Database Processing for Identification of Concomitant Drug Frequencies in a Forensic Material Positive for Antidepressant Drugs

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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 ______

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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, 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.

Keywords: TCA, TeCA, SSRI, SNRI, MAOI, antidepressant drug, drug interaction, intoxication

2. List of abbreviations TCA : Tricyclic antidepressant TeCA : Tetracyclic antidepressants SSRI : Selective-serotonin reuptake inhibitors SNRI : Serotonin/noradrenaline reuptake inhibitors MAOI : Monoamine oxidase inhibitors ICD-9 : International Classification of Diseases, Ninth Revision OR : Odds ratio RR : Relative risk CI : Confidence interval

3. Introduction

3.1. Background Access to parts of a nationwide database for forensic pathology and forensic toxicology was available at the department of clinical pharmacology, Linköping University, Linköping. This database contained drug concentration data obtained from femoral venous blood samples collected at medico legal autopsies in Sweden. The concentration data is accompanied with, among other information, the cause of death and the manner of death [1]. All handling and processing of the blood samples of medico legal autopsies are strictly standardized at all forensic pathology units according to guidelines set by the Swedish National Board of Forensic Medicine. During the period January 1992 to June 2005, 55 042 samples were screened for substances, including antidepressant drugs. The data from the samples positive for antidepressant drugs formed the basis for the article Reis et al. [2], and constitutes the base for the present project.

3.1.1. Assignment The aim was to process the antidepressant concentration data for further findings. More specifically, to investigate frequencies of concomitant drugs and combination of concomitant drugs used together with different antidepressant drugs. Subsequently, concentrations of antidepressant drugs were scrutinized for concentration deviations that could be linked to concomitant drugs detected in the samples. This might lead to proposals of unknown drug interactions that should be further studied or strengthen the evidence for known drug interactions.

3.1.2. Data The data used in this project included all cases with a positive detection of one of 15 different antidepressant drugs. These cases were divided into 1 of 3 distinct groups for each antidepressant drug detected in the blood sample. This division was made in the former study [2] were every single case was systematically investigated and divided in to these groups. All in accordance with the Swedish version of International Classification of Diseases, Ninth Revision (ICD-9)[3], together with the death diagnosis made by the pathologist. Further, cases that gave rise to confusion or uncertainties as well as unreasonably high or low concentrations of the antidepressant were excluded. The three groups that were formed as in the previous study were denominated A-cases, B-cases, and C-cases: A-cases: cases dead by intoxication, with only one single drug detected in the blood sample. Influence by alcohol was allowed up to 0.1%. B-cases: cases dead by intoxication, with more than one drug detected in the blood sample. Influence by alcohol was tolerated at all concentrations. C-cases: cases where the cause of death was NOT intoxication and at least one drug was detected in the blood sample.

This means that a case can only be present in one A-case group. However, a case with more than one antidepressant drug present could be represented in B-case groups for different antidepressant drugs or in C-case groups for different antidepressant drugs.

3.1.3. Antidepressant drugs The most common theory of depressions is the monoamine theory, proposed by Schildkraut in 1965. The theory states that a depression is caused by a deficit of the monoamine neurotransmitters, serotonin and noradrenaline, at specific sites in the brain. The base for this theory is derived from the clinical effect of the drugs used to treat depressions. Antidepressant drugs induce in various different ways an increase of the amount of neurotransmitters in the synaptic cleft between two neurons. This is supposed to improve the mood of the patient. [4]

There are a many types of antidepressant drugs, and below comes a short introduction of the types of antidepressant drugs relevant to this project and brief theories behind the drug actions.

Tricyclic antidepressants (TCAs) increase the amount of neurotransmitters in the synaptic cleft by inhibiting the reuptake of both serotonin and noradrenaline from the synaptic cleft. These were the first generation of antidepressant drugs [4]. The antidepressant effect is good but side effects are common and sometimes serious/life-threatening. Even today, the more severe the depression is, the more likely the patient is to be treated with TCAs. Seizures and ventricular arrhythmia account for the mortality associated with TCA overdoses [5].

Selective-serotonin reuptake inhibitors (SSRIs) are antidepressants that are more prone to inhibit serotonin reuptake than noradrenaline reuptake from the synaptic cleft. These antidepressants have fewer side effects than TCAs and are harder to overdose. [4, 6]

Serotonin/noradrenaline reuptake inhibitors (SNRIs) are more selective for inhibition of noradrenaline reuptake. SNRIs are considered safer in overdose than TCAs [4].

Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme monoamine oxidase which regulates serotonin and noradrenaline concentrations. MAOIs are used less than other antidepressants due to their adverse effects and interactions [4, 7]. MAOIs should not be used in combination with other serotonin enhancing drugs, e.g. other antidepressant drugs, because of the increased risk for serotonin syndrome [8]. Serotonin syndrome is a potentially life-threatening syndrome that can occur by therapeutic use of serotonergic drugs alone or by drug interaction between two serotonergic drugs [9].

Tetracyclic antidepressants (TeCAs) are a group of antidepressants named after their chemical structure in the same manner as TCAs. Mianserin and Mirtazapine act by blocking adrenergic and serotonergic receptors which leads to an enhanced release of the neurotransmitters serotonin and noradrenaline. Maprotiline is another TeCA it works as a noradrenalin reuptake inhibitor. [4] 3

Antidepressants can be used as treatments for other conditions than depressions for example anxiety, neuropathic pain, anorexia, bulimia and social phobia [4, 10]. The different antidepressant drugs display a wide variety of side effects and the risk for life threatening effects differ [4, 8].

3.1.4. Drug interactions Drugs in general can interact with other drugs and the more drugs a patient has taken the higher is the risk for unwanted side effects due to interactions. There are two general types of drug interactions [4]: Pharmacodynamic interaction: the effect of a drug is changed without a change in concentration of that drug. Pharmacokinetic interaction: the concentration of a drug is changed.

Drug interactions can lead to intoxications and even to death. In this study there was information about the drugs that were taken prior to death, evidenced by post mortal blood concentrations. This can be used to propose combinations of drugs that might have underlying drug interactions.

3.2. Purpose The main purpose of this project was to compare previously defined B-cases and C-cases to find frequencies of concomitant drugs and combinations of concomitant drugs that could be linked to intoxications with antidepressant drugs.

