleles (n = 10), sertraline exposure was 35.4% lower compared to the reference group, whereas in subjects being poor metabolizers (PM) in both the CYP2C19 and CYP2B6 gene, the sertraline concentrations were raised by 189%. In summary, the CYP2C19 variants including the CYP2C:TG haplotype had a significant impact on sertraline metabolism, as well as the CYP2B6*4, *6, and *9 alleles. Knowing the CYP2B6 and CYP2C19 genotype, including the CYP2C:TG haplotype status, can prospectively be useful to clinicians in making more appropriate sertraline dosing decisions.
PB  - John Wiley and Sons Inc
T2  - Clinical and Translational Science
T1  - Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population
VL  - 15
IS  - 9
SP  - 2135
EP  - 2145
DO  - 10.1111/cts.13347
ER  - 

@article{
author = "Bråten, Line Skute and Ingelman-Sundberg, Magnus and Jukić, Marin and Molden, Espen and Kringen, Marianne Kristiansen",
year = "2022",
abstract = "Sertraline is a commonly used SSRI antidepressant drug, metabolized by CYP2C19 and CYP2B6, that exhibits a substantial interindividual variation in clinical response, of which only a part can be attributed to known genetic variants. In the current study we have examined the role of a newly discovered ultrarapid CYP2C:TG haplotype and CYP2B6 variants in order to identify the possible missing heritability for such variation in sertraline response in a large patient population (n = 840). Compared to the reference group (CYP2C19*1/*1, n = 160), sertraline exposure was increased by 128% in CYP2C19 PMs (n = 29, p < 0.001) and decreased by about 20% in CYP2C19 ultrarapid metabolizers (UMs) (homozygous carriers of CYP2C19*17 and/or CYP2C:TG haplotype) with the diplotypes CYP2C19*17/*17, CYP2C:TG/TG, or CYP2C19*17/CYP2C:TG (n = 135, p < 0.003, p = 0.022, p < 0.003, respectively). Interestingly, in patients carrying the increased function CYP2B6*4 allele, and also carrying the CYP2C19*17 and CYP2C:TG alleles (n = 10), sertraline exposure was 35.4% lower compared to the reference group, whereas in subjects being poor metabolizers (PM) in both the CYP2C19 and CYP2B6 gene, the sertraline concentrations were raised by 189%. In summary, the CYP2C19 variants including the CYP2C:TG haplotype had a significant impact on sertraline metabolism, as well as the CYP2B6*4, *6, and *9 alleles. Knowing the CYP2B6 and CYP2C19 genotype, including the CYP2C:TG haplotype status, can prospectively be useful to clinicians in making more appropriate sertraline dosing decisions.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical and Translational Science",
title = "Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population",
volume = "15",
number = "9",
pages = "2135-2145",
doi = "10.1111/cts.13347"
}

Bråten, L. S., Ingelman-Sundberg, M., Jukić, M., Molden, E.,& Kringen, M. K.. (2022). Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population. in Clinical and Translational Science
John Wiley and Sons Inc., 15(9), 2135-2145.
https://doi.org/10.1111/cts.13347

Bråten LS, Ingelman-Sundberg M, Jukić M, Molden E, Kringen MK. Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population. in Clinical and Translational Science. 2022;15(9):2135-2145.
doi:10.1111/cts.13347 .

Bråten, Line Skute, Ingelman-Sundberg, Magnus, Jukić, Marin, Molden, Espen, Kringen, Marianne Kristiansen, "Impact of the novel CYP2C:TG haplotype and CYP2B6 variants on sertraline exposure in a large patient population" in Clinical and Translational Science, 15, no. 9 (2022):2135-2145,
https://doi.org/10.1111/cts.13347 . .

TY  - JOUR
AU  - Pridgeon, Chris
AU  - Bolhuis, Dian
AU  - Milosavljević, Filip
AU  - Manojlović, Marina
AU  - Végvári, Ákos
AU  - Gaetani, Massimiliano
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4111
AB  - The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.
PB  - MDPI
T2  - Cells
T1  - Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids
VL  - 11
IS  - 10
DO  - 10.3390/cells11101597
ER  - 

@article{
author = "Pridgeon, Chris and Bolhuis, Dian and Milosavljević, Filip and Manojlović, Marina and Végvári, Ákos and Gaetani, Massimiliano and Jukić, Marin and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPARα antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.",
publisher = "MDPI",
journal = "Cells",
title = "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids",
volume = "11",
number = "10",
doi = "10.3390/cells11101597"
}

Pridgeon, C., Bolhuis, D., Milosavljević, F., Manojlović, M., Végvári, Á., Gaetani, M., Jukić, M.,& Ingelman-Sundberg, M.. (2022). Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells
MDPI., 11(10).
https://doi.org/10.3390/cells11101597

Pridgeon C, Bolhuis D, Milosavljević F, Manojlović M, Végvári Á, Gaetani M, Jukić M, Ingelman-Sundberg M. Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids. in Cells. 2022;11(10).
doi:10.3390/cells11101597 .

Pridgeon, Chris, Bolhuis, Dian, Milosavljević, Filip, Manojlović, Marina, Végvári, Ákos, Gaetani, Massimiliano, Jukić, Marin, Ingelman-Sundberg, Magnus, "Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids" in Cells, 11, no. 10 (2022),
https://doi.org/10.3390/cells11101597 . .

TY  - JOUR
AU  - Lenk, Hasan Çağın
AU  - Klöditz, Katharina
AU  - Johansson, Inger
AU  - Løvsletten Smith, Robert
AU  - Jukić, Marin
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4075
AB  - 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.
PB  - John Wiley and Sons Inc
T2  - Clinical Pharmacology and Therapeutics
T1  - The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients
DO  - 10.1002/cpt.2571
ER  - 

@article{
author = "Lenk, Hasan Çağın and Klöditz, Katharina and Johansson, Inger and Løvsletten Smith, Robert and Jukić, Marin and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2022",
abstract = "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.",
publisher = "John Wiley and Sons Inc",
journal = "Clinical Pharmacology and Therapeutics",
title = "The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients",
doi = "10.1002/cpt.2571"
}

Lenk, H. Ç., Klöditz, K., Johansson, I., Løvsletten Smith, R., Jukić, M., Molden, E.,& Ingelman-Sundberg, M.. (2022). The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. in Clinical Pharmacology and Therapeutics
John Wiley and Sons Inc..
https://doi.org/10.1002/cpt.2571

Lenk HÇ, Klöditz K, Johansson I, Løvsletten Smith R, Jukić M, Molden E, Ingelman-Sundberg M. The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients. in Clinical Pharmacology and Therapeutics. 2022;.
doi:10.1002/cpt.2571 .

Lenk, Hasan Çağın, Klöditz, Katharina, Johansson, Inger, Løvsletten Smith, Robert, Jukić, Marin, Molden, Espen, Ingelman-Sundberg, Magnus, "The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients" in Clinical Pharmacology and Therapeutics (2022),
https://doi.org/10.1002/cpt.2571 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Brusini, Irene
AU  - Atanasov, Andrea
AU  - Manojlović, Marina
AU  - Vučić, Marija
AU  - Oreščanin-Dušić, Zorana
AU  - Brkljačić, Jelena
AU  - Sitarica, Pavle
AU  - Miljević, Čedo
AU  - Nikolić-Kokić, Aleksandra
AU  - Blagojević, Duško
AU  - Wang, Chunliang
AU  - Damberg, Peter
AU  - Pešić, Vesna
AU  - Tyndale, Rachel
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4729
AB  - Background: Animal models are essential for understanding aetiology and pathophysiology of movement disorders. Previously, it had been found that mice transgenic for the human CYP2C19 gene, which is expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality [1, 2]. The aim of this study was to characterize motoric phenotype of the CYP2C19 transgenic mouse and validate its potential usefulness as an animal model for ataxia.

