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Skogh, Elisabeth
Publications (10 of 13) Show all publications
Schwieler, L., Larsson, M. K., Skogh, E., Kegel, M. E., Orhan, F., Abdelmoaty, S., . . . Engberg, G. (2015). Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway.. Journal of Psychiatry & Neuroscience, 40(2), 126-13
Open this publication in new window or tab >>Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia - significance for activation of the kynurenine pathway.
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2015 (English)In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 40, no 2, p. 126-13Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway.

METHODS: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were analyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry.

RESULTS: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA.

LIMITATIONS: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age.

CONCLUSION: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-D-aspartate receptor antagonist KYNA in patients with schizophrenia.

Place, publisher, year, edition, pages
CMA-CANADIAN MEDICAL ASSOC, 2015
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-116363 (URN)10.1503/jpn.140126 (DOI)000351206800008 ()25455350 (PubMedID)
Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-01-11Bibliographically approved
Kegel, M. E., Bhat, M., Skogh, E., Samuelsson, M., Lundberg, K., Dahl, M.-L., . . . Erhardt, S. (2014). Imbalanced Kynurenine Pathway in Schizophrenia. International Journal of Tryptophan Research, 7, 15-22
Open this publication in new window or tab >>Imbalanced Kynurenine Pathway in Schizophrenia
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2014 (English)In: International Journal of Tryptophan Research, ISSN 1178-6469, Vol. 7, p. 15-22Article in journal (Refereed) Published
Abstract [en]

Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls (P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.

Place, publisher, year, edition, pages
Libertas Academica, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-110785 (URN)10.4137/IJTR.S16800 (DOI)
Available from: 2014-09-22 Created: 2014-09-22 Last updated: 2017-12-05Bibliographically approved
Samuelsson, M., Skogh, E., Lundberg, K., Vrethem, M. & Öllinger, K. (2013). Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia. Psychiatry Research, 210(3), 819-824
Open this publication in new window or tab >>Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia
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2013 (English)In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 210, no 3, p. 819-824Article in journal (Refereed) Published
Abstract [en]

Objectives: Oxidative stress has been implicated in the pathophysiology of schizophrenia. Taurine and glutathione (GSH) have antioxidant and central nervous system protective properties and are proposed to be involved in the pathology of schizophrenia. The aim of this study was to compare the blood and cerebrospinal fluid (CSF) levels of taurine and GSH in patients with schizophrenia medicated with oral olanzapine compared with controls.

Methods: In total, 37 patients with schizophrenia being medicated with olanzapine and 45 healthy volunteers were recruited. Taurine and GSH levels were analysed in plasma and CSF and correlated to symptoms and level of function.

Results: Plasma taurine levels were elevated in patients compared with controls (p=0.000003). No differences were found between patients and controls regarding taurine in CSF or GSH concentrations in plasma and CSF.

Conclusion: The significantly higher levels of plasma but not CSF taurine in patients with schizophrenia treated with olanzapine compared with controls may implicate the involvement of taurine in the pathophysiology of the disease. The absence of GSH differences in plasma and CSF between patients and controls is interesting in the perspective of earlier research proposing a dysregulation of GSH metabolism as a vulnerability factor for the development of schizophrenia.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Glutathione; taurine; schizophrenia; cerebrospinal fluid; olanzapine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84601 (URN)10.1016/j.psychres.2013.09.014 (DOI)000329417500024 ()
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
Linderholm, K. R., Skogh, E., Olsson, S. K., Dahl, M.-L., Holtze, M., Engberg, G., . . . Erhardt, S. (2012). Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia. Schizophrenia Bulletin, 38(3), 426-432
Open this publication in new window or tab >>Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia
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2012 (English)In: Schizophrenia Bulletin, ISSN 0586-7614, E-ISSN 1745-1701, Vol. 38, no 3, p. 426-432Article in journal (Refereed) Published
Abstract [en]

Background: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and alpha7* nicotinic receptors. Methods: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n = 16) was compared with healthy male volunteers (n = 29). Results: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 +/- 4.37nM and 2.03 +/- 0.23nM, respectively) compared with healthy volunteers (28.6 +/- 1.44nM and 1.36 +/- 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. Conclusion: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.