3.3. Clinical relevance Depression is a growing health burden estimated to be one of the leading causes of mental and health disability by 2030 [11]. Information about drugs used together with antidepressant drugs is highly relevant for the safety of drug users, and for the subscribing doctors. This study gives insight into poly-drug use and the prevalence of different drugs used in combination with antidepressant drugs. The dangers associated with poly-drug use is hard to interpret and common in intoxications [12]. Also the data in this project give information from doses higher than therapeutic levels [2]. High toxic doses are not studied in human trials. Drugs considered safe in combination might in high doses show different tendencies. With all this in mind it is easy to understand why extended knowledge about antidepressant drugs and their drug interactions is essential to future healthcare.

4. Process The project started with the development of a structured timetable, see figure 1. This timetable was followed without any major changes.

Figure 1: Timetable for the project.

The first part of the project was to get familiar with the data. This was followed by anonymization of the data so that work could be conducted without the possibility of leaking classified information. After this all groups where extracted, divided and stored. The number of cases in each group were compared with the number of cases in the previous article [2]. Some small differences were found and those were linked to human errors made in the former study. This was thoroughly discussed with the supervisor.

Concomitant drug frequencies and concomitant drug combination frequencies were calculated. With this in hand statistical analyzes could be conducted. Lots of focus was put on making sure the numbers were correct and how to do the statistical analyzes. A couple of times tasks performed earlier had to be remade because of initial programming errors. All in all the project went fine and always forward. Regular meetings were held with the supervisor for asking questions and to check in with direction to continue the project.

The halftime meeting was held week 13, to follow up what had been done and how to direct future work. No major changes were made and the project could continue as planned. In the end of the project time was only spent on the report. However, sometimes earlier steps in the timetable had to remade to obtain more or different information.

5. Methods MATLAB® a high-level language and interactive environment for numerical computation, visualization, and programming was used for this project. Functions and scripts were specifically designed for all different parts handling the data, both for extraction/handling of data and for calculations conducted on the extracted data.

5.1. Extract data Per definition the A-cases have no other substances present and are therefore not interesting when researching drug combinations and drug interactions. Hence, only B-cases and C-cases were extracted for the 15 different antidepressant drugs; i.e. 15 groups of B-cases and 15 groups of C-cases. One B-case group and one C-case group will have the same antidepressant drug in common, this antidepressant drug will be referred to as the index-antidepressant. The total number of cases in each group and the 15 antidepressant drugs are found in Table 1. The information of concomitant drugs detected in each case was also extracted. Classification codes from ICD-9 [3] for the cause of death and the manner of death were used to exclude unreliable cases, for codes that lead to exclusion of C-cases see Table 2.

Table 1: Shows the different antidepressant drugs, type of antidepressant, number of B-cases, number of C-cases, total number of cases for each antidepressant, total number, number of unique B-cases and number of unique C-cases.

Table 2: Classification codes for the manner of death and the cause of death that lead to exclusion of C-cases, where death by incapacitation and intoxication could not be ruled out. Table by courtesy of Reis et al. [2].

The index-antidepressants were also combined into two total groups; all B-cases and all C-cases. This serves a purpose by giving a more general view over concomitant drug use in cases positive for antidepressant drugs. Cases that were present in more than one of the index-antidepressant groups that were combined were only used once in the new group. For these two groups the concentration of the index-antidepressants is not interesting, only the presence of them is relevant.

5.2. Parent drug and metabolite Drugs are metabolized to different extent. In this study parent drugs or main metabolites were viewed as an indication of the parent drug in question. The indication of a drug was named by the parent drug, but includes the following three possible findings in the blood sample: parent drug, metabolite or parent drug and metabolite. Parent drugs and their respective main metabolites are listed in Table 3. The antidepressant amitriptyline has an active metabolite nortriptyline which is sold as an antidepressant drug by itself. Therefore, these two were not seen as the same drug.

Table 3: Shows index-antidepressants, the most common concomitant drugs and their respective main metabolites.

For the index-antidepressants the parent drug had to be present in the blood sample for a case to be included in that index-antidepressants group. Concentrations were not used for the concomitant drugs, they were only seen as present or not present. This enabled both inclusion of cases were a concomitant drug was indicated but the concentration was not measurable, and the possibility of combining parent drugs and metabolites.

5.3. Frequencies MATLAB® scripts were made to go through the data case by case for each index-antidepressants B-case and C-case group. While doing this all detected substances used by the cases in the group were noted and the frequencies of them were calculated. Simultaneously, different double and triple combinations of concomitant substances were detected and the frequencies of these combinations were calculated. The result from this is shown in frequency tables, where the number of cases in the group, the total number of different substances in the group and the number of cases with 1, 2 or 3 substances in addition to the index-antidepressant (or in addition to all index-antidepressants in the two combined groups). This gives an idea of how common it is to mix drugs. Median concentration of the index-antidepressant was calculated and tabulated. For the C-cases the 8 median concentration was also calculated for the cases with at least one concomitant substance and for the cases without any concomitant substances. These two groups were compared to see if there was any significant difference between the concentrations in the two groups, see 5.4.6. Comparisons of concentrations.

When analyzing the frequencies of concomitant drugs the 15 most common substances were considered. When combinations of concomitant drugs used together with the index-antidepressant were analyzed the 20 most common combinations were considered. The combinations are either consisting of 2 or 3 drugs in addition to the index-antidepressant. Combinations of more than three drugs were possible but very rare, therefore these were not analyzed.

5.4. Statistical analysis Differences with a p < 0.05 were α = 0.05 was considered significant.

5.4.1. Contingency tables Statistical analyses were made to find concomitant drugs that were statistically more common in B-cases than in C-cases or statistically more common in C-cases than in B-cases. Contingency tables were formed for all concomitant drugs that were present in at least 10% of the B-cases or C-cases. Figure 2 shows both a common contingency table and an example of how they were formed in this project. Contingency tables are not displayed but the numbers for a, b, c and d are shown were needed.

Figure 2: Contingency tables, on the left a common example and to the right an example of a contingency table in this project. a: the number of B-cases where the concomitant drug was present. b: the number of C-cases where the concomitant drug was present. c: the number of B-cases where the concomitant drug was NOT present. d: the number of C-cases where the concomitant the drug was NOT present.

5.4.2. Fisher´s exact test Fisher’s exact test was conducted on all contingency tables for investigating if there were differences between the variables in the rows and columns of the contingency tables. Fisher’s exact test is suitable when small numbers could be present in any of the rows or columns. Other methods like a Chi squared test would have to be corrected if numbers are small, this is not the case with Fisher’s exact test. [13]

Corrections for multiple tests were performed with the Benjamini-Hochberg procedure, see 5.4.5. Correction for multiple comparisons.

5.4.3. Odds Ratio This project is a case-control study and from the contingency tables odds ratios (OR) can be calculated to give information about if the odds of an outcome is higher or lower if an exposure is present [14]. The formula for calculating the odds ratio and its confidence interval is given below [13].

