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  - Pelgrim, Teuntje A. D.
AU  - Philipsen, Alexandra
AU  - Young, Allan H.
AU  - Juruena, Mario
AU  - Jimenez, Ester
AU  - Vieta, Eduard
AU  - Jukić, Marin
AU  - Van der Eycken, Erik
AU  - Heilbronner, Urs
AU  - Moldovan, Ramona
AU  - Kas, Martien J. H.
AU  - Jagesar, Raj R.
AU  - Nöthen, Markus M.
AU  - Hoffmann, Per
AU  - Shomron, Noam
AU  - Kilarski, Laura L
AU  - van Amelsvoort, Thérèse
AU  - Campforts, Bea
AU  - van Westrhenen, Roos
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5548
AB  - (1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.
PB  - MDPI
T2  - Pharmaceuticals
T1  - A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study
VL  - 17
IS  - 2
DO  - 10.3390/ph17020151
ER  - 

@article{
author = "Pelgrim, Teuntje A. D. and Philipsen, Alexandra and Young, Allan H. and Juruena, Mario and Jimenez, Ester and Vieta, Eduard and Jukić, Marin and Van der Eycken, Erik and Heilbronner, Urs and Moldovan, Ramona and Kas, Martien J. H. and Jagesar, Raj R. and Nöthen, Markus M. and Hoffmann, Per and Shomron, Noam and Kilarski, Laura L and van Amelsvoort, Thérèse and Campforts, Bea and van Westrhenen, Roos",
year = "2024",
abstract = "(1) Background Pharmacological treatment for psychiatric disorders has shown to only be effective in about one-third of patients, as it is associated with frequent treatment failure, often because of side effects, and a long process of trial-and-error pharmacotherapy until an effective and tolerable treatment is found. This notion emphasizes the urgency for a personalized medicine approach in psychiatry. (2) Methods This prospective patient- and rater-blinded, randomized, controlled study will investigate the effect of dose-adjustment of antidepressants escitalopram and sertraline or antipsychotics risperidone and aripiprazole according to the latest state-of-the-art international dosing recommendations for CYP2C19 and CYP2D6 metabolizer status in patients with mood, anxiety, and psychotic disorders. A total sample of N = 2500 will be recruited at nine sites in seven countries (expected drop-out rate of 30%). Patients will be randomized to a pharmacogenetic group or a dosing-as-usual group and treated over a 24-week period with four study visits. The primary outcome is personal recovery using the Recovery Assessment Scale as assessed by the patient (RAS-DS), with secondary outcomes including clinical effects (response or symptomatic remission), side effects, general well-being, digital phenotyping, and psychosocial functioning. (3) Conclusions This is, to our knowledge, the first international, multi-center, non-industry-sponsored randomized controlled trial (RCT) that may provide insights into the effectiveness and utility of implementing pharmacogenetic-guided treatment of psychiatric disorders, and as such, results will be incorporated in already available dosing guidelines.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study",
volume = "17",
number = "2",
doi = "10.3390/ph17020151"
}

Pelgrim, T. A. D., Philipsen, A., Young, A. H., Juruena, M., Jimenez, E., Vieta, E., Jukić, M., Van der Eycken, E., Heilbronner, U., Moldovan, R., Kas, M. J. H., Jagesar, R. R., Nöthen, M. M., Hoffmann, P., Shomron, N., Kilarski, L. L., van Amelsvoort, T., Campforts, B.,& van Westrhenen, R.. (2024). A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study. in Pharmaceuticals
MDPI., 17(2).
https://doi.org/10.3390/ph17020151

Pelgrim TAD, Philipsen A, Young AH, Juruena M, Jimenez E, Vieta E, Jukić M, Van der Eycken E, Heilbronner U, Moldovan R, Kas MJH, Jagesar RR, Nöthen MM, Hoffmann P, Shomron N, Kilarski LL, van Amelsvoort T, Campforts B, van Westrhenen R. A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study. in Pharmaceuticals. 2024;17(2).
doi:10.3390/ph17020151 .

Pelgrim, Teuntje A. D., Philipsen, Alexandra, Young, Allan H., Juruena, Mario, Jimenez, Ester, Vieta, Eduard, Jukić, Marin, Van der Eycken, Erik, Heilbronner, Urs, Moldovan, Ramona, Kas, Martien J. H., Jagesar, Raj R., Nöthen, Markus M., Hoffmann, Per, Shomron, Noam, Kilarski, Laura L, van Amelsvoort, Thérèse, Campforts, Bea, van Westrhenen, Roos, "A New Intervention for Implementation of Pharmacogenetics in Psychiatry: A Description of the PSY-PGx Clinical Study" in Pharmaceuticals, 17, no. 2 (2024),
https://doi.org/10.3390/ph17020151 . .

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  - Joković, Danilo
AU  - Milosavljević, Filip
AU  - Stojanović, Zvezdana
AU  - Šupić, Gordana
AU  - Vojvodić, Danilo
AU  - Uzelac, Bojana
AU  - Jukić, Marin
AU  - Petković Ćurčin, Aleksandra
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4080
AB  - The inter-individual variability in CYP2C19-mediated metabolism may affect the antidepressant treatment. The aim of this study is to evaluate differences in antidepressant efficacy and tolerability between different CYP2C19 metabolizer categories in inpatients suffering from major depressive disorder. The cohort was divided into experimental groups based on CYP2C19 genotype and it contained 24 slow (SMs), 41 normal (NMs), and 37 fast metabolizers (FMs). Efficacy and tolerability were assessed at baseline, and after two and four weeks as a follow- up. The primary efficacy measurement was the change from baseline in Hamilton’s Depression Rating Scale (HAMD), while the primary tolerability measurement was the Toronto Side-Effects Scale (TSES) intensity scores at the last visit. The reduction in HAMD score was 36% less pronounced and response rate was exceedingly less prevalent (75% lower) in SMs, compared with NMs. The TSES intensity score was increased in SMs, compared with NMs, by 43% for central nervous system and by 22% for gastrointestinal adverse drug reactions. No sig- nificant differences in measured parameters were observed between NMs and FMs. Compared with NM and RM, lower antidepressant efficacy and tolerability was observed in SMs; this association is likely connected with the lower SM capacity to metabolize antidepressant drugs.
PB  - Elsevier Ireland Ltd
T2  - Psychiatry Research
T1  - CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability
VL  - 312
DO  - 10.1016/j.psychres.2022.114535
ER  - 

@article{
author = "Joković, Danilo and Milosavljević, Filip and Stojanović, Zvezdana and Šupić, Gordana and Vojvodić, Danilo and Uzelac, Bojana and Jukić, Marin and Petković Ćurčin, Aleksandra",
year = "2022",
abstract = "The inter-individual variability in CYP2C19-mediated metabolism may affect the antidepressant treatment. The aim of this study is to evaluate differences in antidepressant efficacy and tolerability between different CYP2C19 metabolizer categories in inpatients suffering from major depressive disorder. The cohort was divided into experimental groups based on CYP2C19 genotype and it contained 24 slow (SMs), 41 normal (NMs), and 37 fast metabolizers (FMs). Efficacy and tolerability were assessed at baseline, and after two and four weeks as a follow- up. The primary efficacy measurement was the change from baseline in Hamilton’s Depression Rating Scale (HAMD), while the primary tolerability measurement was the Toronto Side-Effects Scale (TSES) intensity scores at the last visit. The reduction in HAMD score was 36% less pronounced and response rate was exceedingly less prevalent (75% lower) in SMs, compared with NMs. The TSES intensity score was increased in SMs, compared with NMs, by 43% for central nervous system and by 22% for gastrointestinal adverse drug reactions. No sig- nificant differences in measured parameters were observed between NMs and FMs. Compared with NM and RM, lower antidepressant efficacy and tolerability was observed in SMs; this association is likely connected with the lower SM capacity to metabolize antidepressant drugs.",
publisher = "Elsevier Ireland Ltd",
journal = "Psychiatry Research",
title = "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability",
volume = "312",
doi = "10.1016/j.psychres.2022.114535"
}

Joković, D., Milosavljević, F., Stojanović, Z., Šupić, G., Vojvodić, D., Uzelac, B., Jukić, M.,& Petković Ćurčin, A.. (2022). CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability. in Psychiatry Research
Elsevier Ireland Ltd., 312.
https://doi.org/10.1016/j.psychres.2022.114535

Joković D, Milosavljević F, Stojanović Z, Šupić G, Vojvodić D, Uzelac B, Jukić M, Petković Ćurčin A. CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability. in Psychiatry Research. 2022;312.
doi:10.1016/j.psychres.2022.114535 .