Methods: Experiments were performed on CYP2C19 transgenic mice and control wild-type littermate mice. Body weight of mice was measured between the 21st and 42nd postnatal day. Mouse gait was analysed with footprint test [3] in young animals at four time points and once in adult mice. The maximal height of hindpaw elevation while walking was measured offline from the video footage of the footprint test. Motoric function was quantified by the rotarod and beam-walking tests. Structural differences in 20 brain regions of wild-type and transgenic mice were investigated with 9.4T gadolinium-enhanced postmortem neuroimaging. Antioxidative enzyme status was determined in the brain tissue in order to assess potential differences in the brain oxidative-antioxidative balance between wild-type and transgenic mice. When multiple brain regions or multiple antioxidant enzyme activities were analysed, p-values were FDR corrected for multiple comparisons.

Results: CYP2C19 transgenic (TG) animals exhibited approximately 5-10% reduced body weight (p=0.015) during 3rd and 4th postnatal week, while after postnatal day 31, the differences in the body weight were no longer statistically significant. The TG animals exhibited approximately two fold higher maximal hindpaw elevation in young (2.1-fold [CI95%: 2.0, 2.2], p<0.0001) and adult mice (1.9-fold [CI95%: 1.8, 2.1], p<0.0001), compared to wild-types. In the 5th postnatal week, all transgenic mice exhibited increase in elevation of both hindpaws, while after this point they gradually started exhibiting unilateral phenotype until almost all (49 of 51) animals became unilaterally affected in the adulthood. Footprint analysis and rotarod test did not detect significant differences (p>0.1) between TG and control mice in any of the analysed parameters, accounting for all examined time points. CYP2C19 transgenic mice exhibited 14% increase in beam crossing time (14%, [95%CI: 6.4, 22], p=0.0014) and 5.6-fold more paw-slips (p<0.0001, n=89) in the beam-walking test. CYP2C19 transgenic mice exhibited profound reduction in cerebellar volume (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59) and moderate reduction in hippocampal volume (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59); compared to the corresponding volumes measured in WT mice. Superoxide dismutase activity was slightly increased (1.14-fold [CI95%: 1.06, 1.23], p=0.0010, q=0.023) in the cerebelli and moderately increased (1.3-fold, [CI95%: 1.18, 1.47], p<0.0001, q=0.0013) in the hippocampi of transgenic mice compared to wild-types, while glutathione reductase activity was significantly increased (1.2-fold [CI95%: 1.13, 1.35], p<0.0001, q=0.0021) in the hippocampi of TG mice.

Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function, functional motoric impairments and reduced cerebellar volume. CYP2C19 transgenic mice can be a useful tool for the studies focused on understanding the physiology of cerebellar development, as well as aetiology and pathophysiology of cerebellum-related disorders.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia
VL  - 1
IS  - Supplement 2
SP  - 64
EP  - 64
DO  - 10.1016/j.nsa.2022.100236
ER  - 

@conference{
author = "Milosavljević, Filip and Brusini, Irene and Atanasov, Andrea and Manojlović, Marina and Vučić, Marija and Oreščanin-Dušić, Zorana and Brkljačić, Jelena and Sitarica, Pavle and Miljević, Čedo and Nikolić-Kokić, Aleksandra and Blagojević, Duško and Wang, Chunliang and Damberg, Peter and Pešić, Vesna and Tyndale, Rachel and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2022",
abstract = "Background: Animal models are essential for understanding aetiology and pathophysiology of movement disorders. Previously, it had been found that mice transgenic for the human CYP2C19 gene, which is expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality [1, 2]. The aim of this study was to characterize motoric phenotype of the CYP2C19 transgenic mouse and validate its potential usefulness as an animal model for ataxia.

Methods: Experiments were performed on CYP2C19 transgenic mice and control wild-type littermate mice. Body weight of mice was measured between the 21st and 42nd postnatal day. Mouse gait was analysed with footprint test [3] in young animals at four time points and once in adult mice. The maximal height of hindpaw elevation while walking was measured offline from the video footage of the footprint test. Motoric function was quantified by the rotarod and beam-walking tests. Structural differences in 20 brain regions of wild-type and transgenic mice were investigated with 9.4T gadolinium-enhanced postmortem neuroimaging. Antioxidative enzyme status was determined in the brain tissue in order to assess potential differences in the brain oxidative-antioxidative balance between wild-type and transgenic mice. When multiple brain regions or multiple antioxidant enzyme activities were analysed, p-values were FDR corrected for multiple comparisons.

Results: CYP2C19 transgenic (TG) animals exhibited approximately 5-10% reduced body weight (p=0.015) during 3rd and 4th postnatal week, while after postnatal day 31, the differences in the body weight were no longer statistically significant. The TG animals exhibited approximately two fold higher maximal hindpaw elevation in young (2.1-fold [CI95%: 2.0, 2.2], p<0.0001) and adult mice (1.9-fold [CI95%: 1.8, 2.1], p<0.0001), compared to wild-types. In the 5th postnatal week, all transgenic mice exhibited increase in elevation of both hindpaws, while after this point they gradually started exhibiting unilateral phenotype until almost all (49 of 51) animals became unilaterally affected in the adulthood. Footprint analysis and rotarod test did not detect significant differences (p>0.1) between TG and control mice in any of the analysed parameters, accounting for all examined time points. CYP2C19 transgenic mice exhibited 14% increase in beam crossing time (14%, [95%CI: 6.4, 22], p=0.0014) and 5.6-fold more paw-slips (p<0.0001, n=89) in the beam-walking test. CYP2C19 transgenic mice exhibited profound reduction in cerebellar volume (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59) and moderate reduction in hippocampal volume (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59); compared to the corresponding volumes measured in WT mice. Superoxide dismutase activity was slightly increased (1.14-fold [CI95%: 1.06, 1.23], p=0.0010, q=0.023) in the cerebelli and moderately increased (1.3-fold, [CI95%: 1.18, 1.47], p<0.0001, q=0.0013) in the hippocampi of transgenic mice compared to wild-types, while glutathione reductase activity was significantly increased (1.2-fold [CI95%: 1.13, 1.35], p<0.0001, q=0.0021) in the hippocampi of TG mice.

Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function, functional motoric impairments and reduced cerebellar volume. CYP2C19 transgenic mice can be a useful tool for the studies focused on understanding the physiology of cerebellar development, as well as aetiology and pathophysiology of cerebellum-related disorders.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia",
volume = "1",
number = "Supplement 2",
pages = "64-64",
doi = "10.1016/j.nsa.2022.100236"
}

Milosavljević, F., Brusini, I., Atanasov, A., Manojlović, M., Vučić, M., Oreščanin-Dušić, Z., Brkljačić, J., Sitarica, P., Miljević, Č., Nikolić-Kokić, A., Blagojević, D., Wang, C., Damberg, P., Pešić, V., Tyndale, R., Ingelman-Sundberg, M.,& Jukić, M.. (2022). Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia. in Neuroscience Applied
Elsevier., 1(Supplement 2), 64-64.
https://doi.org/10.1016/j.nsa.2022.100236

Milosavljević F, Brusini I, Atanasov A, Manojlović M, Vučić M, Oreščanin-Dušić Z, Brkljačić J, Sitarica P, Miljević Č, Nikolić-Kokić A, Blagojević D, Wang C, Damberg P, Pešić V, Tyndale R, Ingelman-Sundberg M, Jukić M. Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia. in Neuroscience Applied. 2022;1(Supplement 2):64-64.
doi:10.1016/j.nsa.2022.100236 .