Place, publisher, year, edition, pages
Oxford University Press, 2012
Keywords
psychosis, kynurenate, olanzapine, cerebrospinal fluid, tryptophan
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66972 (URN)10.1093/schbul/sbq086 (DOI)000303169000011 ()20729465 (PubMedID)
Available from: 2011-03-23 Created: 2011-03-23 Last updated: 2017-12-11
Mao, M., Skogh, E., Scordo, M. G. & Dahl, M.-L. (2012). Letter: Interindividual Variation in Olanzapine Concentration Influenced by UGT1A4 L48V Polymorphism in Serum and Upstream FMO Polymorphisms in Cerebrospinal Fluid [Letter to the editor]. Journal of Clinical Psychopharmacology, 32(2), 287-289
Open this publication in new window or tab >>Letter: Interindividual Variation in Olanzapine Concentration Influenced by UGT1A4 L48V Polymorphism in Serum and Upstream FMO Polymorphisms in Cerebrospinal Fluid
2012 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 32, no 2, p. 287-289Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Lippincott, Williams and Wilkins, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76186 (URN)10.1097/JCP.0b013e31824997a8 (DOI)000301121100023 ()
Available from: 2012-03-31 Created: 2012-03-30 Last updated: 2017-12-07Bibliographically approved
Skogh, E., Sjödin, I., Josefsson, M. & Dahl, M.-L. (2011). High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug. Journal of Clinical Psychopharmacology, 31(1), 4-9
Open this publication in new window or tab >>High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug
2011 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 31, no 1, p. 4-9Article in journal (Refereed) Published
Abstract [en]

The primary aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) concentrations of olanzapine (OLA) and its metabolite 4-N-desmethylolanzapine (DMO) in patients with schizophrenia or schizoaffective disorder treated with oral OLA as the only antipsychotic drug. The influence of smoking, gender, age, as well as polymorphisms in cytochrome P450 CYP2D6, CYP1A2, and ABCB1 genes on the serum and CSF drug levels was also analyzed. Thirty-seven white outpatients (10 smokers and 27 nonsmokers) were included. From 29 of them, CSF was collected successfully. A strong correlation (Spearman rank correlation [r(s)] = 0.93; P = 0.05) was found between serum and CSF concentrations of OLA and a somewhat weaker correlation (r(s) = 0.5; P = 0.05) between those of DMO. The CSF concentrations of OLA and DMO were on average 12% and 16% of those in serum. Extensive metabolizers of CYP2D6 had higher (P = 0.05) daily doses than poor metabolizers when the influence of smoking was taken into account. Smokers had lower (P = 0.01) concentration-to-dose ratios of OLA in serum (mean, 2.23 ng/mL per mg vs 3.32 ng/mL per mg) and CSF (0.27 ng/mL per mg vs 0.41 ng/mL per mg) than nonsmokers. The concentration-to-dose ratio for serum DMO decreased with increasing age (r(s) = -0.41; P = 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (mean, 37.7 ng/mL vs 22.5 ng/mL; P = 0.035) and CSF (4.7 ng/mL vs 2.6 ng/mL; P = 0.018) OLA concentrations than patients without this haplotype. The present study shows a strong correlation between serum and CSF concentrations of OLA, indicating that concentrations of OLA in serum reflect those in CSF.