Joković, Danilo, Milosavljević, Filip, Stojanović, Zvezdana, Šupić, Gordana, Vojvodić, Danilo, Uzelac, Bojana, Jukić, Marin, Petković Ćurčin, Aleksandra, "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability" in Psychiatry Research, 312 (2022),
https://doi.org/10.1016/j.psychres.2022.114535 . .

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  - JOUR
AU  - Jeremić, Aleksandra
AU  - Milosavljević, Filip
AU  - Opanković, Ana
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4305
AB  - The use of antidepressants has been steadily increasing. Even though the amount of evidence on the usefulness of personalized drug dosing in depression treatment is growing, there is still resistance and skepticism among physicians and regulators regarding the implementation of CYP450 genotyping and therapeutic drug monitoring in psychiatric clinical practice. The aim of this study was to quantify the opinions of psychiatrists and patients from three large psychiatric clinics in Belgrade, Serbia, and to examine what requirements need to be met to make changes in clinical guidelines or recommendations. All participants completed an anonymous questionnaire that was developed at the Faculty of Pharmacy, University of Belgrade. Fourteen practicing psychiatrists and 30 patients currently treated for depression completed the questionnaire. Distributions of opinion scores were compared between the psychiatrists and patients upon the visual inspection of the violin plots. Our results show that psychiatrists predominantly have a positive opinion on personalized dosing in psychiatry and that patients are most likely to comply with new approaches in depression pharmacotherapy. However, due to the long time needed for regulatory change, it is very unlikely that personalized dosing would be rapidly implemented in clinical practice, even if adequate evidence was to emerge.
AB  - Upotreba antidepresiva je u stalnom porastu. Iako raste količina dokaza o korisnosti personalizovanog doziranja lekova u lečenju depresije, još uvek postoji veliki otpor i skepticizam među lekarima i regulatorima u pogledu primene CYP450 genotipizacije i terapijskog praćenja lekova u psihijatrijskoj kliničkoj praksi. Cilj ove studije je bio da se kvantifikuju mišljenja psihijatara i pacijenata sa tri velike psihijatrijske klinike u Beogradu, u Srbiji, i da se ispita koji zahtevi treba da budu ispunjeni da bi se izvršile promene u kliničkim smernicama ili preporukama za doziranje antidepresiva. Svi učesnici su popunili anonimni upitnik koji je izrađen na Farmaceutskom fakultetu Univerziteta u Beogradu. Upitnik je popunilo 44 učesnika, od kojih 14 psihijatara i 30 pacijenata koji se trenutno leče od depresije. Dodatno je kontaktiran i jedan stručnjak za farmakologiju. Distribucija ocena mišljenja je poređena između psihijatara i pacijenata nakon vizuelnog pregleda violina dijagrama. Naši rezultati pokazuju da psihijatri uglavnom imaju pozitivno mišljenje o personalizovanom doziranju u psihijatriji i da bi se pacijenti većinski pridržavali novih pristupa u farmakoterapiji depresije. Međutim, malo je verovatno da bi regulatorna tela u Srbiji brzo ažurirala svoje smernice, čak i ako bi se pojavili adekvatni dokazi.
PB  - Pharmaceutical Association of Serbia
T2  - Arhiv za farmaciju
T1  - Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects
T1  - Stav pacijenata i psihijatara o trenutnom stanju farmakoterapije depresije u Srbiji i mogućnosti uvođenja personalizovane farmakoterapije i njenim potencijalnim efektima
VL  - 72
IS  - 4
SP  - 381
EP  - 391
DO  - 10.5937/arhfarm72-37613
ER  - 

@article{
author = "Jeremić, Aleksandra and Milosavljević, Filip and Opanković, Ana and Jukić, Marin",
year = "2022",
abstract = "The use of antidepressants has been steadily increasing. Even though the amount of evidence on the usefulness of personalized drug dosing in depression treatment is growing, there is still resistance and skepticism among physicians and regulators regarding the implementation of CYP450 genotyping and therapeutic drug monitoring in psychiatric clinical practice. The aim of this study was to quantify the opinions of psychiatrists and patients from three large psychiatric clinics in Belgrade, Serbia, and to examine what requirements need to be met to make changes in clinical guidelines or recommendations. All participants completed an anonymous questionnaire that was developed at the Faculty of Pharmacy, University of Belgrade. Fourteen practicing psychiatrists and 30 patients currently treated for depression completed the questionnaire. Distributions of opinion scores were compared between the psychiatrists and patients upon the visual inspection of the violin plots. Our results show that psychiatrists predominantly have a positive opinion on personalized dosing in psychiatry and that patients are most likely to comply with new approaches in depression pharmacotherapy. However, due to the long time needed for regulatory change, it is very unlikely that personalized dosing would be rapidly implemented in clinical practice, even if adequate evidence was to emerge., Upotreba antidepresiva je u stalnom porastu. Iako raste količina dokaza o korisnosti personalizovanog doziranja lekova u lečenju depresije, još uvek postoji veliki otpor i skepticizam među lekarima i regulatorima u pogledu primene CYP450 genotipizacije i terapijskog praćenja lekova u psihijatrijskoj kliničkoj praksi. Cilj ove studije je bio da se kvantifikuju mišljenja psihijatara i pacijenata sa tri velike psihijatrijske klinike u Beogradu, u Srbiji, i da se ispita koji zahtevi treba da budu ispunjeni da bi se izvršile promene u kliničkim smernicama ili preporukama za doziranje antidepresiva. Svi učesnici su popunili anonimni upitnik koji je izrađen na Farmaceutskom fakultetu Univerziteta u Beogradu. Upitnik je popunilo 44 učesnika, od kojih 14 psihijatara i 30 pacijenata koji se trenutno leče od depresije. Dodatno je kontaktiran i jedan stručnjak za farmakologiju. Distribucija ocena mišljenja je poređena između psihijatara i pacijenata nakon vizuelnog pregleda violina dijagrama. Naši rezultati pokazuju da psihijatri uglavnom imaju pozitivno mišljenje o personalizovanom doziranju u psihijatriji i da bi se pacijenti većinski pridržavali novih pristupa u farmakoterapiji depresije. Međutim, malo je verovatno da bi regulatorna tela u Srbiji brzo ažurirala svoje smernice, čak i ako bi se pojavili adekvatni dokazi.",
publisher = "Pharmaceutical Association of Serbia",
journal = "Arhiv za farmaciju",
title = "Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects, Stav pacijenata i psihijatara o trenutnom stanju farmakoterapije depresije u Srbiji i mogućnosti uvođenja personalizovane farmakoterapije i njenim potencijalnim efektima",
volume = "72",
number = "4",
pages = "381-391",
doi = "10.5937/arhfarm72-37613"
}

Jeremić, A., Milosavljević, F., Opanković, A.,& Jukić, M.. (2022). Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects. in Arhiv za farmaciju
Pharmaceutical Association of Serbia., 72(4), 381-391.
https://doi.org/10.5937/arhfarm72-37613

Jeremić A, Milosavljević F, Opanković A, Jukić M. Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects. in Arhiv za farmaciju. 2022;72(4):381-391.
doi:10.5937/arhfarm72-37613 .

Jeremić, Aleksandra, Milosavljević, Filip, Opanković, Ana, Jukić, Marin, "Patients’ and psychiatrists’ stance on the current state of pharmacological depression treatment in Serbia and prospects of introduction of personalized pharmacotherapy and its potential effects" in Arhiv za farmaciju, 72, no. 4 (2022):381-391,
https://doi.org/10.5937/arhfarm72-37613 . .

