Database processing for identification of concomitant drug frequencies in a forensic material positive for antidepressant drugs Niklas Björn, 2014-06-11 LiU−IMH−EX−14/01−SE Master Thesis conducted at the department of Medical and Health Sciences, division of Drug Research, Clinical Pharmacology Supervisor: Margareta Reis, Department of Medical and Health Science, University of Linköping Examinator: Henrik Gréen, Department of Medical and Health Science, University of Linköping Department of Medical and Health Sciences Linköping University SE-581 85 Linköping, Sweden Avdelning, institution Datum Division, Department Division of Drug Research, Clinical Pharmacology Date Department of Medical and Health Science Linköping University 2014-06-11 Språk Rapporttyp ISBN Language Report category Svenska/Swedish Licentiatavhandling ISRN: LiU−IMH−EX−14/01−SE Engelska/English Examensarbete _________________________________________________________________ C-uppsats ________________ D-uppsats Serietitel och serienummer ISSN Övrig rapport Title of series, numbering ______________________________ _____________ URL för elektronisk version Titel Title Database processing for identification of concomitant drug frequencies in a forensic material positive for antidepressant drugs Författare Author Niklas Björn Sammanfattning Abstract This article presents a study conducted on data containing drug concentrations. The data was obtained from femoral venous blood samples collected at medico legal autopsies in Sweden. Cases positive for antidepressant drugs were scrutinized and divided in to two groups for 15 antidepressant drugs: B-cases, where the cause of death was intoxication with more than one drug detected in the blood sample. C-cases, where the cause of death was NOT intoxication and at least one drug (the antidepressant) was detected in the blood sample. This data was then processed to find frequencies of concomitant drugs taken together with the antidepressant drugs. Frequencies of the most common concomitant drugs were then compared between B-cases and C-cases for each antidepressant drug. This revealed that the drugs dextropropoxyphene, ethanol, codeine, flunitrazepam, paracetamol, propiomazine and alimemazine were signifcantly more common as concomitant drugs in B-cases (intoxications) than in C-cases (non-intoxications). With regards to unknown interactions the most interesting combinations were: Propiomazine with mirtazapine, venlafaxine, citalopram or fluoxetine; Paracetamol with paroxetine; Flunitrazepam with mirtazapine, venlafaxine or citalopram; Codeine with mirtazapine or sertraline. These combinations should be further investigated. Nyckelord Keywords TCA, TeCA, SSRI, SNRI, MAOI, antidepressant drug, drug interaction, intoxication Table of Contents 1. Abstract .......................................................................................................................................... 1 2. List of abbreviations ..................................................................................................................... 1 3. Introduction ................................................................................................................................... 2 3.1. Background ........................................................................................................................... 2 3.1.1. Assignment .................................................................................................................... 2 3.1.2. Data................................................................................................................................. 2 3.1.3. Antidepressant drugs................................................................................................... 3 3.1.4. Drug interactions .......................................................................................................... 4 3.2. Purpose .................................................................................................................................. 4 3.3. Clinical relevance.................................................................................................................. 4 4. Process ............................................................................................................................................ 4 5. Methods ......................................................................................................................................... 5 5.1. Extract data ............................................................................................................................ 6 5.2. Parent drug and metabolite ................................................................................................ 7 5.3. Frequencies ............................................................................................................................ 8 5.4. Statistical analysis ................................................................................................................. 9 5.4.1. Contingency tables ....................................................................................................... 9 5.4.2. Fisher´s exact test .......................................................................................................... 9 5.4.3. Odds Ratio ................................................................................................................... 10 5.4.4. Relative Risk ................................................................................................................ 10 5.4.5. Correction for multiple comparisons ....................................................................... 11 5.4.6. Comparisons of concentrations ................................................................................ 11 5.5. Known drug interactions................................................................................................... 12 6. Result ............................................................................................................................................ 12 6.1. All cases ............................................................................................................................... 12 6.2. Index-antidepressants and concomitant drugs .............................................................. 12 6.2.1. Amitriptyline ............................................................................................................... 13 6.2.2. Citalopram ................................................................................................................... 14 6.2.3. Clomipramine ............................................................................................................. 14 6.2.4. Fluoxetine .................................................................................................................... 15 6.2.5. Mianserin ..................................................................................................................... 15 6.2.6. Mirtazapine ................................................................................................................. 16 6.2.7. Paroxetine .................................................................................................................... 16 6.2.8. Sertraline ...................................................................................................................... 17 6.2.9. Venlafaxine .................................................................................................................. 17 7. Discussion .................................................................................................................................... 18 8. Conclusions ................................................................................................................................. 20 9. Acknowledgments...................................................................................................................... 20 10. References .................................................................................................................................... 21 Appendix I – Known drug interactions .......................................................................................... 23 Appendix II – Relative risk ............................................................................................................... 27 Appendix III – Frequency tables ...................................................................................................... 44 Appendix IV – Statistical data .......................................................................................................... 77 1. Abstract This article presents a study conducted on data containing drug concentrations. The data was obtained from femoral venous blood samples collected at medico legal autopsies in Sweden. Cases positive for antidepressant drugs were scrutinized and divided in to two groups for 15 antidepressant drugs: B-cases, where the cause of death was intoxication with more than one drug detected in the blood sample. C-cases, where the cause of death was NOT intoxication and at least one drug (the antidepressant) was detected in the blood sample. This data was then processed to find frequencies of concomitant drugs taken together with the antidepressant drugs. Frequencies of the most common concomitant drugs were then compared between B-cases and C-cases for each antidepressant drug. This revealed that the drugs dextropropoxyphene,