Place, publisher, year, edition, pages
Williams and Wilkins, 2011
Keywords
olanzapine, smoking, serum concentration, cerebrospinal fluid, pharmacogenetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64762 (URN)10.1097/JCP.0b013e318204d9e2 (DOI)000285771000002 ()
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2017-12-11Bibliographically approved
Skogh, E. (2011). Studies on Variability in Olanzapine Disposition. (Licentiate dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Studies on Variability in Olanzapine Disposition
2011 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Schizophrenia and schizoaffective disorders are chronic conditions with a significant impact on many functions. Positive, negative, cognitive and motor symptoms appear in different degrees and constellations. Antipsychotics are of fundamental importance to reduce symptoms. However, insufficient clinical effect and adverse drug reactions (ADRs) are important limitations of this drug therapy. Olanzapine (OLA) is a second-generation antipsychotic (SGA) drug widely used in the treatment of schizophrenia and schizoaffective disorder. The drug has well-documented effects against positive symptoms and has been claimed to be efficacious also against negative symptoms.

This thesis comprises of two studies. The aim of study 1 was to investigate factors that may influence the inter- and intra-individual variability of steady-state trough concentrations of OLA and its N-desmethyl metabolite (DMO) in serum. This was done in a cohort of patients treated with oral OLA in a routine clinical setting. In study 2 steady-state trough serum OLA and DMO concentrations were studied in relation to cerebrospinal fluid (CSF) OLA and DMO concentrations in patients with schizophrenia or schizoaffective disorder, medicated with oral OLA as the only antipsychotic drug. We also analysed the effects of age, gender smoking and concomitant medication in both studies and in study 2 we also analysed polymorphisms in genes with suggested importance for OLA disposition. The drug metabolizing enzymes CYP1A2 and CYP2D6 have earlier been found to be of importance for OLA metabolism and one animal study has suggested a role for P-gp for the transport of OLA into the brain. Therefore we analysed the influence of single nucleotide polymorphisms in the CYP1A2 gene (-3860G>A, -2467T>delT, -739T>G, -729C>T, -163C>A, and in the CYP2D6 gene (*3, *4, *5,*6, and*41) and in the ABCB1 gene (1236C>T, 3435C>T, and 2677G>A/T).

Study 1 started as a post-marketing surveillance project. In 1997 a high-performance liquid chromatography (HPLC)-based therapeutic drug monitoring (TDM) routine for serum OLA and DMO was established. During 1997–1999, a total of 753 TDM requests for a total of 545 Swedish patients were analysed. Additional patient information on certain clinical variables was collected on a specifically designed TDM request form. Samples from 194 patients were found to be eligible for further scrutiny. We found that the concentration-to-dose ratio (C/D) for OLA varied 25-fold and that of DMO 22-fold between individuals. The intraindividual variability over time was lower. Women had significantly higher median C/D ratio for OLA than men. However, the higher C/D ratio for OLA in women was statistically significant only in the non-smoking group. Non-smokers had significantly higher C/D ratio for OLA than smokers. Smokers received significantly higher daily doses of OLA than non-smokers. In the group with reported ADRs, the serum OLA concentration was 22% higher than in the group without ADRs. Patients co-medicated with carbamazepine had a 71% lower C/D ratio for OLA than patients who did not co-medicate with carbamazepine.

Study 2 included 37 Caucasian outpatients (10 smokers and 27 non-smokers). CSF was collected from 29 out of them. Because of very low OLA and DMO concentrations in CSF, a new liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for determination of OLA and DMO in serum and CSF was developed. We found a strong correlation between serum and CSF concentrations of OLA and a somewhat weaker corresponding correlation regarding DMO. The median CSF concentrations of OLA and DMO were on an average 13% and 16% of the serum levels. Non-smokers had higher (P <0.01) C/D ratio for OLA in serum and in CSF than smokers. Extensive metabolizers (EM) of CYP2D6 had higher daily OLA dosages than poor metabolizers (PM) when the influence of smoking was taken into account. EM smokers also showed lower CSF C/D for DMO than PM smokers. The DMO/OLA ratio in CSF showed a similar pattern, with a statistically significant combined effect of smoking and CYP2D6 genotype, EM smokers having the lowest and PM smokers the highest ratio. The combination of smoking and CYP2D6 genotype also affected the CSF/serum DMO ratio, PM smokers having the highest and EM smokers the lowest ratio (mean 20%, vs 9.5%). Patients co-medicating with benzodiazepines also showed higher CSF DMO/OLA ratio than patients without benzodiazepines. Moreover, DMO concentrations in CSF in relation to serum were higher in benzodiazepine users than in patients not comedicating with benzodiazepines (mean 24% vs 14.4%). Smoking habits did not affect these results. Carriers of the ABCB1 1236T/2677T/3435T haplotype had higher serum and CSF OLA concentrations than patients without this haplotype. The C/D ratios for serum DMO decreased with increasing age (P < 0.05).