TY  - CONF
AU  - Manojlović, Marina
AU  - Milosavljević, Filip
AU  - Atanasov, Andrea
AU  - Batinić, Bojan
AU  - Sitarica, Pavle
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4728
AB  - Background: Due to the COVID-19 pandemic, the prevalence of anxiety and
depression disorders increased by approximately 25-30% [1]. Reasons behind
this are likely associated with the increased average daily level of stress, especially during social isolation. Since one of the main adolescence hallmarks is
formation of meaningful social and love relationships, it represents a particularly
vulnerable period for social stress [2]. The aim of this study was to evaluate
whether isolation stress during the adolescence causes general and social anxiety
in rats.
Methods: Sprague-Dawley rats of both sexes were used for the adolescence social
isolation experiment. From the fourth postnatal week, 24 rats were single caged
and therefore subjected to the social isolation stress, while 24 non-stressed
control rats remained in groups of four per cage and were handled three times a
week. All rats were handled daily for one week and weighted before behavioural
tests. From eleventh week, rats were subjected to the open field, elevated plus
maze, and three-chamber sociability tests, with two-day gap between different
tests. In open field test, time spent in the centre was measured, while in the
elevated plus maze test, the time spent in open arms, normalized to time spent in
all arms was measured; reduction in values of these parameters was interpreted
as general anxiety. In the social preference test, social preference ratio was
calculated for each animal, according to the previously published protocol [3],
and reduction in this ratio was interpreted as social anxiety. 2-way ANOVA, with
sex and isolation stress as factors, was used for parametric data analysis, and
Fischer’s post hoc test was used to detect statistically significant between group
differences. Kruskal-Wallis test was used for non-parametric data analysis, and
Mann-Whitney post hoc test with multiple comparison correction was used to
detect statistically significant between group differences.
Results: Compared to control rats, time spent in the centre of open field (-44%
[95%CI: -76%, -12%] p¼0,008) and total distance travelled (-17% [95%CI:
-32%, -2%], p¼0.028) were decreased in isolated males, but not in females
(p>0.1). In elevated plus maze test, time spent in the open arms was significantly
decreased in male isolated rats (isolated: [median: 0.76, IQR: 0.00 – 2.06] vs
control: [median: 4.96, IQR: 2.04 – 17.75], p¼0.034); however, this change did
not remain significant after multiple comparisons corrections. In sociability tests,
both male and female isolated rats exhibited increase in social preference ratio
(+32% [95%CI: 12%, 51%], p¼0.002) and preference for novel animal over
familiar one (+48% [95%CI: 10%, 86%], p¼0.015), compared to control rats.
Body weight, measured after six weeks of social isolation at week ten, was
increased in isolated male compared to control rats (+19% [95%CI: 14%, 24%],
p<0.001), while there was no such difference observed in female rats.
Conclusion: Social isolation caused increase in general anxiety in male, but not
female rats. In addition, both male and female rats exhibited robust increase in
preference for social interaction and novel social stimulus, which is the result
opposite from the expected social anxiety as initially hypothesized.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats
VL  - 1
IS  - Supplement 2
SP  - 19
EP  - 19
DO  - 10.1016/j.nsa.2022.100149
ER  - 

@conference{
author = "Manojlović, Marina and Milosavljević, Filip and Atanasov, Andrea and Batinić, Bojan and Sitarica, Pavle and Jukić, Marin",
year = "2022",
abstract = "Background: Due to the COVID-19 pandemic, the prevalence of anxiety and
depression disorders increased by approximately 25-30% [1]. Reasons behind
this are likely associated with the increased average daily level of stress, especially during social isolation. Since one of the main adolescence hallmarks is
formation of meaningful social and love relationships, it represents a particularly
vulnerable period for social stress [2]. The aim of this study was to evaluate
whether isolation stress during the adolescence causes general and social anxiety
in rats.
Methods: Sprague-Dawley rats of both sexes were used for the adolescence social
isolation experiment. From the fourth postnatal week, 24 rats were single caged
and therefore subjected to the social isolation stress, while 24 non-stressed
control rats remained in groups of four per cage and were handled three times a
week. All rats were handled daily for one week and weighted before behavioural
tests. From eleventh week, rats were subjected to the open field, elevated plus
maze, and three-chamber sociability tests, with two-day gap between different
tests. In open field test, time spent in the centre was measured, while in the
elevated plus maze test, the time spent in open arms, normalized to time spent in
all arms was measured; reduction in values of these parameters was interpreted
as general anxiety. In the social preference test, social preference ratio was
calculated for each animal, according to the previously published protocol [3],
and reduction in this ratio was interpreted as social anxiety. 2-way ANOVA, with
sex and isolation stress as factors, was used for parametric data analysis, and
Fischer’s post hoc test was used to detect statistically significant between group
differences. Kruskal-Wallis test was used for non-parametric data analysis, and
Mann-Whitney post hoc test with multiple comparison correction was used to
detect statistically significant between group differences.
Results: Compared to control rats, time spent in the centre of open field (-44%
[95%CI: -76%, -12%] p¼0,008) and total distance travelled (-17% [95%CI:
-32%, -2%], p¼0.028) were decreased in isolated males, but not in females
(p>0.1). In elevated plus maze test, time spent in the open arms was significantly
decreased in male isolated rats (isolated: [median: 0.76, IQR: 0.00 – 2.06] vs
control: [median: 4.96, IQR: 2.04 – 17.75], p¼0.034); however, this change did
not remain significant after multiple comparisons corrections. In sociability tests,
both male and female isolated rats exhibited increase in social preference ratio
(+32% [95%CI: 12%, 51%], p¼0.002) and preference for novel animal over
familiar one (+48% [95%CI: 10%, 86%], p¼0.015), compared to control rats.
Body weight, measured after six weeks of social isolation at week ten, was
increased in isolated male compared to control rats (+19% [95%CI: 14%, 24%],
p<0.001), while there was no such difference observed in female rats.
Conclusion: Social isolation caused increase in general anxiety in male, but not
female rats. In addition, both male and female rats exhibited robust increase in
preference for social interaction and novel social stimulus, which is the result
opposite from the expected social anxiety as initially hypothesized.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats",
volume = "1",
number = "Supplement 2",
pages = "19-19",
doi = "10.1016/j.nsa.2022.100149"
}

Manojlović, M., Milosavljević, F., Atanasov, A., Batinić, B., Sitarica, P.,& Jukić, M.. (2022). Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats. in Neuroscience Applied
Elsevier., 1(Supplement 2), 19-19.
https://doi.org/10.1016/j.nsa.2022.100149

Manojlović M, Milosavljević F, Atanasov A, Batinić B, Sitarica P, Jukić M. Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats. in Neuroscience Applied. 2022;1(Supplement 2):19-19.
doi:10.1016/j.nsa.2022.100149 .

Manojlović, Marina, Milosavljević, Filip, Atanasov, Andrea, Batinić, Bojan, Sitarica, Pavle, Jukić, Marin, "Social adolescent stress causes increased general anxiety in male rats and reduced social anxiety in both male and female rats" in Neuroscience Applied, 1, no. Supplement 2 (2022):19-19,
https://doi.org/10.1016/j.nsa.2022.100149 . .

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  - CONF
AU  - Joković, Danilo
AU  - Milosavljević, Filip
AU  - Stojanović, Zvezdana
AU  - Šupić, Gordana
AU  - Vojvodić, Danilo
AU  - Jukić, Marin
AU  - Uzelac, Bojana
AU  - Petković-Ćurčić, Aleksandra
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4730
AB  - Introduction: Available antidepressants are not always effective and the discovery of new antidepressants is slow. Since most antidepressants are metabolized by polymorphic CYP450 liver enzymes, it has been hypothesized that personalized dosing that takes into the account genotype-predicted CYP450 enzyme capacity may improve their effectiveness [1]. Even though it is well known that CYP450 polymorphism impacts plasma levels of many antidepressants [2,3], available evidence on the impact of CYP450 polymorphism on antidepressant efficacy and tolerability is insufficiently strong and often conflicting.

Aim: The aim of this study was to test if CYP2C19 genotype influences efficacy and tolerability of antidepressant therapy in the cohort of 102 inpatients.

Methods: The study was performed at the Military Medical Academy in Belgrade, Serbia. Patients hospitalized for depression and treated with at least one antidepressant were included if they signed the informed consent form. Patients were monitored at the hospital admission and after two and four weeks of follow-up. The drug efficacy was measured with HAM-D (Hamilton depression rating) scale, while tolerability was monitored by TSES (Toronto Side-effects scale) [4]. Patients were retrospectively genotyped for CYP2C19 after the study completion and subsequently categorized as Slow (SM), Normal (NM), or Fast metabolizers (FM). Differences between CYP2C19 metabolizer groups at week four were compared with ANCOVA for HAM-D score, Kruskal-Wallis test for TSES and binary-logistic regression for response rate. Individual adverse reactions were analysed with post-hoc Man-Whitney test.

Results: In total, 102 patients were included; 41 were NM controls, 24 were SM and 37 were RM. Most commonly prescribed primary antidepressants were escitalopram (n=20), trazodone (n=14), mirtazapine (n=12), sertraline (n=12) and venlafaxine (n=10). The fluoxetine-equivalent doses were the not different across groups (p>0.1). While all categories experienced significant reduction in HAMD score during 4 weeks, compared with NMs, the reduction was 36% ([CI95%: 20% - 52%], p<0.0001) less pronounced among SMs. Similarly, response rate was 75% lower in SMs compared with NMs (NM: 34/41 vs SM: 5/24, p<0.0001); response was defined as ≥50% reduction in HAMD score [5]. Finally, SM patients had higher median intensity scores than NMs at week 4 (NM median: 2.5 [IQR: 2.0 - 3.2] vs SM median: 3.2 [IQR: 2.8 - 3.7]; p=0.021, q=0.042). Post hoc analysis revealed that increased burden of nervousness, agitation, and dyspepsia contributed the most to the worse tolerability in SMs. There were no significant differences between FM and NM patients in any of the measured outcomes.