Milosavljević, Filip, Brusini, Irene, Atanasov, Andrea, Manojlović, Marina, Vučić, Marija, Oreščanin-Dušić, Zorana, Brkljačić, Jelena, Sitarica, Pavle, Miljević, Čedo, Nikolić-Kokić, Aleksandra, Blagojević, Duško, Wang, Chunliang, Damberg, Peter, Pešić, Vesna, Tyndale, Rachel, Ingelman-Sundberg, Magnus, Jukić, Marin, "Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia" in Neuroscience Applied, 1, no. Supplement 2 (2022):64-64,
https://doi.org/10.1016/j.nsa.2022.100236 . .

TY  - JOUR
AU  - Smith, Robert
AU  - Tveito, Marit
AU  - Kyllesø, Lennart
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
AU  - Andreassen, Ole
AU  - Molden, Espen
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3805
AB  - Background: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. Methods: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. Results: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. Conclusions: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.
PB  - Elsevier B.V.
T2  - Schizophrenia Research
T1  - Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders
VL  - 228
SP  - 590
EP  - 596
DO  - 10.1016/j.schres.2020.11.025
ER  - 

@article{
author = "Smith, Robert and Tveito, Marit and Kyllesø, Lennart and Jukić, Marin and Ingelman-Sundberg, Magnus and Andreassen, Ole and Molden, Espen",
year = "2021",
abstract = "Background: Nonadherence to antipsychotics may cause relapse and hospitalizations in patients with psychotic disorders. The purpose was to quantify and compare the outpatient's nonadherence rates of atypical antipsychotics by objective detection in blood samples. Methods: Totally, 13,217 outpatients with therapeutic drug monitoring (TDM) data of atypical antipsychotics were included. An event of complete nonadherence was defined as an occurrence of undetectable level of a prescribed antipsychotic in the blood sample submitted for TDM. Patients with such an event(s) were defined as nonadherent of the respective drug treatment (outcome). The rates of nonadherence patients were compared between the drugs by logistic regression. Results: In the study population, 70.2% of the patients were prescribed doses compliant with a schizophrenia diagnosis. The mean olanzapine equivalent dose in the population was 13.4 mg (95% confidence interval (CI): 13.3, 13.6). The frequency of nonadherence patients, regardless of drug, was 3.7% (CI: 3.4–4.0). The nonadherence patient rate was lowest in clozapine-treated patients (2.2%; CI: 1.5–2.8), followed by aripiprazole (2.3%; 1.7–2.8), risperidone (2.4%; 1.6–3.0), quetiapine (2.8%; 2.3–3.2) and olanzapine (4.9%; 4.1–5.3). Users of olanzapine had significantly higher risk of complete nonadherence (Odds ratio: 1.9; CI: 1.6–2.3, p < 0.001) compared to patients treated with other antipsychotics as a group. Conclusions: In this study, complete nonadherence of atypical antipsychotics, measured as undetectable blood level, was disclosed for ~5% of outpatients with psychotic disorders. The rate of complete nonadherence was significantly higher during olanzapine treatment compared to other atypical antipsychotics. Further studies should investigate if this reflects drug differences in tolerability or other causal relationships.",
publisher = "Elsevier B.V.",
journal = "Schizophrenia Research",
title = "Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders",
volume = "228",
pages = "590-596",
doi = "10.1016/j.schres.2020.11.025"
}

Smith, R., Tveito, M., Kyllesø, L., Jukić, M., Ingelman-Sundberg, M., Andreassen, O.,& Molden, E.. (2021). Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders. in Schizophrenia Research
Elsevier B.V.., 228, 590-596.
https://doi.org/10.1016/j.schres.2020.11.025

Smith R, Tveito M, Kyllesø L, Jukić M, Ingelman-Sundberg M, Andreassen O, Molden E. Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders. in Schizophrenia Research. 2021;228:590-596.
doi:10.1016/j.schres.2020.11.025 .

Smith, Robert, Tveito, Marit, Kyllesø, Lennart, Jukić, Marin, Ingelman-Sundberg, Magnus, Andreassen, Ole, Molden, Espen, "Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders" in Schizophrenia Research, 228 (2021):590-596,
https://doi.org/10.1016/j.schres.2020.11.025 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pavlović, Zorana
AU  - Miljević, Čedo
AU  - Pešić, Vesna
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Leucht, Stefan
AU  - Jukić, Marin
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4761
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis
VL  - 40
IS  - Supplement 1
SP  - S250
EP  - S251
DO  - 10.1016/j.euroneuro.2020.09.325
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pavlović, Zorana and Miljević, Čedo and Pešić, Vesna and Molden, Espen and Ingelman-Sundberg, Magnus and Leucht, Stefan and Jukić, Marin",
year = "2020",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis",
volume = "40",
number = "Supplement 1",
pages = "S250-S251",
doi = "10.1016/j.euroneuro.2020.09.325"
}

Milosavljević, F., Bukvić, N., Pavlović, Z., Miljević, Č., Pešić, V., Molden, E., Ingelman-Sundberg, M., Leucht, S.,& Jukić, M.. (2020). Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis. in European Neuropsychopharmacology
Elsevier., 40(Supplement 1), S250-S251.
https://doi.org/10.1016/j.euroneuro.2020.09.325

Milosavljević F, Bukvić N, Pavlović Z, Miljević Č, Pešić V, Molden E, Ingelman-Sundberg M, Leucht S, Jukić M. Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis. in European Neuropsychopharmacology. 2020;40(Supplement 1):S250-S251.
doi:10.1016/j.euroneuro.2020.09.325 .