In summary, smoking habits and co-medication with carbamazepine should be taken into consideration when dosing OLA. In study 1 we noted that women had higher serum C/D OLA ratio than men among non-smokers. This could not be confirmed in study 2, probably due to the small study population. Polymorphisms in genes of importance for OLA metabolism (CYP1A2 and CYP2D6) and transport (ABCB1) over membranes have some, but probably a minor, effect on serum and CSF concentrations. Larger studies are needed to confirm these observations. Smoking in combination with CYP2D6 polymorphism and the use of benzodiazepines affected the DMO metabolism in the brain in this study. However, because of low precision in the method at low DMO concentrations and a low number of patients, these results must also be confirmed in larger studies. The strong correlation between serum and CSF OLA concentrations established in study 2 indicates that factors influencing serum concentrations (such as smoking) also influence these concentrations in CSF. When patients are non-responsive to treatment, not compliant, vulnerable to ADRs on standard doses, or when drug interactions are suspected, TDM serum-OLA concentrations can be used as a diagnostic tool. Therapeutic drug monitoring is also of value to optimize long-term treatment of patients as environmental factors such as smoking and drug interactions may differ over time and could markedly interact with a patient´s metabolic capacity and thereby the therapeutic outcome.

Abstract [sv]

Schizofreni och schizoaffektiv sjukdom är livslånga tillstånd som oftast medför påtaglig funktionsnedsättning och betydande lidande både för patienten och närstående. Trots att antipsykotika är avgörande för behandlingsframgång vid dessa sjukdomar förekommer inte sällan problem med bristande behandlingseffekt och/eller biverkningar. Olanzapin (OLA) är ett läkemedel godkänt för akut- och underhållsbehandling av schizofreni och schizoaffektiv sjukdom. OLA blev godkänt för allmän förskrivning i Sverige 1996.

Det övergripande syftet med detta projekt var att undersöka variation i omsättningen av OLA och dess metabolit N-desmetylolanzapin (DMO) vid behandling av patienter med schizofreni eller schizoaffektiv sjukdom. Projektet utgörs av två delstudier. Studie 1 syftade till att klargöra hur OLA- och DMO-koncentrationer varierar i blodet mellan individer och inom individer vid upprepade mätningar. Syftet med studie 2 var att utforska om det fanns någon korrelation mellan OLA- och DMO-koncentrationer i serum och i likvor hos patienter som behandlades med enbart OLA som antipsykotiskt läkemedel. Effekten av rökning, kön, ålder och eventuell annan pågående medicinering undersöktes i båda studierna. I arbete 2 analyserades även samband till varianter av gener som kodar för läkemedelsmetabolism (CYP2D6, CYP1A2) och läkemedelstransport (ABCB1).

Materialet till studie 1 insamlades under 1997-1999. Med vätskekromatografi analyserades OLA- och DMO-koncentrationer i 753 serumprover från 545 patienter. Kliniska data registrerades enligt ett strukturerat protokoll. För de 194 patienter där provet var korrekt taget (jämvikt, dalvärde) och där relevant klinisk information fanns tillgänglig gjordes ytterligare dataanalys. Vi fann att förhållandet mellan serumkoncentration och OLA dos (C/D OLA) varierade 25-faldigt och C/D DMO varierade 22-faldigt mellan individer. Kvinnor hade signifikant högre C/D OLA än män och icke-rökare hade högre C/D OLA än rökare. Rökare ordinerades högre doser av OLA än icke-rökare. I gruppen med rapporterade biverkningar var medianvärdet av OLA i serum 22 % högre än i gruppen utan biverkningar. Patienter som samtidigt medicinerade med karbamazepin hade ett 71% lägre medianvärde av C/D OLA än patienter utan karbamazepinmedicinering. Variabiliteten av C/D OLA var lägre inom individer vid upprepade mätningar vid olika tillfällen än mellan individer.