Conclusions: This study revealed that, in the cohort of inpatients treated with heterogeneous antidepressants, the reduced CYP2C19 metabolic capacity is associated with worse therapy efficacy and tolerability, whereas the increased CYP2C19 metabolic capacity is not. Therefore, it is likely that SM group does not receive the appropriate treatment under standard psychiatric practice, which is in most cases unaware of the patients’ CYP2C19 genotype. Even though this study does not have sufficient power for an unequivocal conclusion related to the need of pre-emptive CYP2C19 genotyping of antidepressant treated patients, it contributes to the body of already existing evidence on the clinical usefulness of CYP2C19 genotyping in psychiatry.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients
VL  - 1
IS  - Supplement 2
SP  - 54
EP  - 55
DO  - 10.1016/j.nsa.2022.100217
ER  - 

@conference{
author = "Joković, Danilo and Milosavljević, Filip and Stojanović, Zvezdana and Šupić, Gordana and Vojvodić, Danilo and Jukić, Marin and Uzelac, Bojana and Petković-Ćurčić, Aleksandra",
year = "2022",
abstract = "Introduction: Available antidepressants are not always effective and the discovery of new antidepressants is slow. Since most antidepressants are metabolized by polymorphic CYP450 liver enzymes, it has been hypothesized that personalized dosing that takes into the account genotype-predicted CYP450 enzyme capacity may improve their effectiveness [1]. Even though it is well known that CYP450 polymorphism impacts plasma levels of many antidepressants [2,3], available evidence on the impact of CYP450 polymorphism on antidepressant efficacy and tolerability is insufficiently strong and often conflicting.

Aim: The aim of this study was to test if CYP2C19 genotype influences efficacy and tolerability of antidepressant therapy in the cohort of 102 inpatients.

Methods: The study was performed at the Military Medical Academy in Belgrade, Serbia. Patients hospitalized for depression and treated with at least one antidepressant were included if they signed the informed consent form. Patients were monitored at the hospital admission and after two and four weeks of follow-up. The drug efficacy was measured with HAM-D (Hamilton depression rating) scale, while tolerability was monitored by TSES (Toronto Side-effects scale) [4]. Patients were retrospectively genotyped for CYP2C19 after the study completion and subsequently categorized as Slow (SM), Normal (NM), or Fast metabolizers (FM). Differences between CYP2C19 metabolizer groups at week four were compared with ANCOVA for HAM-D score, Kruskal-Wallis test for TSES and binary-logistic regression for response rate. Individual adverse reactions were analysed with post-hoc Man-Whitney test.

Results: In total, 102 patients were included; 41 were NM controls, 24 were SM and 37 were RM. Most commonly prescribed primary antidepressants were escitalopram (n=20), trazodone (n=14), mirtazapine (n=12), sertraline (n=12) and venlafaxine (n=10). The fluoxetine-equivalent doses were the not different across groups (p>0.1). While all categories experienced significant reduction in HAMD score during 4 weeks, compared with NMs, the reduction was 36% ([CI95%: 20% - 52%], p<0.0001) less pronounced among SMs. Similarly, response rate was 75% lower in SMs compared with NMs (NM: 34/41 vs SM: 5/24, p<0.0001); response was defined as ≥50% reduction in HAMD score [5]. Finally, SM patients had higher median intensity scores than NMs at week 4 (NM median: 2.5 [IQR: 2.0 - 3.2] vs SM median: 3.2 [IQR: 2.8 - 3.7]; p=0.021, q=0.042). Post hoc analysis revealed that increased burden of nervousness, agitation, and dyspepsia contributed the most to the worse tolerability in SMs. There were no significant differences between FM and NM patients in any of the measured outcomes.

Conclusions: This study revealed that, in the cohort of inpatients treated with heterogeneous antidepressants, the reduced CYP2C19 metabolic capacity is associated with worse therapy efficacy and tolerability, whereas the increased CYP2C19 metabolic capacity is not. Therefore, it is likely that SM group does not receive the appropriate treatment under standard psychiatric practice, which is in most cases unaware of the patients’ CYP2C19 genotype. Even though this study does not have sufficient power for an unequivocal conclusion related to the need of pre-emptive CYP2C19 genotyping of antidepressant treated patients, it contributes to the body of already existing evidence on the clinical usefulness of CYP2C19 genotyping in psychiatry.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients",
volume = "1",
number = "Supplement 2",
pages = "54-55",
doi = "10.1016/j.nsa.2022.100217"
}

Joković, D., Milosavljević, F., Stojanović, Z., Šupić, G., Vojvodić, D., Jukić, M., Uzelac, B.,& Petković-Ćurčić, A.. (2022). CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients. in Neuroscience Applied
Elsevier., 1(Supplement 2), 54-55.
https://doi.org/10.1016/j.nsa.2022.100217

Joković D, Milosavljević F, Stojanović Z, Šupić G, Vojvodić D, Jukić M, Uzelac B, Petković-Ćurčić A. CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients. in Neuroscience Applied. 2022;1(Supplement 2):54-55.
doi:10.1016/j.nsa.2022.100217 .

Joković, Danilo, Milosavljević, Filip, Stojanović, Zvezdana, Šupić, Gordana, Vojvodić, Danilo, Jukić, Marin, Uzelac, Bojana, Petković-Ćurčić, Aleksandra, "CYP2C19 slow metabolizer phenotype is associated with lower antidepressant efficacy and tolerability: clinical study on 102 inpatients" in Neuroscience Applied, 1, no. Supplement 2 (2022):54-55,
https://doi.org/10.1016/j.nsa.2022.100217 . .

TY  - CONF
AU  - Vuković, Petar
AU  - Jeremić, Aleksandra
AU  - Vezmar, Milica
AU  - Pešić, Danilo
AU  - Drakulić, Jelena
AU  - Milosavljević, Filip
AU  - Miljević, Čedo
AU  - Marić-Bojović, Nađa
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4732
AB  - Background: Considering the negative impact of anxiety and depression on society and lack of emergence of new antidepressants, it is of paramount importance to utilize the available treatment options in the best manner possible. Escitalopram is a commonly prescribed antidepressant that is predominantly metabolized by the polymorphic CYP2C19 liver enzyme and consequently, CYP2C19 genotype affects escitalopram metabolism. Previous report showed a strong association between CYP2C19 genotype and escitalopram exposure [1]; therefore, CYP2C19 genotype is a potentially clinically relevant feature in escitalopram treatment, since underdosed patients exhibit lower escitalopram treatment effectiveness [2] and since escitalopram adverse drug reactions (ADR) are dose dependent [3]. Objective of this prospective cohort clinical trial is to evaluate the impact of escitalopram dose adjustment based on escitalopram exposure on treatment efficacy and safety.

Methods: In this prospective cohort study patients suffering from depression were assessed for potential clinical benefits of a personalized dosing regimen for escitalopram, which is based on therapeutic drug monitoring of escitalopram plasma level. Treatment effectiveness was evaluated based on Hamilton depression rating scale (HAM-D), which was performed one day prior to escitalopram treatment initiation (Baseline, Visit 0), as well as after four (Visit 1) and eight (Visit 2) weeks of follow-up. Side effect assessment was based on Scandinavian UKU Side effects rating scale, which was performed at V1 and V2. In case of need, dose adjustment was performed at V1 and was guided by the measured steady state drug plasma level using HPLC two weeks after treatment initiation, with the aim to achieve the optimal exposure to escitalopram in every patient at V2. Relative change in HAM-D and UKU scale readouts from V1 to V2, were compared between comparator (dose was adjusted) and control (dose was not adjusted) groups by independent samples t-test and Chi-square test, respectively. The study protocol in full detail is available on clincaltrials.gov [4]

Results: To this day, 25 participants completed the study, and out of these, 19 participants required dose adjustment between visits. There were no statistically significant differences in the change in HAM-D scores from V1 to V2 between groups (p>0.1). In the comparator group, 11/19 patients reported ADRs, compared to 2/6 patients in control group. Appearance of new, or worsening of the existing ADRs between V1 and V2 was reported in 6/19 patients in the comparator group and in 1/6 patients in the control group. There was no statistically significant difference between groups in ADR emergence or worsening (p>0.1)