The odds ratio is given by:

The standard error (SE) of the log odds ratio is given by: √

( ) The confidence interval (CI) is given by: note that N(x) is a value taken from the normal distribution

An OR = 1 means that the odds of the outcome (intoxication) is the same for both the exposed (concomitant drug present) and the non-exposed (concomitant drug NOT present). For the OR to be statistically significant the CI should not contain 1. If the OR > 1, then the odds for the outcome is higher for the exposed group. If the OR < 1, then the odds for the outcome is lower for the exposed group, a somewhat protective effect is seen. [14]

5.4.4. Relative Risk In a case-control study should the relative risk (RR) not be directly calculated and often it is completely wrong to calculate it [15]. However there are methods for deriving the RR from the OR (and the corresponding CI). This can be done if control groups were properly derived and by using some auxiliary information. The method used for this can be seen below [16].

Probability of diseased among the exposed:

Conversion of odds ratio to relative risk:

This conversion has flaws and some argue that it is not proper to do [17]. This conversion might give values that still not should be viewed as risks. I argue that it still is appropriate to do because a RR is much easier to understand compared to an OR [15]. The interesting is if the RR and the associated CI is separated from 1 not how high or low the actual RR values are.

An RR = 1 means that the risk of the outcome (intoxication) is the same for both the exposed (concomitant drug present) and the non-exposed (concomitant drug NOT present). For the RR to be statistically significant the CI should not contain 1. If the RR > 1, the risk for the outcome is higher for the exposed group. If the RR < 1, then the risk for the outcome is lower for the exposed group, a somewhat protective effect is seen. [14]

Specific explanation for the present project: RR > 1 means that death by intoxication is more likely if the index-antidepressant is taken in combination with the concomitant drug in question, compared to when the concomitant drug is not taken. An RR < 1 indicates the 10 opposite, that death by intoxication is less likely if the index-antidepressant is taken in combination with the concomitant drug in question, compared to when the concomitant drug is not taken.

5.4.5. Correction for multiple comparisons Correction for multiple tests was done with the Benjamini-Hochberg procedure. The procedure was conducted separately on all index-antidepressants or group of index-antidepressants studied. The p-values from Fisher’s exact test on the most common concomitant drugs were corrected. This controls the amount of type I errors (false discoveries). [18]

Benjamini-Hochberg procedure, as explained in:

 For n tests, rank corresponding p-values in ascending order , p(1) < … < p(n)

 Let k be the largest i for which is true

 Tests corresponding to p(1) … p(k) can be considered significant at level α

 Other tests possibly with p < α but with p > p(k) are not significant

In tables the p-value from Fisher´s exact test has to be lower than the value from Benjamini-Hochberg procedure. This correction applies to the OR/RR results directly because they were calculated from the same data. In RR plots there will be a black horizontal line, if a confidence interval is beneath this line in the plot it is significant, otherwise it is not significant even if the confidence interval does not include 1. So for a drug to be significantly more common in one group both the p-value from Fisher´s exact test has to be lower than the value from the Benjamini-Hochberg procedure and the OR/RR confidence interval has to be separated from 1.

5.4.6. Comparisons of concentrations Comparisons of concentrations between two groups were conducted with Mann-Whitney U-test, a non-parametric test for unevenly distributed data.

Concentration comparisons were only made on the index-antidepressants. First comparisons of C-cases with no concomitant drugs were compared with C-cases that have at least one concomitant drug. Secondly comparisons were made within B-cases and C–cases for drugs that were significantly more common (Fisher´s exact test was significant) in B-cases or C-cases. For finding differences in the concentration between cases with a certain concomitant drug compared to cases without that concomitant drug. For example; for index-antidepressant X, the concomitant drug Y was significantly more common in B-cases than C-cases. Then a comparison of index-antidepressant X ´s concentration between B-cases with drug Y and B-cases without drug Y was conducted. Also a comparison of index-antidepressant X ´s concentration between C-cases with drug Y and C-cases without drug Y was conducted.

No corrections for multiple comparisons are made for the statistical tests on the concentration differences.

5.5. Known drug interactions The number of known drug-drug interactions is extensive and growing. In Appendix I recognized interactions with index-antidepressants are listed. This was done manually by searching SFINX (Swedish, Finnish, Interaction X-referencing) [19], a drug-drug interaction database. This database is under constant development and these interactions could be found April 4, 2014.

6. Result All relative risk plots are displayed in appendix II. The most common combinations of concomitant drugs are not shown in the results, however they can be found along with all information from the frequency tables in appendix III. Further, results from the statistical analysis including number of cases in each group (a, b, c, d), OR, RR, CI, p-values, Benjamini-Hochberg correction and consentration comparisons are all listed in appendix IV.

6.1. All cases All B-cases consisted of 749 cases and a total of 111 different drugs in addition to the index-antidepressants were found. 736 cases had positive detections of drugs in addition to the index-antidepressants. The 5 most common concomitant drugs were ethanol (found in 47% of the cases), paracetamol (32%), dextropropoxyphene (30%), propiomazine (24%) and diazepam (16%).

All C-cases consisted of 1654 cases and a total of 89 different drugs in addition to the index-antidepressants were found. 922 cases had positive detections of drugs in addition to the index-antidepressants. The 5 most common concomitant drugs were ethanol (27%), diazepam (22%), paracetamol (18%), zopiclone (15%) and propiomazine (13%).

Comparisons of frequencies of concomitant drugs between all B-cases and all C-cases is displayed a relative risk plot (figure A, appendix II). This plot, p-values and confidence intervals reveals that the drugs dextropropoxyphene, ethanol, codeine, flunitrazepam, paracetamol, propiomazine, alimemazine were signifcantly more common in B-cases (intoxications) than in C-cases (non-intoxications). Dextropropoxyphene was more common than ethanol, paracetamol, propiomazine and alimemazine. Codein was more common than than paracetamol, propiomazine and alimemazine. Furhtermore, flunitrazepam was more common than alimemazine.

6.2. Index-antidepressants and concomitant drugs A summary of the 5 most common concomitant drugs for all B-cases can be seen in Table 4.

Table 4: Lists the 5 most common concomitant drugs in ascending order for each index-antidepressant. For the combined group of all B-cases the 10 most common concomitant drugs are listed. The index-antidepressants are listed in no particular order.

Further results for the index-antidepressants fluvoxamine, imipramine, maprotiline, moclobemide, nortriptyline and trimipramine will not be displayed, due to too few cases. However, all the results for these index-antidepressants can be found in the appendices.