I studie 2 inkluderades 37 svenska polikliniska patienter (10 rökare och 27 icke-rökare). Från 29 avdessa erhölls likvor via lumbalpunktion. Vi fann stark korrelation mellan OLA-koncentration iserum och likvor och något svagare korrelation mellan serum- och likvorkoncentration av DMO. Likvorkoncentrationerna av OLA och DMO var i genomsnitt 12% respektive 16% avkoncentrationerna i serum. Icke-rökare hade högre C/D OLA i serum och likvor än rökare.Snabba metaboliserare via CYP2D6 förskrevs högre dagliga doser än långsammametaboliserare när hänsyn togs till rökvanor. Rökande långsamma metaboliserare hade högreC/D DMO i likvor, högre DMO/OLA ratio och högre likvor/serum DMO än rökande snabbametaboliserare. Även patienter som samtidigt medicinerade med bensodiazepiner hade högreCSF DMO/OLA ratio och högre likvor/serum DMO än patienter som inte medicinerade medbensodiazepiner. Bärare av haplotypen 1236T/2677T/3435T för ABCB1 hade högre serumochlikvorkoncentrationer av OLA än patienter utan denna haplotyp. C/D DMO minskademed ökande ålder.

Sammanfattningsvis fann vi att rökvanor och samtidig medicinering med karbamazepin påverkar metabolismen av OLA, vilket ska beaktas vid dosering av OLA. I studie 1 visade serumanalyser högre C/D OLA hos kvinnor än hos män. Denna könsskillnad var statistiskt signifikant enbart för icke rökare. Genetiska varianter av de metaboliserande enzymerna CYP2D6 och CYP1A2 hade en viss, men till synes underordnad, effekt. De effekter vi noterade avseende likvoromsättningen av DMO hos rökande långsamma metaboliserare samt hos patienter som använde bensodiazepiner måste undersökas närmare i framtida studier pga. viss metodosäkerhet vid låga DMO-koncentrationer. Det fanns en stark korrelation mellan serum- och likvorkoncentrationer av OLA och en något svagare motsvarande korrelation för DMO. Resultaten talar för att koncentrationer av OLA i serum reflekterar dem i likvor. Den intraindividuella variabiliteten av C/D OLA var som väntat lägre än den interindividuella variabiliteten. OLA-behandling kan betraktas som förutsägbart i så måtto att vid ökad dosering ökar likvorkoncentrationen linjärt med koncentrationen i serum. Serumkoncentrationsmätning av OLA kan, förutom att vara vägledande avseende ordinationsföljsamhet, användas för optimering av OLA-behandling och för långsiktig individuell uppföljning. Omgivningsfaktorer, som t.ex. rökning eller samtidig medicinering med vissa andra läkemedel, kan interagera med genetiska faktorer avseende läkemedelsmetabolism. Detta kan i sin tur markant påverka individuell variation över tid. Ändrade rök- och medicineringsvanor kan därför kräva betydande justeringar av OLAdosering.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. p. 62
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 116
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71231 (URN)9789173931465 (ISBN)
Presentation
2011-10-14, Consensussalen, psyk US, pl 10, ingång 27, Campus US, Linköpnigs universitet, Linköping, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-07 Created: 2011-10-07 Last updated: 2019-10-12Bibliographically approved
Josefsson, M., Roman, M., Skogh, E. & Dahl, M.-L. (2010). Liquid chromatography/tandem mass spectrometry method for determination of olanzapine and N-desmethylolanzapine in human serum and cerebrospinal fluid. Journal of Pharmaceutical and Biomedical Analysis, 53(3), 576-582
Open this publication in new window or tab >>Liquid chromatography/tandem mass spectrometry method for determination of olanzapine and N-desmethylolanzapine in human serum and cerebrospinal fluid
2010 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 3, p. 576-582Article in journal (Refereed) Published
Abstract [en]