Conclusion: The dose of escitalopram in 19 participants was augmented, but did not show statistically significant improvement in treatment effectiveness when compared to control group. There was no statistically significant increase in ADR frequencies in the dose augmentation group either, which is in concordance with the hypothesis that dose increase in underdosed patients does not lead to the increase of ADR frequency and severity. Noteworthy, since this report represents interim analysis on a sample which is approximately one fourth of the planned cohort, the conclusions are not yet unequivocal.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment
VL  - 1
IS  - Supplement 2
SP  - 331
EP  - 332
DO  - 10.1016/j.nsa.2022.100765
ER  - 

@conference{
author = "Vuković, Petar and Jeremić, Aleksandra and Vezmar, Milica and Pešić, Danilo and Drakulić, Jelena and Milosavljević, Filip and Miljević, Čedo and Marić-Bojović, Nađa and Jukić, Marin",
year = "2022",
abstract = "Background: Considering the negative impact of anxiety and depression on society and lack of emergence of new antidepressants, it is of paramount importance to utilize the available treatment options in the best manner possible. Escitalopram is a commonly prescribed antidepressant that is predominantly metabolized by the polymorphic CYP2C19 liver enzyme and consequently, CYP2C19 genotype affects escitalopram metabolism. Previous report showed a strong association between CYP2C19 genotype and escitalopram exposure [1]; therefore, CYP2C19 genotype is a potentially clinically relevant feature in escitalopram treatment, since underdosed patients exhibit lower escitalopram treatment effectiveness [2] and since escitalopram adverse drug reactions (ADR) are dose dependent [3]. Objective of this prospective cohort clinical trial is to evaluate the impact of escitalopram dose adjustment based on escitalopram exposure on treatment efficacy and safety.

Methods: In this prospective cohort study patients suffering from depression were assessed for potential clinical benefits of a personalized dosing regimen for escitalopram, which is based on therapeutic drug monitoring of escitalopram plasma level. Treatment effectiveness was evaluated based on Hamilton depression rating scale (HAM-D), which was performed one day prior to escitalopram treatment initiation (Baseline, Visit 0), as well as after four (Visit 1) and eight (Visit 2) weeks of follow-up. Side effect assessment was based on Scandinavian UKU Side effects rating scale, which was performed at V1 and V2. In case of need, dose adjustment was performed at V1 and was guided by the measured steady state drug plasma level using HPLC two weeks after treatment initiation, with the aim to achieve the optimal exposure to escitalopram in every patient at V2. Relative change in HAM-D and UKU scale readouts from V1 to V2, were compared between comparator (dose was adjusted) and control (dose was not adjusted) groups by independent samples t-test and Chi-square test, respectively. The study protocol in full detail is available on clincaltrials.gov [4]

Results: To this day, 25 participants completed the study, and out of these, 19 participants required dose adjustment between visits. There were no statistically significant differences in the change in HAM-D scores from V1 to V2 between groups (p>0.1). In the comparator group, 11/19 patients reported ADRs, compared to 2/6 patients in control group. Appearance of new, or worsening of the existing ADRs between V1 and V2 was reported in 6/19 patients in the comparator group and in 1/6 patients in the control group. There was no statistically significant difference between groups in ADR emergence or worsening (p>0.1)

Conclusion: The dose of escitalopram in 19 participants was augmented, but did not show statistically significant improvement in treatment effectiveness when compared to control group. There was no statistically significant increase in ADR frequencies in the dose augmentation group either, which is in concordance with the hypothesis that dose increase in underdosed patients does not lead to the increase of ADR frequency and severity. Noteworthy, since this report represents interim analysis on a sample which is approximately one fourth of the planned cohort, the conclusions are not yet unequivocal.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment",
volume = "1",
number = "Supplement 2",
pages = "331-332",
doi = "10.1016/j.nsa.2022.100765"
}

Vuković, P., Jeremić, A., Vezmar, M., Pešić, D., Drakulić, J., Milosavljević, F., Miljević, Č., Marić-Bojović, N.,& Jukić, M.. (2022). Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment. in Neuroscience Applied
Elsevier., 1(Supplement 2), 331-332.
https://doi.org/10.1016/j.nsa.2022.100765

Vuković P, Jeremić A, Vezmar M, Pešić D, Drakulić J, Milosavljević F, Miljević Č, Marić-Bojović N, Jukić M. Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment. in Neuroscience Applied. 2022;1(Supplement 2):331-332.
doi:10.1016/j.nsa.2022.100765 .

Vuković, Petar, Jeremić, Aleksandra, Vezmar, Milica, Pešić, Danilo, Drakulić, Jelena, Milosavljević, Filip, Miljević, Čedo, Marić-Bojović, Nađa, Jukić, Marin, "Effects of personalized dosing based on drug plasma level quantification on effectiveness and safety of escitalopram treatment" in Neuroscience Applied, 1, no. Supplement 2 (2022):331-332,
https://doi.org/10.1016/j.nsa.2022.100765 . .

TY  - CONF
AU  - Jeremić, Aleksandra
AU  - Vuković, Petar
AU  - Vezmar, Milica
AU  - Pešić, Danilo
AU  - Drakulić, Jelena
AU  - Milosavljević, Filip
AU  - Miljević, Čedo
AU  - Marković, Bojan
AU  - Marić-Bojović, Nađa
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4731
AB  - Background: Depression causes significant burden to the society world-wide. Escitalopram is a commonly prescribed antidepressant, predominantly metabolized by the polymorphic CYP2C19 enzyme; however, this drug isn’t always effective [1]. The CYP2C19 genotype determines the CYP2C19 enzymatic capacity and CYP2C19*2 is the main loss-of-function (Null) allele [2]. In the most psychiatric clinics worldwide, escitalopram therapy usually starts with the standard recommended dose of 10 mg/day, regardless of CYP2C19 genotype [3]. The objective of this study was the quantification of difference in the escitalopram exposure among patients between genetically associated CYP2C19 slow and normal metabolizers, considering also the body weight [4].

Methods: In this ongoing prospective cross sectional study, the drug concentration was measured in 53 outpatients treated with 10 mg of escitalopram, 2 weeks after treatment initiation, 24 hours after the last dose. Measured plasma concentration was 25-50 ng/ml was considered the ideal drug exposure. [5] If the drug concentration was 5-25 ng/ml, patients were classified as underdosed/underexposed, while patients with drug concentration <5ng/ml were classified as non-compliers and excluded from the further analysis. Patients were genotyped by polymerase chain reaction–based assay for the CYP2C19*2 allele. All participants were included from the Institute for Mental Health in Belgrade outpatient clinic and daily hospital. The patients were classified based on their CYP2C19 genotype; those carrying CYP2C19*2 variant alleles were categorized into slow metabolizer group, while non-carriers were categorized into normal metabolizer group. Difference in body weight and age between slow and metabolizer groups was analysed by the Mann-Whitney’s test. The effects of CYP2C19 metabolizer category (normal vs. slow metabolizer) and body weight on escitalopram plasma level were evaluated by the linear regression model.

Results: Out of 53 outpatients, who completed the study to date, 24 participants were slow metabolizers and 29 participants were normal metabolizers. After two weeks of treatment with 10mg of escitalopram, only 13 patients (24%) were within the therapeutic range (25-50ng/ml), no patient was underexposed, while the remaining 40 patients were underexposed. Median age body weight in the slow metabolizers group were 41 years [IQR: 27-47] and 77kg [IQR: 65-88,5], while in normal metabolizers group age and body weight were 35 years [IQR: 22-49] and 66kg [IQR: 59-88]. The drug level increase due to lower body weight and due to occurrence of CYP2C19*2 allele observed in the regression equation did not reach statistical significance.

Conclusion: While the result directionality was in accordance with the previously published studies, the effects of body weight and CYP2C19*2 allele occurrence were not significant in the analysed cohort. The absence of significant effects was likely due to still limited power of the study. Since this interim analysis includes only approximately one third of patients compared with what had been originally planned, it is expected that firmer conclusions related to the combined effect of CYP2C19 genotype and body weight on escitalopram exposure will emerge after all planned patients are included.
PB  - Elsevier
C3  - Neuroscience Applied
T1  - Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study
VL  - 1
IS  - Supplement 2
SP  - 330
EP  - 331
DO  - 10.1016/j.nsa.2022.100763
ER  - 

@conference{
author = "Jeremić, Aleksandra and Vuković, Petar and Vezmar, Milica and Pešić, Danilo and Drakulić, Jelena and Milosavljević, Filip and Miljević, Čedo and Marković, Bojan and Marić-Bojović, Nađa and Jukić, Marin",
year = "2022",
abstract = "Background: Depression causes significant burden to the society world-wide. Escitalopram is a commonly prescribed antidepressant, predominantly metabolized by the polymorphic CYP2C19 enzyme; however, this drug isn’t always effective [1]. The CYP2C19 genotype determines the CYP2C19 enzymatic capacity and CYP2C19*2 is the main loss-of-function (Null) allele [2]. In the most psychiatric clinics worldwide, escitalopram therapy usually starts with the standard recommended dose of 10 mg/day, regardless of CYP2C19 genotype [3]. The objective of this study was the quantification of difference in the escitalopram exposure among patients between genetically associated CYP2C19 slow and normal metabolizers, considering also the body weight [4].