6.2.1. Amitriptyline Amitriptyline B-cases consisted of 119 cases and a total of 71 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (56%), paracetamol (28%), dextropropoxyphene (25%), diazepam (23%) and flunitrazepam (18%).

Amitriptyline C-cases consisted of 89 cases and a total of 39 different drugs in addition to the index-antidepressant were found. 55 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were diazepam (33%), paracetamol (22%), ethanol (20%), dextropropoxyphene (16%) and carbamazepine (13%). No concentration differences could be seen (p = 0.36) between C-cases with concomitant drugs in addition to the index-antidepressant compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between amitriptyline B-cases and C-cases is displayed in the relative risk plot (figure B, appendix II). Ethanol was significantly more common in B-cases than in C-cases. No changes in the concentration of amitriptyline could be linked to ethanol.

6.2.2. Citalopram Citalopram B-cases consisted of 243 cases and a total of 85 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (48%), dextropropoxyphene (36%), paracetamol (31%), propiomazine (26%) and diazepam (23%).

Citalopram C-cases consisted of 629 cases and a total of 78 different drugs in addition to the index-antidepressant were found. 363 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were ethanol (25%), paracetamol (19%), diazepam (16%), propiomazine (14%) and zopiclone (13%). Concentration differences could be seen (p = 0.03) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs. Median concentration of citalopram was significantly higher for C-cases with concomitant drugs.

Comparisons of frequencies of concomitant drugs between citalopram B-cases and C-cases is displayed in the relative risk plot (figure C, appendix II). Dextropropoxyphene, ethanol, levomepromazine, propiomazine, flunitrazepam, paracetamol, diazepam and alimemazine were all significantly more common in B-cases than in C-cases. Differences in concentration of citalopram for cases with compared to without these drugs could be found for 3 of them: Dextropropoxyphene; B-cases had no differences (p = 0.09), C-cases had higher citalopram concentrations for cases with dextropropoxyphene (p = 0.01). Propiomazine; B-cases had no differences (p = 0.16), C-cases had higher citalopram concentrations for cases with propiomazine (p = 0.01). Flunitrazepam; B-cases had no differences (p = 0.35), C-cases had higher citalopram concentrations for cases with flunitrazepam (p = 0.00). The plot also reveles that dextropropoxyphene was more common than ethanol, propiomazine, flunitrazepam, paracetamol, diazepam and alimemazine. Levomepromazine was more common than paracetamol, diazepam and alimemazine.

6.2.3. Clomipramine Clomipramine B-cases consisted of 107 cases and a total of 76 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (40%), paracetamol (31%), dextropropoxyphene (27%) diazepam (23%) and flunitrazepam (14%).

Clomipramine C-cases consisted of 141 cases and a total of 51 different drugs in addition to the index-antidepressant were found. 84 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were diazepam (29%), ethanol (27%), alimemazine (13%), paracetamol (12%) and dextropropoxyphene (7%). No concentration differences could

14 be seen (p = 0.37) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between clomipramine B-cases and C-cases is displayed in the relative risk plot (figure D, appendix II). Dextropropoxyphene and paracetamol was significantly more common in B-cases than in C-cases. No changes in the concentration of clomipramine could be linked to these drugs.

6.2.4. Fluoxetine Fluoxetine B-cases consisted of 36 cases and a total of 50 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were diazepam (44%), ethanol (42%), dextropropoxyphene (39%) propiomazine (31%) and paracetamol (28%).

Fluoxetine C-cases consisted of 53 cases and a total of 37 different drugs in addition to the index-antidepressant were found. 42 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were ethanol (45%), diazepam (31%), paracetamol (14%), zopiclone (10%) and alimemazine (7%). No concentration differences could be seen (p = 0.81) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between fluoxetine B-cases and C-cases is displayed in the relative risk plot (figure E, appendix II). Dextropropoxyphene and propiomazine were significantly more common in B-cases than in C-cases. Differences in concentration of fluoxetine for cases with compared to without these drugs could be found for 1 of them: Dextropropoxyphene; B-cases had lower fluoxetine concentrations for cases with dextropropoxyphene (p = 0.02), C-cases had no differences (p = 0.112).

6.2.5. Mianserin Mianserin B-cases consisted of 28 cases and a total of 40 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (43%), paracetamol (36%), citalopram (25%) propiomazine (21%) and dextropropoxyphene (18%).

Mianserin C-cases consisted of 156 cases and a total of 50 different drugs in addition to the index-antidepressant were found. 108 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were citalopram (21%), ethanol (16%), diazepam (14%), sertraline (14%) and paracetamol (13%). No concentration differences could be seen (p = 0.39) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between mianserin B-cases and C-cases is displayed in the relative risk plot (figure I, appendix II). Levomepromazine, ethanol, trimipramine, flunitrazepam, paracetamol, dextropropoxyphene were significantly more 15 common in B-cases than in C-cases. No changes in the concentration of mianserin could be linked to these drugs.

6.2.6. Mirtazapine Mirtazapine B-cases consisted of 67 cases and a total of 60 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (49%), propiomazine (34%), zopiclone (34%), dextropropoxyphene (33%) and diazepam (30%).

Mirtazapine C-cases consisted of 237 cases and a total of 48 different drugs in addition to the index-antidepressant were found. 162 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were zopiclone (22%), diazepam (19%), citalopram (14%), ethanol (14%) and paracetamol (14%). Concentration differences could be seen (p = 0.01) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs. Median concentration of mirtazapine was significantly higher for C-cases with concomitant drugs.

Comparisons of frequencies of concomitant drugs between mirtazapine B-cases and C-cases is displayed in the relative risk plot (figure J, appendix II). Dextropropoxyphene, ethanol, codeine, morphine, propiomazine, flunitrazepam, paracetamol and alimemazine were significantly more common in B-cases than in C-cases. Differences in concentration of mirtazapine for cases with compared to without these concomitant drugs could be found for 2 of them: Dextropropoxyphene; B-cases had lower mirtazapine concentrations for cases with dextropropoxyphene (p = 0.01), C-cases had no differences (p = 0.92). Propiomazine; B-cases had no differences (p = 0.67), C-cases had higher mirtazapine concentrations for cases with propiomazine (p = 0.00). The plot also show that dextropropoxyphene was more common than alimemazine.

6.2.7. Paroxetine Paroxetine B-cases consisted of 31 cases and a total of 41 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were paracetamol (48%), dextropropoxyphene (36%), ethanol (32%), propiomazine (29%) and alprazolam (16%).