Milosavljević, Filip, Bukvić, Nikola, Pavlović, Zorana, Miljević, Čedo, Pešić, Vesna, Molden, Espen, Ingelman-Sundberg, Magnus, Leucht, Stefan, Jukić, Marin, "Impact of CYP2C19 and CYP2D6 polymorphism on antidepressants and antipsychotics exposure; a meta-analysis" in European Neuropsychopharmacology, 40, no. Supplement 1 (2020):S250-S251,
https://doi.org/10.1016/j.euroneuro.2020.09.325 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Vučić, Marija
AU  - Manojlović, Marina
AU  - Miloševski, Teodora
AU  - Batinić, Bojan
AU  - Novalen, Maria
AU  - Miksys, Sharon
AU  - Tyndale, Rachel
AU  - Ingelman-Sundberg, Magnus
AU  - Pešić, Vesna
AU  - Jukić, Marin
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4753
AB  - Introduction: CYP2C19 transgenic mouse (2C19TG) is generated by the insertion of 12 copies of the human CYP2C19 gene into mouse genome. This animal model is a tool to study the neurodevelopmental role of CYP2C19 in vivo, since this enzyme is expressed in the foetal brains of 2C19TG mice and humans. Previous studies [1,2] showed anxiety and depression-like behaviour in these mice, while the aim of this study was to characterize the motoric function of the 2C19TG mouse.
Methods: Whole brain dopamine concentration was measured in the brain homogenate of 23 adult mice by the HPLC-MS method. Motoric function in 50 mutant and 43 control mice of both genders was tested by the rotarod and beam walking tests. Beam walking test was repeated after treatment with dopaminergic receptor antagonists, Ecopipam (0.1 mg/kg) and Raclopride (0.25 mg/kg) as a follow-up. The sections of 10 6-month old and 8 15-months old mice were stained with anti-tyrosine hydroxylase antibody and the number of dopaminergic neurons was counted on histological slides under microscope. Next, after transcardial perfusion of 30 2C19TG and 30 control mice of both genders with contrast agent (4% Paraformaldehyde, 0.05M Gadoteridole, 0.01M Phosphate buffered saline, pH=7.4), cranium containing the whole brain was scanned overnight by the 9.4T MRI scanner. The volumes of 39 brain regions were quantified according to the mouse brain atlas [3]. Student's t-test and two-way ANOVA were used to evaluate statistical significance of between-group differences.
Results: Adult 2C19TG mice are hyperdopaminergic, as they exhibit 15% increased dopamine concentration (p<0.001). They also show hyperkinetic motoric phenotype with the ataxia-like walking pattern and pathological clasping reflex. In the beam walking test 2C19TG mice had 20% longer beam crossing time (p=0.007) and 60% more paw slips (p<0.001) then the controls, and this motoric impairment could not be improved with antidopaminergic drugs. Both younger and older 2C19TG mice exhibited only a marginal reduction in the number of dopaminergic neurons of both substantia nigra and ventral tegmental area in a subset of coronal sections. This was confirmed by the gadolinium-enhanced neuroimaging that showed no change in substantia nigra volume in 2C19TG mice. On the other hand, significant differences in volume were identified in 11 regions, including cerebellum (-8.3% p<0.001) and striatum (+3.0%, p<0.001), which are the regions connected with the motoric function. The volumetric changes were detected in the hippocampus (-1.3%, p=0.027), amygdala (+2.8%, p<0.001), septum (+3.3%, p=0.014) and nucleus accumbens (+3.5, p=0.004) of 2C19TG mice. These brain regions are involved in emotional and motivational functions.
Conclusion: Ataxia-like motoric phenotype in 2C19TG transgenic mice is probably caused by changes in cerebellum, while hyperdopaminergism is most likely the compensatory adaptation, whereas the changes in the hippocampus, amygdala, septum, and nucleus accumbens may be connected with the mutants’ depression-like phenotype and susceptibility to stress. Therefore, CYP2C19 transgenic mouse in potentially useful model of hyperkinetic disorders, and our findings hint at the possible impact of CYP2C19 enzyme on the development of the several brain regions involved in motor and emotional functioning.
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene
VL  - 40
IS  - 1
SP  - S207
EP  - S208
DO  - 10.1016/j.euroneuro.2020.09.271
ER  - 

@conference{
author = "Milosavljević, Filip and Vučić, Marija and Manojlović, Marina and Miloševski, Teodora and Batinić, Bojan and Novalen, Maria and Miksys, Sharon and Tyndale, Rachel and Ingelman-Sundberg, Magnus and Pešić, Vesna and Jukić, Marin",
year = "2020",
abstract = "Introduction: CYP2C19 transgenic mouse (2C19TG) is generated by the insertion of 12 copies of the human CYP2C19 gene into mouse genome. This animal model is a tool to study the neurodevelopmental role of CYP2C19 in vivo, since this enzyme is expressed in the foetal brains of 2C19TG mice and humans. Previous studies [1,2] showed anxiety and depression-like behaviour in these mice, while the aim of this study was to characterize the motoric function of the 2C19TG mouse.
Methods: Whole brain dopamine concentration was measured in the brain homogenate of 23 adult mice by the HPLC-MS method. Motoric function in 50 mutant and 43 control mice of both genders was tested by the rotarod and beam walking tests. Beam walking test was repeated after treatment with dopaminergic receptor antagonists, Ecopipam (0.1 mg/kg) and Raclopride (0.25 mg/kg) as a follow-up. The sections of 10 6-month old and 8 15-months old mice were stained with anti-tyrosine hydroxylase antibody and the number of dopaminergic neurons was counted on histological slides under microscope. Next, after transcardial perfusion of 30 2C19TG and 30 control mice of both genders with contrast agent (4% Paraformaldehyde, 0.05M Gadoteridole, 0.01M Phosphate buffered saline, pH=7.4), cranium containing the whole brain was scanned overnight by the 9.4T MRI scanner. The volumes of 39 brain regions were quantified according to the mouse brain atlas [3]. Student's t-test and two-way ANOVA were used to evaluate statistical significance of between-group differences.
Results: Adult 2C19TG mice are hyperdopaminergic, as they exhibit 15% increased dopamine concentration (p<0.001). They also show hyperkinetic motoric phenotype with the ataxia-like walking pattern and pathological clasping reflex. In the beam walking test 2C19TG mice had 20% longer beam crossing time (p=0.007) and 60% more paw slips (p<0.001) then the controls, and this motoric impairment could not be improved with antidopaminergic drugs. Both younger and older 2C19TG mice exhibited only a marginal reduction in the number of dopaminergic neurons of both substantia nigra and ventral tegmental area in a subset of coronal sections. This was confirmed by the gadolinium-enhanced neuroimaging that showed no change in substantia nigra volume in 2C19TG mice. On the other hand, significant differences in volume were identified in 11 regions, including cerebellum (-8.3% p<0.001) and striatum (+3.0%, p<0.001), which are the regions connected with the motoric function. The volumetric changes were detected in the hippocampus (-1.3%, p=0.027), amygdala (+2.8%, p<0.001), septum (+3.3%, p=0.014) and nucleus accumbens (+3.5, p=0.004) of 2C19TG mice. These brain regions are involved in emotional and motivational functions.
Conclusion: Ataxia-like motoric phenotype in 2C19TG transgenic mice is probably caused by changes in cerebellum, while hyperdopaminergism is most likely the compensatory adaptation, whereas the changes in the hippocampus, amygdala, septum, and nucleus accumbens may be connected with the mutants’ depression-like phenotype and susceptibility to stress. Therefore, CYP2C19 transgenic mouse in potentially useful model of hyperkinetic disorders, and our findings hint at the possible impact of CYP2C19 enzyme on the development of the several brain regions involved in motor and emotional functioning.",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene",
volume = "40",
number = "1",
pages = "S207-S208",
doi = "10.1016/j.euroneuro.2020.09.271"
}

Milosavljević, F., Vučić, M., Manojlović, M., Miloševski, T., Batinić, B., Novalen, M., Miksys, S., Tyndale, R., Ingelman-Sundberg, M., Pešić, V.,& Jukić, M.. (2020). Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene. in European Neuropsychopharmacology
Elsevier., 40(1), S207-S208.
https://doi.org/10.1016/j.euroneuro.2020.09.271

Milosavljević F, Vučić M, Manojlović M, Miloševski T, Batinić B, Novalen M, Miksys S, Tyndale R, Ingelman-Sundberg M, Pešić V, Jukić M. Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene. in European Neuropsychopharmacology. 2020;40(1):S207-S208.
doi:10.1016/j.euroneuro.2020.09.271 .

Milosavljević, Filip, Vučić, Marija, Manojlović, Marina, Miloševski, Teodora, Batinić, Bojan, Novalen, Maria, Miksys, Sharon, Tyndale, Rachel, Ingelman-Sundberg, Magnus, Pešić, Vesna, Jukić, Marin, "Reduced cerebellum volume and ataxia-like motoric phenotype in transgenic mouse, carrier of human CYP2C19 gene" in European Neuropsychopharmacology, 40, no. 1 (2020):S207-S208,
https://doi.org/10.1016/j.euroneuro.2020.09.271 . .