Methods: In this ongoing prospective cross sectional study, the drug concentration was measured in 53 outpatients treated with 10 mg of escitalopram, 2 weeks after treatment initiation, 24 hours after the last dose. Measured plasma concentration was 25-50 ng/ml was considered the ideal drug exposure. [5] If the drug concentration was 5-25 ng/ml, patients were classified as underdosed/underexposed, while patients with drug concentration <5ng/ml were classified as non-compliers and excluded from the further analysis. Patients were genotyped by polymerase chain reaction–based assay for the CYP2C19*2 allele. All participants were included from the Institute for Mental Health in Belgrade outpatient clinic and daily hospital. The patients were classified based on their CYP2C19 genotype; those carrying CYP2C19*2 variant alleles were categorized into slow metabolizer group, while non-carriers were categorized into normal metabolizer group. Difference in body weight and age between slow and metabolizer groups was analysed by the Mann-Whitney’s test. The effects of CYP2C19 metabolizer category (normal vs. slow metabolizer) and body weight on escitalopram plasma level were evaluated by the linear regression model.

Results: Out of 53 outpatients, who completed the study to date, 24 participants were slow metabolizers and 29 participants were normal metabolizers. After two weeks of treatment with 10mg of escitalopram, only 13 patients (24%) were within the therapeutic range (25-50ng/ml), no patient was underexposed, while the remaining 40 patients were underexposed. Median age body weight in the slow metabolizers group were 41 years [IQR: 27-47] and 77kg [IQR: 65-88,5], while in normal metabolizers group age and body weight were 35 years [IQR: 22-49] and 66kg [IQR: 59-88]. The drug level increase due to lower body weight and due to occurrence of CYP2C19*2 allele observed in the regression equation did not reach statistical significance.

Conclusion: While the result directionality was in accordance with the previously published studies, the effects of body weight and CYP2C19*2 allele occurrence were not significant in the analysed cohort. The absence of significant effects was likely due to still limited power of the study. Since this interim analysis includes only approximately one third of patients compared with what had been originally planned, it is expected that firmer conclusions related to the combined effect of CYP2C19 genotype and body weight on escitalopram exposure will emerge after all planned patients are included.",
publisher = "Elsevier",
journal = "Neuroscience Applied",
title = "Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study",
volume = "1",
number = "Supplement 2",
pages = "330-331",
doi = "10.1016/j.nsa.2022.100763"
}

Jeremić, A., Vuković, P., Vezmar, M., Pešić, D., Drakulić, J., Milosavljević, F., Miljević, Č., Marković, B., Marić-Bojović, N.,& Jukić, M.. (2022). Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study. in Neuroscience Applied
Elsevier., 1(Supplement 2), 330-331.
https://doi.org/10.1016/j.nsa.2022.100763

Jeremić A, Vuković P, Vezmar M, Pešić D, Drakulić J, Milosavljević F, Miljević Č, Marković B, Marić-Bojović N, Jukić M. Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study. in Neuroscience Applied. 2022;1(Supplement 2):330-331.
doi:10.1016/j.nsa.2022.100763 .

Jeremić, Aleksandra, Vuković, Petar, Vezmar, Milica, Pešić, Danilo, Drakulić, Jelena, Milosavljević, Filip, Miljević, Čedo, Marković, Bojan, Marić-Bojović, Nađa, Jukić, Marin, "Association between CYP2C19 genotype and body weight with escitalopram exposure – a cross sectional study" in Neuroscience Applied, 1, no. Supplement 2 (2022):330-331,
https://doi.org/10.1016/j.nsa.2022.100763 . .

TY  - CONF
AU  - Jukić, Marin
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4484
AB  - Determining the correct dose, with the aim to achieve optimal exposure, is very
important in psychiatric clinical practice, since underexposed patients are less likely to
respond to treatment and since adverse drug reactions likelihood and severity is increased
in overexposed patients. CYP2C19 and CYP2D6 enzymes metabolize majority of psychiatric
drugs and their genetic polymorphism determines patient’s metabolic capacity. The aim was
to evaluate the clinical utility of therapeutic drug concentration monitoring and preemptive
CYP genotyping. Several retrospective and prospective cohorts of patients, with known CYP
genotype and drug levels, were analyzed with the aim to evaluate the association between
CYP2C19 and CYP2D6 metabolizer categories on drug exposure, efficacy, and tolerability.
Based on 4,700 patients, currently available CYP2D6 metabolizer categorization is not
correct and it needs revisions (1). Based on data from 8,379 patients, clinically relevant
changes in escitalopram and sertraline exposure are detected in CYP2C19 slow metabolizers,
while clinically relevant changes in aripiprazole and risperidone exposure are detected in
CYP2D6 slow metabolizers (2). Under standard dosing, almost a half of patients treated with
these four drugs are not exposed to optimal drug levels. Since such a substantial amount of
patients is wrongly dosed for these four drugs, therapeutic drug monitoring of blood
concentration, appropriate metabolizer categorization, and pre-emptive CYP genotyping can
improve treatment outcomes for these drugs.
AB  - Utvrđivanje tačne doze leka, sa ciljem da se postigne optimalna izloženost leku, je
veoma važna u psihijatrijskoj kliničkoj praksi, zato što subdozirani pacijenti lošije
odgovaraju na lek, a predozirani pacijenti bivaju izloženi neželjenim efektima češće i
neželjeni efekti su intenzivniji. CYP2C19 i CYP2D6 enzimi metabolišu većinu psihijatrijskih
lekova i genetski polimorfizam na odgovarajućim genima određuje metabolički kapacitet
pacijenta. Cilj je bio da se oceni klinička korisnost terapeutskog praćenja koncentracije leka i
genotipizacije CYP gena. Nekoliko retrospektivnih i prospektivnih kohorti pacijenata, sa
poznatim vrednostima koncentracije leka i CYP genotipom su analizirani sa ciljem evaluacije
i kvantifikacije uticaja CYP2C19 i CYP2D6 metaboličkih kategorija na izloženost
psihijatrijskim lekovima, kao i na efikasnost i sigurnost terapije ovim lekovima. Na osnovu
podataka dobijenih na 4.700 pacijenata, trenutno važeća klasifikacija CYP2D6 metaboličkih
kategorija nije tačna i potrebno ju je izmeniti (1). Na osnovu podataka dobijenih na 8.379
pacijenata, klinički značajne promene izloženosti escitalopramu i sertralinu su primećene
kod CYP2C19 sporih metabolizera, dok su klinički značajne promene izloženosti aripiprazolu
i risperidonu primećene kod CYP2D6 sporih metabolizera (2). Pod standardnim doznim
režimom, gotovo polovina pacijenata nije izložena optimalnoj koncentraciji ova četiri leka.
Budući da je značajan broj pacijenata pod terapijom pogrešnom dozom ova četiri leka,
terapeutsko praćenje nivoa leka u krvi, adekvatna kategorizacija metabolizera i CYP
genotipizacija pre početka terapije mogu da poboljšaju ishod terapije ovim lekovima.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Utility of molecular diagnostic tools in improving personalized dosing of psychiatric drugs
T1  - Unapređenje personalizacije doziranja psihijatrijskih lekova uz pomoć molekularne dijagnostike
VL  - 72
IS  - 4 suplement
SP  - S165
EP  - S166
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4484
ER  - 