Paroxetine C-cases consisted of 49 cases and a total of 24 different drugs in addition to the index-antidepressant were found. 34 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were ethanol (29%), mianserin (21%), propiomazine (18%), zopiclone (15%) and alprazolam (12%). No concentration differences could be seen (p = 0.65) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between paroxetine B-cases and C-cases is displayed in the relative risk plot (figure M, appendix II). Paracetamol and

16 dextropropoxyphene were significantly more common in B-cases than in C-cases. No changes in the concentration of paroxetine could be linked to these drugs.

6.2.8. Sertraline Sertraline B-cases consisted of 46 cases and a total of 52 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were ethanol (41%), dextropropoxyphene (26%), paracetamol (26%), propiomazine (22%) and citalopram (17%).

Sertraline C-cases consisted of 196 cases and a total of 40 different drugs in addition to the index-antidepressant were found. 124 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were ethanol (27%), diazepam (19%), zopiclone (18%), paracetamol (15%) and mirtazapine (13%). No concentration differences could be seen (p = 0.277) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between sertraline B-cases and C-cases is displayed in the relative risk plot (figure N, appendix II). Codeine, dextropropoxyphene, citalopram, caffeine and zolpidem were significantly more common in B-cases than in C-cases. Differences in concentration of sertraline for cases with compared to without these concomitant drugs could be found for 2 of them: Citalopram; B-cases had higher sertraline concentrations for cases with citalopram (p = 0.03), C-cases had no differences (p = 0.42). Caffeine; B-cases had lower sertraline concentrations for cases with caffeine (p = 0.05), C-cases had no differences (p = 0.26).

6.2.9. Venlafaxine Venlafaxine B-cases consisted of 54 cases and a total of 51 different drugs in addition to the index-antidepressant were found. The 5 most common concomitant drugs were propiomazine (41%), paracetamol (33%), ethanol (31%), zopiclone (31%) and alimemazine (30%).

Venlafaxine C-cases consisted of 142 cases and a total of 37 different drugs in addition to the index-antidepressant were found. 86 cases had positive detections of concomitant drugs. The 5 most common concomitant drugs were ethanol (29%), diazepam (21%), paracetamol (16%), zopiclone (16%) and propiomazine (13%). No concentration differences could be seen (p = 0.38) between C-cases with concomitant drugs compared to C-cases without any concomitant drugs.

Comparisons of frequencies of concomitant drugs between venlafaxine B-cases and C-cases is displayed in the relative risk plot (figure P, appendix II). Dextropropoxyphene, propiomazine, nortriptyline, codeine, alimemazine, amitriptyline, flunitrazepam, citalopram and paracetamol were significantly more common in B-cases than in C-cases. Differences in concentration of venlafaxine for cases with compared to without these concomitant drugs

17 could be found for 3 of them: Propiomazine; B-cases had no differences (p = 0.20), C-cases had higher venlafaxine concentrations for cases with propiomazine (p = 0.01). Codeine; B-cases had lower venlafaxine concentrations for cases with codeine (p = 0.05), C-cases had no differences (p = 0.19). Alimemazine; B-cases had no differences (p = 0.33), C-cases had higher venlafaxine concentrations for cases with alimemazine (p = 0.01).

7. Discussion Table 5 presents a compilation of all concomitant drugs that were significantly more common in B-cases (intoxications) than in C-cases (non-intoxications). Note that no concomitant drugs were found to be significantly more common in C-cases than in B-cases.

Of the concomitant drugs significantly more common in “all B-cases” the painkiller paracetamol (e.g. Alvedon®) is the only over the counter drug, a drug found in most homes. The other concomitant drugs require prescriptions and are either sedatives/hypnotics or analgesics; Dextropropoxyphene: e.g. Dexofen®, deregistered, analgesic; Codeine: e.g. Citodon®, analgesic; Flunitrazepam: Rohypnol®, deregistered or Flunitrazepam Mylan®, hypnotic and sedative benzodiazepine; Propiomazine: Propavan®, sedative; Alimemazine: e.g. Theralen®, drug with unspecific sedative effect. [20]

The concomitant drugs more common in B-cases than in C-cases for the different index-antidepressant were somewhat repetitive and included the drugs seen in the general groups listed above.

Table 5: Shows all drugs that were significantly more common in B-cases than in C-cases. Some drugs are marked with “X”, these drugs are listed in SFINX [19] (appendix I), for these specific interactions the clinical significance is unknown or varies.

When examining Table 5 only 4 interactions are known and listed in SFINX [19] (appendix I), these are marked with “X”. The clinical significance of these 4 interactions is unknown or varies and therefore they should be further studied.

For amitriptyline only the concomitant drug ethanol was more common in B-cases than in C-cases. Ethanol is known to increase the blood plasma concentration of amitriptyline, by decreasing the hepatic clearance of amitriptyline [21]. Hence, the combination of amitriptyline and alcohol (ethanol) increases the risk for intoxication of amitriptyline.

Paracetamol or rather one of the metabolites is known to be toxic by itself [22, 23]. At the moment there are no known interactions between paracetamol and any of the index-antidepressants listed in SFINX [19]. For paroxetine, paracetamol was more common in B-cases than in C-cases. Paracetamol was detected in almost half of the B-cases with paroxetine, 15 cases with paracetamol and 16 without paracetamol. On the contrary, among the C-cases only 1 of 34 samples contained paracetamol. This pattern was not seen for any of the other index-antidepressants. This could, however, be a random finding.

Propiomazine does not have any known drug interactions listed in SFINX [19]. However, interaction studies with propiomazine are sparse and limited: A PubMed search May 13, 2014 with the search criteria “Propiomazine” and “Interaction” gave 4 hits, none of them with particular relevance. Propiomazine is more common in B-cases than in C-cases for the antidepressant drugs; mirtazapine, venlafaxine, citalopram and fluoxetine.

Flunitrazepam was more common in B-cases than in C-cases with the antidepressant drugs mianserin, mirtazapine, venlafaxine and citalopram. Flunitrazepam is overall one of the most common drugs found in fatal poisonings [24]. Therefor it is not surprising that flunitrazepam is overrepresented in the fatal poisonings cases in this study. But still flunitrazepam comes out as more common in fatal poisonings in combination with some antidepressant drugs.

Concomitant use of tramadol with antidepressant drugs is not recommended, at least not without initial monitoring [25]. In SFINX codeine is recommended instead of tramadol, as a painkiller, if venlafaxine or sertraline are also administered to the patient [19]. Codeine was more common in B-cases than in C-cases for the antidepressant drugs mirtazapine, venlafaxine and sertraline. Codeine has no known interactions with these index-antidepressants in SFINX [19]. In the data there are no C-cases with codeine and sertraline (7 of 46 B-cases and 0 of 124 C-cases) or with codeine and mirtazapine (12 of 67 B-cases and 0 of 162 C-cases).