TY  - JOUR
AU  - van Westrhenen, Roos
AU  - Aitchison, Katherine J.
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3575
AB  - In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions.
PB  - Frontiers Media S.A.
T2  - Frontiers in Psychiatry
T1  - Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?
VL  - 11
DO  - 10.3389/fpsyt.2020.00094
ER  - 

@article{
author = "van Westrhenen, Roos and Aitchison, Katherine J. and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2020",
abstract = "In recent decades, very few new psychiatric drugs have entered the market. Thus, improvement in the use of antidepressant and antipsychotic therapy has to focus mainly on enhanced and more personalized treatment with the currently available drugs. One important aspect of such individualization is emphasizing interindividual differences in genes relevant to treatment, an area that can be termed neuropsychopharmacogenomics. Here, we review previous efforts to identify such critical genetic variants and summarize the results obtained to date. We conclude that most clinically relevant genetic variation is connected to phase I drug metabolism, in particular to genetic polymorphism of CYP2C19 and CYP2D6. To further improve individualized pharmacotherapy, there is a need to take both common and rare relevant mutations into consideration; we discuss the present and future possibilities of using whole genome sequencing to identify patient-specific genetic variation relevant to treatment in psychiatry. Translation of pharmacogenomic knowledge into clinical practice can be considered for specific drugs, but this requires education of clinicians, instructive guidelines, as well as full attention to polypharmacy and other clinically relevant factors. Recent large patient studies (n > 1,000) have replicated previous findings and produced robust evidence warranting the clinical utility of relevant genetic biomarkers. To further judge the clinical and financial benefits of preemptive genotyping in psychiatry, large prospective randomized trials are needed to quantify the value of genetic-based patient stratification in neuropsychopharmacotherapy and to demonstrate the cost-effectiveness of such interventions.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Psychiatry",
title = "Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?",
volume = "11",
doi = "10.3389/fpsyt.2020.00094"
}

van Westrhenen, R., Aitchison, K. J., Ingelman-Sundberg, M.,& Jukić, M.. (2020). Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?. in Frontiers in Psychiatry
Frontiers Media S.A.., 11.
https://doi.org/10.3389/fpsyt.2020.00094

van Westrhenen R, Aitchison KJ, Ingelman-Sundberg M, Jukić M. Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?. in Frontiers in Psychiatry. 2020;11.
doi:10.3389/fpsyt.2020.00094 .

van Westrhenen, Roos, Aitchison, Katherine J., Ingelman-Sundberg, Magnus, Jukić, Marin, "Pharmacogenomics of Antidepressant and Antipsychotic Treatment: How Far Have We Got and Where Are We Going?" in Frontiers in Psychiatry, 11 (2020),
https://doi.org/10.3389/fpsyt.2020.00094 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pešić, Vesna
AU  - Pavlović, Zorana
AU  - Miljević, Čedo
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4752
PB  - Springer Nature
C3  - Neuropsychopharmacology
T1  - Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status
IS  - 44
SP  - 139
DO  - 10.1038/s41386-019-0545-y
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pešić, Vesna and Pavlović, Zorana and Miljević, Čedo and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2019",
publisher = "Springer Nature",
journal = "Neuropsychopharmacology",
title = "Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status",
number = "44",
pages = "139",
doi = "10.1038/s41386-019-0545-y"
}

Milosavljević, F., Bukvić, N., Pešić, V., Pavlović, Z., Miljević, Č., Molden, E., Ingelman-Sundberg, M.,& Jukić, M.. (2019). Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status. in Neuropsychopharmacology
Springer Nature.(44), 139.
https://doi.org/10.1038/s41386-019-0545-y

Milosavljević F, Bukvić N, Pešić V, Pavlović Z, Miljević Č, Molden E, Ingelman-Sundberg M, Jukić M. Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status. in Neuropsychopharmacology. 2019;(44):139.
doi:10.1038/s41386-019-0545-y .

Milosavljević, Filip, Bukvić, Nikola, Pešić, Vesna, Pavlović, Zorana, Miljević, Čedo, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "Quantification of Antidepressant and Antipsychotic Exposure Increase Caused by CYP2C19 and CYP2D6 Intermediate and Poor Metabolizer Status" in Neuropsychopharmacology, no. 44 (2019):139,
https://doi.org/10.1038/s41386-019-0545-y . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Bukvić, Nikola
AU  - Pešić, Vesna
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4754
AB  - Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree.
Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval)
Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed.
Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.
PB  - Elsevier
C3  - European Neuropsychopharmacology
T1  - Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis
VL  - 29
IS  - 6
SP  - S533
EP  - S534
DO  - 10.1016/j.euroneuro.2019.09.824
ER  - 

@conference{
author = "Milosavljević, Filip and Bukvić, Nikola and Pešić, Vesna and Molden, Espen and Ingelman-Sundberg, Magnus and Jukić, Marin",
year = "2019",
abstract = "Introduction: Most of the antipsychotics and antidepressants are metabolized by CYP2C19 and CYP2D6 enzymes. Both CYP2D6 and CYP2C19 genes are polymorphic and metabolic capacity of the enzymes is genotype-determined. Homozygous null allele carriers do not possess active enzyme, and they are referred to as CYP2C19 or CYP2D6 poor metabolizers (PM). Certain genotypes do not abolish the enzyme completely, but they do cause drastic reduction of metabolic capacity and carriers of such genotypes are referred to as intermediate metabolizers (IM). It is known that CYP2C19 and CYP2D6 PM and IM status cause increase in exposure of certain antidepressants and antipsychotics; however, due to small sample size of the previously published studies, the magnitude of this effect still cannot be estimated with sufficient precision. Therefore, the aim of this meta-analysis was to pool all these studies and estimate the magnitude of drug exposure increase caused by CYP2C19 and CYP2D6 PM and IM status, compared with normal metabolizers (NM) to the best possible degree.
Methods: The inclusion of the drugs used for the literature survey for meta-analysis was based on the list of new generation antidepressants [1] and antipsychotics [2]. These drugs were screened for inclusion by the PubMed search *DrugName AND (CYP2C19 OR CYP2D6). The studies were included in the meta-analysis if (1) the patients were genotyped for CYP2C19 or CYP2D6; (2) adequate sorting of patients into NM, IM, and PM was possible; (3) the study included at least three patients per subgroup; and (4) drug exposure was measured in representative way by: (a) dose normalized area under plasma level (time) curve, (b) dose normalized steady state plasma levels, or (c) apparent total clearance of the drug from plasma after oral administration (CL/F, reciprocal value represented the drug exposure). Meta-analysis for a specific drug was performed if three or more studies met the inclusion criteria. Drug exposure head-to-head comparisons were made between PM or IM subjects and the NM subject group, which served as a reference. Heterogeneity across the studies was assessed using Cochran's Q test at a given significance level and the percentage of total variability across the studies attributable to heterogeneity was quantified using I2 value. Magnitude of increase is presented as: Odds ratio (95% Confidence interval)
Results: Based on the outcome of the literature survey, it was possible to perform meta-analysis for escitalopram, venlafaxine, risperidone, and aripiprazole. Escitalopram exposure was 1.37-fold (1.30-1.44) increased in CYP2C19 IM and 2.44-fold (2.27-2.61) increased in CYP2C19 PM. Venlafaxine exposure was not significantly changed in CYP2D6 PM, 1.10 (0.99-1.22). Risperidone and aripiprazole exposure increased was similar for CYP2D6 IM and PM. Risperidone exposure was 1.42 (1.36-1.51) increased in CYP2D6 IM and PM admixed. Aripiprazole exposure was 1.52 (1.45-1.58) increased in CYP2D6 IM and PM admixed.
Conclusions: According to the results, reducing escitalopram dose by 60% in CYP2C19 PM and by 30% in CYP2C19 IM are appropriate dosing decision. Next, reducing risperidone and aripiprazole dose by 30% in CYP2D6 PM is appropriate dosing decision. Finallytract, CYP2D6 metabolizer status is not clinically relevant in venlafaxine dosing.",
publisher = "Elsevier",
journal = "European Neuropsychopharmacology",
title = "Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis",
volume = "29",
number = "6",
pages = "S533-S534",
doi = "10.1016/j.euroneuro.2019.09.824"
}

Milosavljević, F., Bukvić, N., Pešić, V., Molden, E., Ingelman-Sundberg, M.,& Jukić, M.. (2019). Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis. in European Neuropsychopharmacology
Elsevier., 29(6), S533-S534.
https://doi.org/10.1016/j.euroneuro.2019.09.824

Milosavljević F, Bukvić N, Pešić V, Molden E, Ingelman-Sundberg M, Jukić M. Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis. in European Neuropsychopharmacology. 2019;29(6):S533-S534.
doi:10.1016/j.euroneuro.2019.09.824 .