@conference{
author = "Jukić, Marin",
year = "2022",
abstract = "Determining the correct dose, with the aim to achieve optimal exposure, is very
important in psychiatric clinical practice, since underexposed patients are less likely to
respond to treatment and since adverse drug reactions likelihood and severity is increased
in overexposed patients. CYP2C19 and CYP2D6 enzymes metabolize majority of psychiatric
drugs and their genetic polymorphism determines patient’s metabolic capacity. The aim was
to evaluate the clinical utility of therapeutic drug concentration monitoring and preemptive
CYP genotyping. Several retrospective and prospective cohorts of patients, with known CYP
genotype and drug levels, were analyzed with the aim to evaluate the association between
CYP2C19 and CYP2D6 metabolizer categories on drug exposure, efficacy, and tolerability.
Based on 4,700 patients, currently available CYP2D6 metabolizer categorization is not
correct and it needs revisions (1). Based on data from 8,379 patients, clinically relevant
changes in escitalopram and sertraline exposure are detected in CYP2C19 slow metabolizers,
while clinically relevant changes in aripiprazole and risperidone exposure are detected in
CYP2D6 slow metabolizers (2). Under standard dosing, almost a half of patients treated with
these four drugs are not exposed to optimal drug levels. Since such a substantial amount of
patients is wrongly dosed for these four drugs, therapeutic drug monitoring of blood
concentration, appropriate metabolizer categorization, and pre-emptive CYP genotyping can
improve treatment outcomes for these drugs., Utvrđivanje tačne doze leka, sa ciljem da se postigne optimalna izloženost leku, je
veoma važna u psihijatrijskoj kliničkoj praksi, zato što subdozirani pacijenti lošije
odgovaraju na lek, a predozirani pacijenti bivaju izloženi neželjenim efektima češće i
neželjeni efekti su intenzivniji. CYP2C19 i CYP2D6 enzimi metabolišu većinu psihijatrijskih
lekova i genetski polimorfizam na odgovarajućim genima određuje metabolički kapacitet
pacijenta. Cilj je bio da se oceni klinička korisnost terapeutskog praćenja koncentracije leka i
genotipizacije CYP gena. Nekoliko retrospektivnih i prospektivnih kohorti pacijenata, sa
poznatim vrednostima koncentracije leka i CYP genotipom su analizirani sa ciljem evaluacije
i kvantifikacije uticaja CYP2C19 i CYP2D6 metaboličkih kategorija na izloženost
psihijatrijskim lekovima, kao i na efikasnost i sigurnost terapije ovim lekovima. Na osnovu
podataka dobijenih na 4.700 pacijenata, trenutno važeća klasifikacija CYP2D6 metaboličkih
kategorija nije tačna i potrebno ju je izmeniti (1). Na osnovu podataka dobijenih na 8.379
pacijenata, klinički značajne promene izloženosti escitalopramu i sertralinu su primećene
kod CYP2C19 sporih metabolizera, dok su klinički značajne promene izloženosti aripiprazolu
i risperidonu primećene kod CYP2D6 sporih metabolizera (2). Pod standardnim doznim
režimom, gotovo polovina pacijenata nije izložena optimalnoj koncentraciji ova četiri leka.
Budući da je značajan broj pacijenata pod terapijom pogrešnom dozom ova četiri leka,
terapeutsko praćenje nivoa leka u krvi, adekvatna kategorizacija metabolizera i CYP
genotipizacija pre početka terapije mogu da poboljšaju ishod terapije ovim lekovima.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Utility of molecular diagnostic tools in improving personalized dosing of psychiatric drugs, Unapređenje personalizacije doziranja psihijatrijskih lekova uz pomoć molekularne dijagnostike",
volume = "72",
number = "4 suplement",
pages = "S165-S166",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4484"
}

Jukić, M.. (2022). Utility of molecular diagnostic tools in improving personalized dosing of psychiatric drugs. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S165-S166.
https://hdl.handle.net/21.15107/rcub_farfar_4484

Jukić M. Utility of molecular diagnostic tools in improving personalized dosing of psychiatric drugs. in Arhiv za farmaciju. 2022;72(4 suplement):S165-S166.
https://hdl.handle.net/21.15107/rcub_farfar_4484 .

Jukić, Marin, "Utility of molecular diagnostic tools in improving personalized dosing of psychiatric drugs" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S165-S166,
https://hdl.handle.net/21.15107/rcub_farfar_4484 .

TY  - JOUR
AU  - Stanić, Dušanka
AU  - Oved, Keren
AU  - Israel-Elgali, Ifat
AU  - Jukić, Marin
AU  - Batinić, Bojan
AU  - Puškaš, Nela
AU  - Shomron, Noam
AU  - Gurwitz, David
AU  - Pešić, Vesna
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3883
AB  - Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.
PB  - Elsevier Ltd
T2  - Psychoneuroendocrinology
T1  - Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy
VL  - 129
DO  - 10.1016/j.psyneuen.2021.105234
ER  - 

@article{
author = "Stanić, Dušanka and Oved, Keren and Israel-Elgali, Ifat and Jukić, Marin and Batinić, Bojan and Puškaš, Nela and Shomron, Noam and Gurwitz, David and Pešić, Vesna",
year = "2021",
abstract = "Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.",
publisher = "Elsevier Ltd",
journal = "Psychoneuroendocrinology",
title = "Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy",
volume = "129",
doi = "10.1016/j.psyneuen.2021.105234"
}

Stanić, D., Oved, K., Israel-Elgali, I., Jukić, M., Batinić, B., Puškaš, N., Shomron, N., Gurwitz, D.,& Pešić, V.. (2021). Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy. in Psychoneuroendocrinology
Elsevier Ltd., 129.
https://doi.org/10.1016/j.psyneuen.2021.105234

Stanić D, Oved K, Israel-Elgali I, Jukić M, Batinić B, Puškaš N, Shomron N, Gurwitz D, Pešić V. Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy. in Psychoneuroendocrinology. 2021;129.
doi:10.1016/j.psyneuen.2021.105234 .

Stanić, Dušanka, Oved, Keren, Israel-Elgali, Ifat, Jukić, Marin, Batinić, Bojan, Puškaš, Nela, Shomron, Noam, Gurwitz, David, Pešić, Vesna, "Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy" in Psychoneuroendocrinology, 129 (2021),
https://doi.org/10.1016/j.psyneuen.2021.105234 . .

TY  - JOUR
AU  - Jeremić, Aleksandra
AU  - Milosavljević, Filip
AU  - Vladimirov, Sandra
AU  - Batinić, Bojan
AU  - Marković, Bojan
AU  - Jukić, Marin
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4733
AB  - Simultaneous quantification of multiple psychiatric drugs is important for the therapeutic
drug monitoring of psychiatric patients. In addition, it would be highly advantageous if the
method could be simple, straightforward, and not time-consuming. A 200 µl plasma sample was
deproteinized, drugs were separated by a ZORBAX Eclipse XDB-Phenyl column with the
mobile phase composed of acetonitrile and 0.1 % formic acid in water (60:40, v/v), and recorded
in the MRM mode by using a positive electrospray source with tandem mass spectrometry
detection. The dynamic range was 2–256 ng/ml for all the analyzed drugs, except escitalopram
(8-256 ng/ml). Quality control samples were prepared in quintuplicates in three relevant
concentrations for each drug. Coefficients of determination (R2
) were higher than 0.99, while the
relative difference between nominal and measured concentrations (RE) and CV were lower than
15% for all targets. High performance liquid chromatography coupled with the mass detector
(HPLC-MS/MS) method for simultaneous determination of sertraline, escitalopram, risperidone
366
and paliperidone in human plasma was validated with respect to selectivity, linearity, accuracy,
precision, matrix effect and stability. This method has significant advantages in terms of low
sample volume (200 µl), short preparation time (3 hours) and short runtime per sample (4
minutes).
AB  - Simultana kvantifikacija većeg broja psihijatrijskih lekova je 
važna za terapijsko praćenje 
psihijatrijskih  pacijenata.  Takođe
,  od  značaja  iz  praktičnih  ra
zloga  bi  bilo  da  metoda  bude 
jednostavna,  laka  za  izvođenje  i 
da  ne  zahteva  puno  vremena.  Uz
orak  plazme  (200  μl)  je 
deproteinizovan i izvršeno je h
romatografsko razdvajanje lekova
 na 
ZORBAX Eclipse XDB-
Phenyl  koloni  sa  mobilnom  fazom  sačinjenom  od  acetonitrila  i  vo
denog  rastvora 
0,1% 
mravlje kiseline
 (
60:40, v/v). Maseni spektri snimani su u MRM modu korišćenjem i
zvora sa 
elektrosprej pozitivnom jonizacijom i tandemske masene detekcij
e. Ispitivani opseg koncentracija 
bio je 2–256 ng/ml za sve analizirane lekove, osim za escitalop
ram, gde je bio 8-256 ng/ml. 
Kontrolni  uzorci  su  pripremani  u
  kvintuplikatu  u  tri  relevantne
  koncentracije  za  svaki  lek. 
Determinacioni koeficijenti (R
2
) bili su veći od 0,99, dok su relativna razlika između nominal
nih 
i merenih koncentracija (RV) i koeficijent varijacije (CV) bili
 manji od 15% za sve analite. 
Metoda  tečne  hromatografije  visoki
h  performansi  uparena  sa  tand
em  masenim  detektorom 
(HPLC-MS/MS) je validirana u pogledu selektivnosti, linearnosti
, tačnosti, preciznosti, efekata 
matriksa  i  stabilnosti  za  simultano  određivanje 
sertralina,  escitaloprama,  risperidona  i 
paliperidona u humanoj plazmi. Metoda zahteva malu zapreminu uz
orka (200 μl), kratke pripreme 
uzorka (3 sata) i kratko vreme tr
ajanja pojedinačnog merenja (4
 minuta).
T2  - Arhiv za farmaciju
T1  - Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma
T1  - Validacija brze i jednostavne hromatografske 
metode za simultanu kvantifikaciju nivoa 
sertralina, escitaloprama, risperidona i 
paliperidona u humanoj plazmi
VL  - 71
IS  - 5
SP  - 365
EP  - 377
DO  - 10.5937/arhfarm71-31163
ER  - 