Venlafaxine in combination with alcohol has been associated with an elevated risk for fatal poisoning [26]. This cannot be confirmed in this study, because ethanol (alcohol) was not more common in B-cases than in C-cases.

The painkiller dextropropoxyphene was significantly more common in B-cases than in C-cases when taken together with a majority of the index-antidepressants (Table 5). It is 19 reasonable to think that dextropropoxyphene could be dangerous by itself and might have interactions with the index-antidepressants or with the concomitant drugs. Dextropropoxyphen is known to be one of the most common drugs found in fatal poisonings [24]. The data studied was sampled between 1992 and 2005. In 2009 a EU-decision was made to with draw dextropropoxyphene from the market [27, 28]. Due to that the risks, especially the risk of potentially fatal overdoses, are greater than the benefits of the drug. The findings in this project strengthen that decision.

A drawback with the study is the uncertainties with regards to the validities of the blood concentrations of the index-antidepressants. First of all, the doses taken are not known and most B-cases and C-cases are obvious suicides [2]. Blood concentration for high potentially toxic doses can be very different from blood concentrations studied in trials of therapeutic doses. This because differences in pharmacokinetics might occur for drugs in high doses compared to therapeutic doses [29]. Lastly, blood samples were taken after death so postmortem drug redistribution cannot be ruled out. This can affect the blood concentration of substances, for example tricyclic antidepressants [30]. Concentration differences were therefore not discussed.

8. Conclusions In conclusion this study shows drugs that were more common in combination with specific antidepressant drugs in cases of intoxication compared to non-intoxications. These combinations could have underlying drug-drug interactions causing the intoxication. Therefore, further studies on the following drug combinations are recommended: Paroxetine - paracetamol, mirtazapine - flunitrazepam, venlafaxine - flunitrazepam, citalopram - flunitrazepam, mirtazapine - codeine and sertraline - codeine. Also the 4 known interactions between: sertraline - zolpidem, venlafaxine - amitriptyline, venlafaxine - nortriptyline and venlafaxine - citalopram should be studied further. It is important to point out that these combinations cannot be confirmed to be more dangerous than others. But they should be considered as interesting for further studies.

This research method probably comes best into place in cases like the one with propiomazine, which also is the most interesting finding in this paper. Propiomazine is a poorly studied drug and it is more common as a concomitant drug in B-cases than in C-cases for 4 antidepressants drugs. Therefore, interaction studies are recommended to be conducted on the following drug combinations: mirtazapine - propiomazine, venlafaxine - propiomazine, citalopram - propiomazine and fluoxetine - propiomazine.

9. Acknowledgments I want to thank my dedicated supervisor Docent Margareta Reis for discussing ideas and an overall great time. Also I want to thank Martin Singull for his statistical support.

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22. Bender, R.P., et al., N-acetyl-p-benzoquinone imine, the toxic metabolite of acetaminophen, is a topoisomerase II poison. Biochemistry, 2004. 43(12): p. 3731-9. 23. Dart, R.C., et al., Acetaminophen poisoning: an evidence-based consensus guideline for out- of-hospital management. Clin Toxicol (Phila), 2006. 44(1): p. 1-18. 24. Jonasson, B., U. Jonasson, and T. Saldeen, Among fatal poisonings dextropropoxyphene predominates in younger people, antidepressants in the middle aged and sedatives in the elderly. J Forensic Sci, 2000. 45(1): p. 7-10. 25. Park, S.H., R.C. Wackernah, and G.L. Stimmel, Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants? J Pharm Pract, 2014. 27(1): p. 71-8. 26. Koski, A., E. Vuori, and I. Ojanpera, Newer antidepressants: evaluation of fatal toxicity index and interaction with alcohol based on Finnish postmortem data. Int J Legal Med, 2005. 119(6): p. 344-8. 27. Läkemedelsverket. Dextropropoxifen dras bort från marknaden. 2010-02-15 [cited 2014 05-10]. 28. Agency, E.M. European Medicines Agency recommends withdrawal of dextropropoxyphene- containing medicines. 2009-06-26 [cited 2014 05-10]. 29. Sue, Y.J. and M. Shannon, Pharmacokinetics of drugs in overdose. Clin Pharmacokinet, 1992. 23(2): p. 93-105. 30. Yarema, M.C. and C.E. Becker, Key concepts in postmortem drug redistribution. Clin Toxicol (Phila), 2005. 43(4): p. 235-41.

Appendix I – Known drug interactions Known relevant drug interactions with the index-antidepressants found in SFINX (Swedish, Finnish, Interaction X-referencing). This database is under constant development and these interactions could be found April 4, 2014.

Table below shows known drug interactions with the index-antidepressants and the clinical significance meaning. A: The interaction has no clinical significance B: The interactions clinical significance is unknown and/or varies C: Clinically important interaction that can be dealt with, for example by dose adjustment D: Clinically meaningful interaction that should be avoided

index-antidepressant drug interaction with clinical significance Amitriptyline Moclobemide D Paroxetine C Levomepromazine C Fluoxetine C Tramadol C Carbamazepine C Amphetamine C Morphine B Venlafaxine B Fluvoxamine B Mirtazapine A Citalopram Moclobemide D Fluoxetine D Paroxetine D Carbamazepine C Tramadol C Clomipramine B Venlafaxine B Imipramine B Clomipramine Fluvoxamine D Tramadol D Moclobemide D Codeine C Fluoxetine C Paroxetine C Levomepromazine C Venlafaxine C Citalopram B Morphine B Carbamazepine B

Fluoxetine Desipramine D Moclobemide D Codeine D Venlafaxine D Sertraline D Tramadol D Fluvoxamine D Citalopram D Paroxetine D Amitriptyline C Imipramine C Carbamazepine C Alprazolam C Nortriptyline C Clomipramine C Trimipramine C Maprotiline C Diazepam B Mirtazapine B Fluvoxamine Clomipramine D Moclobemide D Mirtazapine D Fluoxetine D Paroxetine D Theophylline D Caffeine C Imipramine C Diazepam C Alprazolam C Tramadol C Maprotiline C Trimipramine C Desipramine B Amitriptyline B Venlafaxine B Imipramine Carbamazepine C Fluoxetine C Fluvoxamine C Paroxetine C Tramadol C Venlafaxine B