Milosavljević, Filip, Bukvić, Nikola, Pešić, Vesna, Molden, Espen, Ingelman-Sundberg, Magnus, Jukić, Marin, "Quantification of antidepressant and antipsychotic exposure increase caused by CYP2C19 and CYP2D6 intermediate and poor metabolizer status by meta-analysis" in European Neuropsychopharmacology, 29, no. 6 (2019):S533-S534,
https://doi.org/10.1016/j.euroneuro.2019.09.824 . .

TY  - CONF
AU  - Milosavljević, Filip
AU  - Vučić, M.
AU  - Manojlović, Marina
AU  - Ašujić, N.
AU  - Batinić, Bojan
AU  - Novalen, M.
AU  - Miksys, S.
AU  - Tyndale, R.F.
AU  - Ingelman-Sundberg, Magnus
AU  - Pešić, Vesna
AU  - Jukić, Marin
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3297
PB  - Elsevier Science BV, Amsterdam
C3  - European Neuropsychopharmacology
T1  - Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia
VL  - 29
IS  - Supplement 2
SP  - S672
EP  - S673
DO  - 10.1016/j.euroneuro.2019.01.056
ER  - 

@conference{
author = "Milosavljević, Filip and Vučić, M. and Manojlović, Marina and Ašujić, N. and Batinić, Bojan and Novalen, M. and Miksys, S. and Tyndale, R.F. and Ingelman-Sundberg, Magnus and Pešić, Vesna and Jukić, Marin",
year = "2019",
publisher = "Elsevier Science BV, Amsterdam",
journal = "European Neuropsychopharmacology",
title = "Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia",
volume = "29",
number = "Supplement 2",
pages = "S672-S673",
doi = "10.1016/j.euroneuro.2019.01.056"
}

Milosavljević, F., Vučić, M., Manojlović, M., Ašujić, N., Batinić, B., Novalen, M., Miksys, S., Tyndale, R.F., Ingelman-Sundberg, M., Pešić, V.,& Jukić, M.. (2019). Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia. in European Neuropsychopharmacology
Elsevier Science BV, Amsterdam., 29(Supplement 2), S672-S673.
https://doi.org/10.1016/j.euroneuro.2019.01.056

Milosavljević F, Vučić M, Manojlović M, Ašujić N, Batinić B, Novalen M, Miksys S, Tyndale R, Ingelman-Sundberg M, Pešić V, Jukić M. Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia. in European Neuropsychopharmacology. 2019;29(Supplement 2):S672-S673.
doi:10.1016/j.euroneuro.2019.01.056 .

Milosavljević, Filip, Vučić, M., Manojlović, Marina, Ašujić, N., Batinić, Bojan, Novalen, M., Miksys, S., Tyndale, R.F., Ingelman-Sundberg, Magnus, Pešić, Vesna, Jukić, Marin, "Transgenic mouse, carrier of human CYP2C19 gene, as an animal model for hyperdopaminergism-induced hyperkinesia" in European Neuropsychopharmacology, 29, no. Supplement 2 (2019):S672-S673,
https://doi.org/10.1016/j.euroneuro.2019.01.056 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Smith, Robert L.
AU  - Haslemo, Tore
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3365
AB  - Background The polymorphic CYP2D6 enzyme metabolises the antipsychotic drugs risperidone and aripiprazole to their active metabolites, 9OH-risperidone and dehydroaripiprazole. The aim of this study was to quantify the effect of CYP2D6 genetic variability on risperidone and aripiprazole exposure and treatment in a large patient population. Methods We retrospectively obtained patient data from a routine therapeutic drug monitoring database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between Jan 1, 2005, and Oct 15, 2018. Individuals included in our analyses were CYP2D6-genotyped patients treated with risperidone or aripiprazole. Inclusion criteria for measurement of pharmacokinetic parameters (drug and metabolite serum concentrations) were oral administration of risperidone or aripiprazole, information known about prescribed daily dose and comedications, and aged older than 18 years. Exclusion criteria included polypharmacy with drugs known to be CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Treatment failure was analysed in all patients treated with risperidone or aripiprazole without these criteria. The first endpoint in our analysis was the metabolism of risperidone to 9OH-risperidone and aripiprazole to dehydroaripiprazole, estimated by the log-transformed ratio between the concentrations of metabolite and parent drug (ie, the metabolic ratio for risperidone [9OH-risperidone]/[risperidone] and the metabolic ratio for aripiprazole [dehydroaripiprazole]/[aripiprazole]). Endpoint two was measurement of drug exposure, quantified by the dose-normalised sum of parent drug and active metabolite serum concentrations (ie, active moiety). The third endpoint of treatment failure was measured as the number of patients switched from risperidone or aripiprazole to another antipsychotic drug within 1 year after the last therapeutic drug monitoring analysis of risperidone or aripiprazole. Patient subgroups were defined by CYP2D6 genotype-determined metaboliser status: poor metabolisers, intermediate metabolisers, normal metabolisers, and ultrarapid metabolisers. ANOVA was used to assess the differences in metabolic ratios, active moieties, and daily doses between individual metaboliser categories, and risperidone and aripiprazole therapeutic failures were compared by logistic regression using the normal metaboliser subgroup as a reference. Findings 1288 risperidone-treated patients and 1334 aripiprazole-treated patients were included in the study, of whom 725 (56%) risperidone-treated and 890 (67%) aripiprazole-treated patients were eligible for the pharmacokinetic analyses. CYP2D6 genotype significantly changed risperidone and aripiprazole metabolism resulting in an approximately 1.6-times and 1.4-times increase in risperidone and aripiprazole active moiety exposure in poor and intermediate metabolisers compared with normal metabolisers, respectively (odds ratios [OR] for the risperidone dose-normalised active moiety concentration 1.568, 95% CI 1.401-1.736, and 1.373, 1.213-1.532; and for the aripiprazole dose-normalised active moiety concentration 1.585, 1.447-1.724, and 1.476, 1.263-1.688, respectively; p lt 0.0001 for all). Compared with doses for normal metabolisers, clinicians reduced daily doses of risperidone and aripiprazole administered to poor metabolisers by 19% (95% CI 5-35, p=0.010) and 15% (95% CI 1-28, p=0.033) respectively. The incidence of switching from risperidone to another antipsychotic was increased in ultrarapid metabolisers (OR 2.934, 95% CI 1.437-5.989, p=0.003) and poor metabolisers (1.874, 1.128-3.112, p=0.015); by contrast, the incidence of switching from aripiprazole to another antipsychotic was not significantly related to CYP2D6 metaboliser status. Interpretation CYP2D6 genotype had a substantial clinical effect on risperidone and aripiprazole exposure and on the therapeutic failure of risperidone. Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimisation. Copyright
PB  - Elsevier Sci Ltd, Oxford
T2  - Lancet Psychiatry
T1  - Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study
VL  - 6
IS  - 5
SP  - 418
EP  - 426
DO  - 10.1016/S2215-0366(19)30088-4
ER  - 