A validated, accurate and sensitive LC-MS/MS method for determination of olanzapine and its metabolite N-desmethylolanzapine has been developed. The analytes were quantified by tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring. Olanzapine and desmethylolanzapine were extracted from serum or cerebral spinal fluid samples, 200 microl, with tert-butyl methyl ether using olanzapine-D3 as internal standard. Calibrations for olanzapine and desmethylolanzapine were linear within the selected range of 0.2-30 ng/ml (6-96 nM) in cerebral spinal fluid and for olanzapine in plasma, in the range of 5-100 ng/ml (16-320 nM). The method was successfully used for the analysis of samples from patients treated with olanzapine in the dose range of 2.5-25mg/day.

Keywords
Olanzapine; N-desmetylolanzapine; Serum; Cerebrospinal fluid; Tandem mass spectrometry; LC–MS/MS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58802 (URN)10.1016/j.jpba.2010.03.040 (DOI)20452161 (PubMedID)
Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12
Skogh, E., Sjödin, I., Josefsson, M. & Dahl, M. (2010). Olanzapine in serum and cerebrospinal fluid in patients with schizophrenia or schizoaffective disorder. Paper presented at The 23rd ECNP Congress, Amsterdam, the Netherlands, 28 August–1 September 2010. European Neuropsychopharmacology, 20(Suppl. 3), S469-S469
Open this publication in new window or tab >>Olanzapine in serum and cerebrospinal fluid in patients with schizophrenia or schizoaffective disorder
2010 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 20, no Suppl. 3, p. S469-S469Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background:  The relationship  between serum and CSF concentrations  of olanzapine  (OLA)  in humans  has  to our  knowledge not been described earlier. Few studies have investigated how the CYP2D6 and CYP1A2 polymorphisms affect OLA pharmacoki- netics in humans [1] [2]. Polymorphisms in the ABCB1 gene have been associated with altered pharmacokinetics of certain drugs including risperidone [3].The aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) con- centrations of OLA and its metabolite 4t -N-desmethylolanzapine (DMO) and to address the influence  of smoking,  gender, age as well as polymorphisms in genes coding for OLA metabolism (CYP2D6, CYP1A2) and transport (ABCB1) in patients with schizophrenia  or schizoaffective  disorder, treated with oral OLAas the only antipsychotic  drug.

Methods: Thirty seven Caucasian outpatients (10 smokers and27 non-smokers),  suffering from schizophrenia or schizoaffective disorder according to DSM-IV criteria were included in the study. From 29 out of them, CSF was collected successfully.Fasting blood samples were collected in the morning for analy- ses of OLA and DMO and for genotyping (polymorphisms of CYP2D6,  CYP1A2  and  ABCB1).  Lumbar  puncture  was  per- formed  at close  connection  to blood  sampling  at the minimum of eight hours in the fasting state. The blood and CSF samples were stored at −70ºC until analysed.A validated accurate and sensitive LC-MS/MS method was used for the analysis of OLA and DMO. Analytes were quantified  by using linear gradient reversed phase chromatography with tandem mass  spectrometry  detection  operating  in  positive  electro-sprayionization mode with multiple reactions monitoring (MRM).