Maprotiline Moclobemide C Fluvoxamine C Fluoxetine C Levomepromazine C Paroxetine C Venlafaxine B Mianserin Moclobemide D Carbamazepine C Thioridazine C Mirtazapine Fluvoxamine D Moclobemide D Carbamazepine C Venlafaxine B Fluoxetine B Amitriptyline A Moclobemide Venlafaxine D Fluoxetine D Clomipramine D Fluvoxamine D Paroxetine D Citalopram D Sertraline D Tramadol D Mianserin D Mirtazapine D Nortriptyline D Amitriptyline D Maprotiline C Trimipramine C Dextropropoxyphene B Nortriptyline Moclobemide D Carbamazepine C Paroxetine C Levomepromazine C Fluoxetine C Dextropropoxyphene B Venlafaxine B

Paroxetine Venlafaxine D Tramadol D Desipramine D Codeine D Moclobemide D Fluvoxamine D Fluoxetine D Sertraline D Citalopram D Amitriptyline C Nortriptyline C Imipramine C Clomipramine C Trimipramine C Sertraline Moclobemide D Fluoxetine D Paroxetine D Carbamazepine C Tramadol C Desipramine B Venlafaxine B Zolpidem B Trimipramine Moclobemide C Fluoxetine C Tramadol C Paroxetine C Venlafaxine B Venlafaxine Paroxetine D Moclobemide D Fluoxetine D Clomipramine C Desipramine B Carbamazepine B Imipramine B Mirtazapine B Trimipramine B Nortriptyline B Amitriptyline B Citalopram B Sertraline B Fluvoxamine B Maprotiline B

Appendix II – Relative risk Relative risk for the prevalence of concomitant drugs in B-cases compared to C-cases.

When studying the following relative risk plots remember that significant findings have to meet the two criteria that are listed below:

1. The confidence interval of the relative risk´s, showed as blue horizontal lines, has to be separated from 1. This means that the confidence interval should not overlap the blue vertical line in the plot.

2. The p-value (shown in the side of the plot for each drug) has to be lower than the value from the Benjamini-Hochberg procedure which can be seen in the header of the plot. To make it easier drugs that meet this criterion will be below a horizontal black line in the plot. If no black line is seen no p-values were significant after the Benjamini-Hochberg correction.

Drugs which have 95% confidence intervals not overlapping are significantly more or less common in B-cases or C-cases.

In the right-hand side of the plot the name and values for the drugs are listed (in the same order as the showed confidence intervals); a, c, b and d are the number of cases corresponding to each of the groups used in the contingency tables.

Figure A: The drugs dextropropoxyphene, ethanol, codeine, flunitrazepam, paracetamol, propiomazine, alimemazine are signifcantly more common in B-cases (intoxications) than in C-cases (nonintoxications).

Figure B: Ethanol is significantly more common in B-cases than C-cases.

Figure C: Dextropropoxyphene, ethanol, levomepromazine, propiomazine, flunitrazepam, paracetamol, diazepam and alimemazine are significantly more common in B-cases than C-cases.

Figure D: Dextropropoxyphene and paracetamol are significantly more common in B-cases than C-cases.

Figure E: Dextropropoxyphene and propiomazine are significantly more common in B-cases than C-cases.

Figure F: No significant differences of concomitant drugs between B-cases and C-cases.

Figure G: No significant differences of concomitant drugs between B-cases and C-cases.

Figure H: No significant differences of concomitant drugs between B-cases and C-cases.

Figure I: Levomepromazine, ethanol, trimipramine, flunitrazepam, paracetamol, dextropropoxyphene are significantly more common in B-cases than C-cases.

Figure J: Dextropropoxyphene, ethanol, codeine, morphine, propiomazine, flunitrazepam, paracetamol and alimemazine are significantly more common in B-cases than C-cases.

Figure K: No significant differences of concomitant drugs between B-cases and C-cases.

Figure L: No significant differences of concomitant drugs between B-cases and C-cases.

Figure M: Paracetamol and dextropropoxyphene are significantly more common in B-cases than C-cases.

Figure N: Codeine, dextropropoxyphene, citalopram, caffeine and zolpidem are significantly more common in B-cases than C-cases.

Figure O: No significant differences of concomitant drugs between B-cases and C-cases.

Figure P: Dextropropoxyphene, propiomazine, nortriptyline, codeine, alimemazine, amitriptyline, flunitrazepam, citalopram and paracetamol are significantly more common in B-cases than in C-case

Appendix III – Frequency tables Frequency tables for both B-cases and C-cases of all different index-antidepressants and the two combined groups of index-antidepressants are displayed on the next pages.

In the tables are the number of cases, the number of concomitant substances, the number of cases with at least ≥ 1, ≥ 2 or ≥ 3 concomitant drugs and the average number of concomitant drugs shown.

For the B-cases the median concentration of the index-antidepressant is displayed along with the highest and lowest concentration found. For C-cases also the median concentration is displayed for the cases with at least one concomitant drug and for the cases with no concomitant drugs. These two are compared and the p-value from the test is shown.

For the two groups “all B-cases” and “all C-cases” no antidepressant blood concentrations are shown.

Further down in each table are the most common concomitant drugs listed along with the number of cases they were detected in, and how big the proportion of the group is (%).

Last in each table the most common double and triple combinations of concomitant drugs are listed and the number of cases they were found in.

44 all b-cases B-cases ------The following results do not include group index-antidepressants or their metabolites The data contains 749 cases The data contains 111 different substances ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressants number of such cases 736, 628, 476 ------Average number of drugs/case average = 3 (cases with at least one substances in addition to the index-antidepressants) ------The most common substances 1 : ethanol 349 47.42% 2 : paracetamol 234 31.79% 3 : dextropropoxyphene 222 30.16% 4 : propiomazine 176 23.91% 5 : diazepam 175 23.78% 6 : zopiclone 121 16.44% 7 : flunitrazepam 92 12.50% 8 : alimemazine 86 11.68% 9 : codeine 81 11.01% 10 : nitrazepam 70 9.51% 11 : levomepromazine 63 8.56% 12 : morphine 50 6.79% 13 : zolpidem 46 6.25% 14 : carbamazepine 44 5.98% 15 : alprazolam 43 5.84% 16 : promethazine 41 5.57% 17 : oxazepam 40 5.43% 18 : hydroxyzine 39 5.30% 19 : tramadol 37 5.03% 20 : carisoprodol 28 3.80% ------The most common combinations 1: paracetamol dextropropoxyphene - 134 2: ethanol paracetamol - 100 3: ethanol dextropropoxyphene - 85 4: ethanol propiomazine - 82 5: ethanol diazepam - 75 6: paracetamol diazepam - 69 7: dextropropoxyphene diazepam - 61 8: paracetamol codeine - 55 9: ethanol zopiclone - 54 10: paracetamol propiomazine - 54 11: ethanol paracetamol dextropropoxyphene 49 12: codeine morphine - 44 13: dextropropoxyphene zopiclone - 41 14: propiomazine diazepam - 41 15: ethanol alimemazine - 40 16: dextropropoxyphene propiomazine - 40 17: propiomazine zopiclone - 40 18: paracetamol flunitrazepam - 37 19: paracetamol zopiclone - 36 20: paracetamol dextropropoxyphene diazepam 35 21: dextropropoxyphene flunitrazepam - 32 22: ethanol codeine - 31 23: ethanol flunitrazepam - 30 24: ethanol nitrazepam - 28 25: paracetamol morphine - 28 26: diazepam flunitrazepam - 28 27: diazepam codeine - 28 28: ethanol paracetamol diazepam 28 29: dextropropoxyphene codeine - 27 30: ethanol paracetamol propiomazine 27 ------