@article{
author = "Jukić, Marin and Smith, Robert L. and Haslemo, Tore and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2019",
abstract = "Background The polymorphic CYP2D6 enzyme metabolises the antipsychotic drugs risperidone and aripiprazole to their active metabolites, 9OH-risperidone and dehydroaripiprazole. The aim of this study was to quantify the effect of CYP2D6 genetic variability on risperidone and aripiprazole exposure and treatment in a large patient population. Methods We retrospectively obtained patient data from a routine therapeutic drug monitoring database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between Jan 1, 2005, and Oct 15, 2018. Individuals included in our analyses were CYP2D6-genotyped patients treated with risperidone or aripiprazole. Inclusion criteria for measurement of pharmacokinetic parameters (drug and metabolite serum concentrations) were oral administration of risperidone or aripiprazole, information known about prescribed daily dose and comedications, and aged older than 18 years. Exclusion criteria included polypharmacy with drugs known to be CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Treatment failure was analysed in all patients treated with risperidone or aripiprazole without these criteria. The first endpoint in our analysis was the metabolism of risperidone to 9OH-risperidone and aripiprazole to dehydroaripiprazole, estimated by the log-transformed ratio between the concentrations of metabolite and parent drug (ie, the metabolic ratio for risperidone [9OH-risperidone]/[risperidone] and the metabolic ratio for aripiprazole [dehydroaripiprazole]/[aripiprazole]). Endpoint two was measurement of drug exposure, quantified by the dose-normalised sum of parent drug and active metabolite serum concentrations (ie, active moiety). The third endpoint of treatment failure was measured as the number of patients switched from risperidone or aripiprazole to another antipsychotic drug within 1 year after the last therapeutic drug monitoring analysis of risperidone or aripiprazole. Patient subgroups were defined by CYP2D6 genotype-determined metaboliser status: poor metabolisers, intermediate metabolisers, normal metabolisers, and ultrarapid metabolisers. ANOVA was used to assess the differences in metabolic ratios, active moieties, and daily doses between individual metaboliser categories, and risperidone and aripiprazole therapeutic failures were compared by logistic regression using the normal metaboliser subgroup as a reference. Findings 1288 risperidone-treated patients and 1334 aripiprazole-treated patients were included in the study, of whom 725 (56%) risperidone-treated and 890 (67%) aripiprazole-treated patients were eligible for the pharmacokinetic analyses. CYP2D6 genotype significantly changed risperidone and aripiprazole metabolism resulting in an approximately 1.6-times and 1.4-times increase in risperidone and aripiprazole active moiety exposure in poor and intermediate metabolisers compared with normal metabolisers, respectively (odds ratios [OR] for the risperidone dose-normalised active moiety concentration 1.568, 95% CI 1.401-1.736, and 1.373, 1.213-1.532; and for the aripiprazole dose-normalised active moiety concentration 1.585, 1.447-1.724, and 1.476, 1.263-1.688, respectively; p lt 0.0001 for all). Compared with doses for normal metabolisers, clinicians reduced daily doses of risperidone and aripiprazole administered to poor metabolisers by 19% (95% CI 5-35, p=0.010) and 15% (95% CI 1-28, p=0.033) respectively. The incidence of switching from risperidone to another antipsychotic was increased in ultrarapid metabolisers (OR 2.934, 95% CI 1.437-5.989, p=0.003) and poor metabolisers (1.874, 1.128-3.112, p=0.015); by contrast, the incidence of switching from aripiprazole to another antipsychotic was not significantly related to CYP2D6 metaboliser status. Interpretation CYP2D6 genotype had a substantial clinical effect on risperidone and aripiprazole exposure and on the therapeutic failure of risperidone. Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimisation. Copyright",
publisher = "Elsevier Sci Ltd, Oxford",
journal = "Lancet Psychiatry",
title = "Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study",
volume = "6",
number = "5",
pages = "418-426",
doi = "10.1016/S2215-0366(19)30088-4"
}

Jukić, M., Smith, R. L., Haslemo, T., Molden, E.,& Ingelman-Sundberg, M.. (2019). Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. in Lancet Psychiatry
Elsevier Sci Ltd, Oxford., 6(5), 418-426.
https://doi.org/10.1016/S2215-0366(19)30088-4

Jukić M, Smith RL, Haslemo T, Molden E, Ingelman-Sundberg M. Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. in Lancet Psychiatry. 2019;6(5):418-426.
doi:10.1016/S2215-0366(19)30088-4 .

Jukić, Marin, Smith, Robert L., Haslemo, Tore, Molden, Espen, Ingelman-Sundberg, Magnus, "Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study" in Lancet Psychiatry, 6, no. 5 (2019):418-426,
https://doi.org/10.1016/S2215-0366(19)30088-4 . .

TY  - JOUR
AU  - Haslemo, Tore
AU  - Eliasson, Erik
AU  - Jukić, Marin
AU  - Ingelman-Sundberg, Magnus
AU  - Molden, Espen
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3364
AB  - Aims CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. Methods A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. Results MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P  lt  0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. Conclusions CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
PB  - Wiley, Hoboken
T2  - British Journal of Clinical Pharmacology
T1  - Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients
VL  - 85
IS  - 1
SP  - 194
EP  - 201
DO  - 10.1111/bcp.13788
ER  - 

@article{
author = "Haslemo, Tore and Eliasson, Erik and Jukić, Marin and Ingelman-Sundberg, Magnus and Molden, Espen",
year = "2019",
abstract = "Aims CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. Methods A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. Results MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P  lt  0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. Conclusions CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.",
publisher = "Wiley, Hoboken",
journal = "British Journal of Clinical Pharmacology",
title = "Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients",
volume = "85",
number = "1",
pages = "194-201",
doi = "10.1111/bcp.13788"
}

Haslemo, T., Eliasson, E., Jukić, M., Ingelman-Sundberg, M.,& Molden, E.. (2019). Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. in British Journal of Clinical Pharmacology
Wiley, Hoboken., 85(1), 194-201.
https://doi.org/10.1111/bcp.13788

Haslemo T, Eliasson E, Jukić M, Ingelman-Sundberg M, Molden E. Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. in British Journal of Clinical Pharmacology. 2019;85(1):194-201.
doi:10.1111/bcp.13788 .

Haslemo, Tore, Eliasson, Erik, Jukić, Marin, Ingelman-Sundberg, Magnus, Molden, Espen, "Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients" in British Journal of Clinical Pharmacology, 85, no. 1 (2019):194-201,
https://doi.org/10.1111/bcp.13788 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Haslemo, Tore
AU  - Molden, Espen
AU  - Ingelman-Sundberg, Magnus
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3237
AB  - Objective: The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. Method: A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Results: Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. Conclusions: The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.
PB  - Amer Psychiatric Publishing, Inc, Washington
T2  - American Journal of Psychiatry
T1  - Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients
VL  - 175
IS  - 5
SP  - 463
EP  - 470
DO  - 10.1176/appi.ajp.2017.17050550
ER  - 

@article{
author = "Jukić, Marin and Haslemo, Tore and Molden, Espen and Ingelman-Sundberg, Magnus",
year = "2018",
abstract = "Objective: The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. Method: A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Results: Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. Conclusions: The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.",
publisher = "Amer Psychiatric Publishing, Inc, Washington",
journal = "American Journal of Psychiatry",
title = "Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients",
volume = "175",
number = "5",
pages = "463-470",
doi = "10.1176/appi.ajp.2017.17050550"
}

Jukić, M., Haslemo, T., Molden, E.,& Ingelman-Sundberg, M.. (2018). Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients. in American Journal of Psychiatry
Amer Psychiatric Publishing, Inc, Washington., 175(5), 463-470.
https://doi.org/10.1176/appi.ajp.2017.17050550

Jukić M, Haslemo T, Molden E, Ingelman-Sundberg M. Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients. in American Journal of Psychiatry. 2018;175(5):463-470.
doi:10.1176/appi.ajp.2017.17050550 .