Results:  A  strong  correlation  (rs =0.93;  p < 0.05)  was  foundbetween serum and CSF concentrations  of OLA and a somewhatweaker (rs =0.5; p < 0.05) between those of DMO. The CSF con- centrations  of  OLA  and  DMO  were  in  average  13%  and  16% of those in serum. Extensive metabolizers of CYP2D6 were pre- scribed higher (p < 0.05) daily doses than poor metabolizers when the influence of smoking habits was taken into account. Smokers had  lower  concentration-to-dose   ratios  (C/D)  of  OLA  both  in serum and CSF than non-smokers  (median  7 vs. 10 nmol/L/mg in serum and 0.8 vs. 1.3 nmol/L/mg  in CSF; p < 0.01). C/D for serum DMO decreased with increasing age (rs = −0.41; p < 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (median 112 vs. 80 nmol/L; p < 0.05) and CSF (13.7 vs. 8.1 nmol/L; p < 0.05) OLA concentrations  than patients without this haplotype. Patients treated with benzodiazepines and/or zopiclone (n = 8) had higher DMO and DMO/OLA ratio (p < 0.05 for both) in CSF compared to patients not co-medicating  with these drugs (n = 21), even when smoking habits were taken into account.

Conclusion:  The present study shows a very good correlation between  serum and CSF concentrations  of OLA, indicating  thatconcentrations  of OLA in serum reflect the situation in CSF.

References

[1]  Hägg S, Spigset O, Lakso H, et al. Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes. Eur J Clin Pharmacol2001;57:493−97.

[2]  Carrillo  JA, Herra´iz  AG, Ramos SI, et al. Role of smoking-inducedcytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-stateconcentration of olanzapine. J Clin Psychopharmacol 2003;23:119−27.

[3]  Gunes A, Spina E, Dahl M-L, et al. ABCB1 polymorphisms influencesteady-state  plasma  levels  of  9-hydroxyrisperidone   and  risperidoneactive moiety. Ther Drug Monit 2008;30:628−33.

Place, publisher, year, edition, pages
Elsevier, 2010
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-63947 (URN)10.1016/S0924-977X(10)70690-8 (DOI)000283687800577 ()
Conference
The 23rd ECNP Congress, Amsterdam, the Netherlands, 28 August–1 September 2010
Available from: 2011-01-10 Created: 2011-01-10 Last updated: 2017-12-11Bibliographically approved
Nilsson-Todd, L. K., Nordin, C., Jönsson, E. G., Skogh, E. & Erhardt, S. (2007). Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - Correlation with monoamine metabolites. Acta Neuropsychiatrica, 19(1), 45-52
Open this publication in new window or tab >>Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - Correlation with monoamine metabolites
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2007 (English)In: Acta Neuropsychiatrica, ISSN 0924-2708, E-ISSN 1601-5215, Vol. 19, no 1, p. 45-52Article in journal (Refereed) Published
Abstract [en]

Background: The tryptophan metabolite kynurenic acid (KYNA) is an endogenous glutamate/nicotinic receptor antagonist. Previous studies have shown that the concentration of the compound is increased in cerebrospinal fluid (CSF) of patients with schizophrenia. Furthermore, it has been found that the CSF concentration of KYNA is positively correlated to CSF concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) in healthy control subjects. Objectives: To study the correlations between KYNA and the monoamine metabolites HVA, 5-HIAA and 4-hydroxy-3- methoxyphenylglycol (HMPG) in CSF of male patients (n = 53, ranging from 20 to 48 years of age) with verified schizophrenia. Methods: CSF was obtained by lumbar puncture, and KYNA analysis was performed with an isocratic reversed-phase high-performance liquid chromatography system connected to a fluorescence detector. HVA, 5-HIAA and HMPG concentrations were measured by mass fragmentography with deuterium-labelled internal standards. Results: Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA, while CSF content of HMPG did not correlate to KYNA or any of the monoamine metabolites in CSF. Conclusion: The results of this study suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover in male patients with schizophrenia. © 2007 Blackwell Munksgaard.

Keywords
Homovanillic acid (HVA); 5-hydroxy-indoleacetic acid (5-HIAA); 4-hydroxy-3-methoxyphenylglycol (HMPG), human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-39546 (URN)10.1111/j.1601-5215.2006.00170.x (DOI)49628 (Local ID)49628 (Archive number)49628 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
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