@article{
author = "Jeremić, Aleksandra and Milosavljević, Filip and Vladimirov, Sandra and Batinić, Bojan and Marković, Bojan and Jukić, Marin",
year = "2021",
abstract = "Simultaneous quantification of multiple psychiatric drugs is important for the therapeutic
drug monitoring of psychiatric patients. In addition, it would be highly advantageous if the
method could be simple, straightforward, and not time-consuming. A 200 µl plasma sample was
deproteinized, drugs were separated by a ZORBAX Eclipse XDB-Phenyl column with the
mobile phase composed of acetonitrile and 0.1 % formic acid in water (60:40, v/v), and recorded
in the MRM mode by using a positive electrospray source with tandem mass spectrometry
detection. The dynamic range was 2–256 ng/ml for all the analyzed drugs, except escitalopram
(8-256 ng/ml). Quality control samples were prepared in quintuplicates in three relevant
concentrations for each drug. Coefficients of determination (R2
) were higher than 0.99, while the
relative difference between nominal and measured concentrations (RE) and CV were lower than
15% for all targets. High performance liquid chromatography coupled with the mass detector
(HPLC-MS/MS) method for simultaneous determination of sertraline, escitalopram, risperidone
366
and paliperidone in human plasma was validated with respect to selectivity, linearity, accuracy,
precision, matrix effect and stability. This method has significant advantages in terms of low
sample volume (200 µl), short preparation time (3 hours) and short runtime per sample (4
minutes)., Simultana kvantifikacija većeg broja psihijatrijskih lekova je 
važna za terapijsko praćenje 
psihijatrijskih  pacijenata.  Takođe
,  od  značaja  iz  praktičnih  ra
zloga  bi  bilo  da  metoda  bude 
jednostavna,  laka  za  izvođenje  i 
da  ne  zahteva  puno  vremena.  Uz
orak  plazme  (200  μl)  je 
deproteinizovan i izvršeno je h
romatografsko razdvajanje lekova
 na 
ZORBAX Eclipse XDB-
Phenyl  koloni  sa  mobilnom  fazom  sačinjenom  od  acetonitrila  i  vo
denog  rastvora 
0,1% 
mravlje kiseline
 (
60:40, v/v). Maseni spektri snimani su u MRM modu korišćenjem i
zvora sa 
elektrosprej pozitivnom jonizacijom i tandemske masene detekcij
e. Ispitivani opseg koncentracija 
bio je 2–256 ng/ml za sve analizirane lekove, osim za escitalop
ram, gde je bio 8-256 ng/ml. 
Kontrolni  uzorci  su  pripremani  u
  kvintuplikatu  u  tri  relevantne
  koncentracije  za  svaki  lek. 
Determinacioni koeficijenti (R
2
) bili su veći od 0,99, dok su relativna razlika između nominal
nih 
i merenih koncentracija (RV) i koeficijent varijacije (CV) bili
 manji od 15% za sve analite. 
Metoda  tečne  hromatografije  visoki
h  performansi  uparena  sa  tand
em  masenim  detektorom 
(HPLC-MS/MS) je validirana u pogledu selektivnosti, linearnosti
, tačnosti, preciznosti, efekata 
matriksa  i  stabilnosti  za  simultano  određivanje 
sertralina,  escitaloprama,  risperidona  i 
paliperidona u humanoj plazmi. Metoda zahteva malu zapreminu uz
orka (200 μl), kratke pripreme 
uzorka (3 sata) i kratko vreme tr
ajanja pojedinačnog merenja (4
 minuta).",
journal = "Arhiv za farmaciju",
title = "Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma, Validacija brze i jednostavne hromatografske 
metode za simultanu kvantifikaciju nivoa 
sertralina, escitaloprama, risperidona i 
paliperidona u humanoj plazmi",
volume = "71",
number = "5",
pages = "365-377",
doi = "10.5937/arhfarm71-31163"
}

Jeremić, A., Milosavljević, F., Vladimirov, S., Batinić, B., Marković, B.,& Jukić, M.. (2021). Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma. in Arhiv za farmaciju, 71(5), 365-377.
https://doi.org/10.5937/arhfarm71-31163

Jeremić A, Milosavljević F, Vladimirov S, Batinić B, Marković B, Jukić M. Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma. in Arhiv za farmaciju. 2021;71(5):365-377.
doi:10.5937/arhfarm71-31163 .

Jeremić, Aleksandra, Milosavljević, Filip, Vladimirov, Sandra, Batinić, Bojan, Marković, Bojan, Jukić, Marin, "Validation of a quick and simple chromatographic method for simultaneous quantification of sertraline, escitalopram, risperidone and paliperidone levels in the human plasma" in Arhiv za farmaciju, 71, no. 5 (2021):365-377,
https://doi.org/10.5937/arhfarm71-31163 . .

TY  - JOUR
AU  - Molden, Espen
AU  - Jukić, Marin
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3884
AB  - Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.
PB  - Frontiers Media S.A.
T2  - Frontiers in Pharmacology
T1  - CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry
VL  - 12
DO  - 10.3389/fphar.2021.650750
ER  - 

@article{
author = "Molden, Espen and Jukić, Marin",
year = "2021",
abstract = "Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Pharmacology",
title = "CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry",
volume = "12",
doi = "10.3389/fphar.2021.650750"
}

Molden, E.,& Jukić, M.. (2021). CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry. in Frontiers in Pharmacology
Frontiers Media S.A.., 12.
https://doi.org/10.3389/fphar.2021.650750

Molden E, Jukić M. CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry. in Frontiers in Pharmacology. 2021;12.
doi:10.3389/fphar.2021.650750 .

Molden, Espen, Jukić, Marin, "CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry" in Frontiers in Pharmacology, 12 (2021),
https://doi.org/10.3389/fphar.2021.650750 . .

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  - Kapor, Slobodan
AU  - Aksić, Milan
AU  - Puškaš, Laslo
AU  - Jukić, Marin
AU  - Poleksić, Joko
AU  - Milosavljević, Filip
AU  - Bjelica, Suncica
AU  - Filipović, Branislav
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3735
AB  - Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.
PB  - Frontiers Media S.A.
T2  - Frontiers in Neuroanatomy
T1  - Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats
VL  - 14
DO  - 10.3389/fnana.2020.578900
ER  - 

@article{
author = "Kapor, Slobodan and Aksić, Milan and Puškaš, Laslo and Jukić, Marin and Poleksić, Joko and Milosavljević, Filip and Bjelica, Suncica and Filipović, Branislav",
year = "2020",
abstract = "Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.",
publisher = "Frontiers Media S.A.",
journal = "Frontiers in Neuroanatomy",
title = "Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats",
volume = "14",
doi = "10.3389/fnana.2020.578900"
}

Kapor, S., Aksić, M., Puškaš, L., Jukić, M., Poleksić, J., Milosavljević, F., Bjelica, S.,& Filipović, B.. (2020). Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats. in Frontiers in Neuroanatomy
Frontiers Media S.A.., 14.
https://doi.org/10.3389/fnana.2020.578900

Kapor S, Aksić M, Puškaš L, Jukić M, Poleksić J, Milosavljević F, Bjelica S, Filipović B. Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats. in Frontiers in Neuroanatomy. 2020;14.
doi:10.3389/fnana.2020.578900 .

Kapor, Slobodan, Aksić, Milan, Puškaš, Laslo, Jukić, Marin, Poleksić, Joko, Milosavljević, Filip, Bjelica, Suncica, Filipović, Branislav, "Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats" in Frontiers in Neuroanatomy, 14 (2020),
https://doi.org/10.3389/fnana.2020.578900 . .

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 . .