Jukić, Marin, Haslemo, Tore, Molden, Espen, Ingelman-Sundberg, Magnus, "Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients" in American Journal of Psychiatry, 175, no. 5 (2018):463-470,
https://doi.org/10.1176/appi.ajp.2017.17050550 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Lauschke, Volker M.
AU  - Saito, Takahiro
AU  - Hiratsuka, Masahiro
AU  - Ingelman-Sundberg, Magnus
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3200
AB  - The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - Functional characterization of CYP2D7 gene variants
VL  - 19
IS  - 12
SP  - 931
EP  - 936
DO  - 10.2217/pgs-2018-0065
ER  - 

@article{
author = "Jukić, Marin and Lauschke, Volker M. and Saito, Takahiro and Hiratsuka, Masahiro and Ingelman-Sundberg, Magnus",
year = "2018",
abstract = "The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "Functional characterization of CYP2D7 gene variants",
volume = "19",
number = "12",
pages = "931-936",
doi = "10.2217/pgs-2018-0065"
}

Jukić, M., Lauschke, V. M., Saito, T., Hiratsuka, M.,& Ingelman-Sundberg, M.. (2018). Functional characterization of CYP2D7 gene variants. in Pharmacogenomics
Future Medicine Ltd, London., 19(12), 931-936.
https://doi.org/10.2217/pgs-2018-0065

Jukić M, Lauschke VM, Saito T, Hiratsuka M, Ingelman-Sundberg M. Functional characterization of CYP2D7 gene variants. in Pharmacogenomics. 2018;19(12):931-936.
doi:10.2217/pgs-2018-0065 .

Jukić, Marin, Lauschke, Volker M., Saito, Takahiro, Hiratsuka, Masahiro, Ingelman-Sundberg, Magnus, "Functional characterization of CYP2D7 gene variants" in Pharmacogenomics, 19, no. 12 (2018):931-936,
https://doi.org/10.2217/pgs-2018-0065 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Opel, N.
AU  - Ström, J.
AU  - Carrillo-Roa, T.
AU  - Miksys, S.
AU  - Novalen, M.
AU  - Renblom, A.
AU  - Sim, S.C.
AU  - Peñas-Lledó, E.M.
AU  - Couvert, Philippe
AU  - Llerena, A.
AU  - Baune, B.T.
AU  - de Quervain, D.J.
AU  - Papassotiropoulos, A.
AU  - Tyndale, R.F.
AU  - Binder, E.B.
AU  - Dannlowski, U.
AU  - Ingelman-Sundberg, Magnus
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2979
AB  - This corrects the article DOI: 10.1038/mp.2016.204.
PB  - NLM (Medline)
T2  - Molecular Psychiatry
T1  - Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment (Molecular psychiatry (2016))
VL  - 22
IS  - 8
SP  - 1224
UR  - https://hdl.handle.net/21.15107/rcub_farfar_2979
ER  - 

@article{
author = "Jukić, Marin and Opel, N. and Ström, J. and Carrillo-Roa, T. and Miksys, S. and Novalen, M. and Renblom, A. and Sim, S.C. and Peñas-Lledó, E.M. and Couvert, Philippe and Llerena, A. and Baune, B.T. and de Quervain, D.J. and Papassotiropoulos, A. and Tyndale, R.F. and Binder, E.B. and Dannlowski, U. and Ingelman-Sundberg, Magnus",
year = "2017",
abstract = "This corrects the article DOI: 10.1038/mp.2016.204.",
publisher = "NLM (Medline)",
journal = "Molecular Psychiatry",
title = "Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment (Molecular psychiatry (2016))",
volume = "22",
number = "8",
pages = "1224",
url = "https://hdl.handle.net/21.15107/rcub_farfar_2979"
}

Jukić, M., Opel, N., Ström, J., Carrillo-Roa, T., Miksys, S., Novalen, M., Renblom, A., Sim, S.C., Peñas-Lledó, E.M., Couvert, P., Llerena, A., Baune, B.T., de Quervain, D.J., Papassotiropoulos, A., Tyndale, R.F., Binder, E.B., Dannlowski, U.,& Ingelman-Sundberg, M.. (2017). Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment (Molecular psychiatry (2016)). in Molecular Psychiatry
NLM (Medline)., 22(8), 1224.
https://hdl.handle.net/21.15107/rcub_farfar_2979

Jukić M, Opel N, Ström J, Carrillo-Roa T, Miksys S, Novalen M, Renblom A, Sim S, Peñas-Lledó E, Couvert P, Llerena A, Baune B, de Quervain D, Papassotiropoulos A, Tyndale R, Binder E, Dannlowski U, Ingelman-Sundberg M. Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment (Molecular psychiatry (2016)). in Molecular Psychiatry. 2017;22(8):1224.
https://hdl.handle.net/21.15107/rcub_farfar_2979 .

Jukić, Marin, Opel, N., Ström, J., Carrillo-Roa, T., Miksys, S., Novalen, M., Renblom, A., Sim, S.C., Peñas-Lledó, E.M., Couvert, Philippe, Llerena, A., Baune, B.T., de Quervain, D.J., Papassotiropoulos, A., Tyndale, R.F., Binder, E.B., Dannlowski, U., Ingelman-Sundberg, Magnus, "Erratum: Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment (Molecular psychiatry (2016))" in Molecular Psychiatry, 22, no. 8 (2017):1224,
https://hdl.handle.net/21.15107/rcub_farfar_2979 .

TY  - JOUR
AU  - Ingelman-Sundberg, Magnus
AU  - Persson, A
AU  - Jukić, Marin
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2249
PB  - Future Medicine Ltd.
T2  - Pharmacogenomics
T1  - Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates
VL  - 15
IS  - 15
SP  - 1841
EP  - 1844
DO  - 10.2217/pgs.14.151
ER  - 

@article{
author = "Ingelman-Sundberg, Magnus and Persson, A and Jukić, Marin",
year = "2014",
publisher = "Future Medicine Ltd.",
journal = "Pharmacogenomics",
title = "Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates",
volume = "15",
number = "15",
pages = "1841-1844",
doi = "10.2217/pgs.14.151"
}

Ingelman-Sundberg, M., Persson, A.,& Jukić, M.. (2014). Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates. in Pharmacogenomics
Future Medicine Ltd.., 15(15), 1841-1844.
https://doi.org/10.2217/pgs.14.151

Ingelman-Sundberg M, Persson A, Jukić M. Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates. in Pharmacogenomics. 2014;15(15):1841-1844.
doi:10.2217/pgs.14.151 .

Ingelman-Sundberg, Magnus, Persson, A, Jukić, Marin, "Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates" in Pharmacogenomics, 15, no. 15 (2014):1841-1844,
https://doi.org/10.2217/pgs.14.151 . .