45 all c-cases C-cases ------The following results do not include group index-antidepressants or their metabolites The data contains 1654 cases The data contains 89 different substances ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressants number of such cases 922, 432, 154 ------Average number of drugs/case average = 2 (cases with at least one substances in addition to the index-antidepressants) ------The most common substances 1 : ethanol 248 26.90% 2 : diazepam 201 21.80% 3 : paracetamol 165 17.90% 4 : zopiclone 136 14.75% 5 : propiomazine 118 12.80% 6 : alimemazine 77 8.35% 7 : nitrazepam 72 7.81% 8 : dextropropoxyphene 67 7.27% 9 : flunitrazepam 33 3.58% 10 : carbamazepine 23 2.49% 11 : tramadol 23 2.49% 12 : zolpidem 21 2.28% 13 : hydroxyzine 20 2.17% 14 : oxazepam 20 2.17% 15 : olanzapine 20 2.17% 16 : promethazine 20 2.17% 17 : alprazolam 18 1.95% 18 : codeine 18 1.95% 19 : orphenadrine 18 1.95% 20 : thioridazine 17 1.84% ------The most common combinations 1: ethanol diazepam - 44 2: paracetamol dextropropoxyphene - 39 3: diazepam paracetamol - 24 4: ethanol zopiclone - 23 5: ethanol paracetamol - 22 6: diazepam zopiclone - 22 7: ethanol propiomazine - 21 8: diazepam alimemazine - 18 9: paracetamol zopiclone - 18 10: paracetamol propiomazine - 18 11: diazepam propiomazine - 16 12: diazepam nitrazepam - 15 13: zopiclone propiomazine - 15 14: paracetamol nitrazepam - 12 15: paracetamol codeine - 11 16: paracetamol tramadol - 10 17: ethanol alimemazine - 9 18: diazepam dextropropoxyphene - 9 19: ethanol alprazolam - 8 20: diazepam codeine - 8 21: codeine morphine - 8 22: ethanol nitrazepam - 7 23: ethanol zolpidem - 7 24: ethanol promethazine - 7 25: ethanol amphetamine - 7 26: diazepam flunitrazepam - 7 27: paracetamol alimemazine - 7 28: zopiclone alimemazine - 7 29: alimemazine hydroxyzine - 7 30: nitrazepam dextropropoxyphene - 7 ------

46 amitriptyline B-cases ------The data contains 119 cases The data contains 71 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 119, 99, 70 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.70 [µg/g] (max = 32.00, min = 0.50) ------The most common substances in addition to the index-antidepressant 1: ethanol 67 56.30% 2: paracetamol 33 27.73% 3: dextropropoxyphene 30 25.21% 4: diazepam 27 22.69% 5: flunitrazepam 21 17.65% 6: propiomazine 17 14.29% 7: nitrazepam 14 11.76% 8: zopiclone 12 10.08% 9: alimemazine 11 9.24% 10: citalopram 11 9.24% 11: venlafaxine 8 6.72% 12: hydroxyzine 7 5.88% 13: carbamazepine 7 5.88% 14: levomepromazine 7 5.88% 15: carisoprodol 6 5.04% ------The most common combinations 1: ethanol dextropropoxyphene - 19 2: ethanol paracetamol - 18 3: paracetamol dextropropoxyphene - 18 4: ethanol diazepam - 17 5: paracetamol diazepam - 12 6: dextropropoxyphene diazepam - 10 7: ethanol paracetamol dextropropoxyphene 10 8: paracetamol flunitrazepam - 9 9: ethanol paracetamol diazepam 9 10: ethanol flunitrazepam - 8 11: ethanol propiomazine - 7 12: dextropropoxyphene propiomazine - 7 13: ethanol dextropropoxyphene diazepam 7 14: paracetamol dextropropoxyphene diazepam 7 15: ethanol nitrazepam - 6 16: ethanol carbamazepine - 6 17: paracetamol propiomazine - 6 18: dextropropoxyphene flunitrazepam - 6 19: diazepam flunitrazepam - 6 20: ethanol zopiclone - 5 ------

47 amitriptyline C-cases ------The data contains 89 cases The data contains 39 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 55, 31, 17 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.20 [µg/g] (max = 2.50, min = 0.05) cases (other substances YES) median = 0.20 [µg/g] (max = 2.50, min = 0.05) cases (other substances NO ) median = 0.10 [µg/g] (max = 0.50, min = 0.06) MMW p value: 0.360 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: diazepam 18 32.73% 2: paracetamol 12 21.82% 3: ethanol 11 20.00% 4: dextropropoxyphene 9 16.36% 5: carbamazepine 7 12.73% 6: nitrazepam 5 9.09% 7: alimemazine 4 7.27% 8: citalopram 4 7.27% 9: codeine 4 7.27% 10: morphine 3 5.45% 11: amphetamine 2 3.64% 12: flunitrazepam 2 3.64% 13: hydroxyzine 2 3.64% 14: clomipramine 2 3.64% 15: levomepromazine 2 3.64% ------The most common combinations 1: paracetamol dextropropoxyphene - 5 2: diazepam paracetamol - 4 3: paracetamol codeine - 4 4: diazepam ethanol - 3 5: diazepam alimemazine - 3 6: paracetamol citalopram - 3 7: diazepam carbamazepine - 2 8: diazepam codeine - 2 9: diazepam morphine - 2 10: diazepam amphetamine - 2 11: diazepam zopiclone - 2 12: paracetamol carbamazepine - 2 13: paracetamol nitrazepam - 2 14: paracetamol alimemazine - 2 15: paracetamol morphine - 2 16: ethanol carbamazepine - 2 17: codeine morphine - 2 18: diazepam paracetamol alimemazine 2 19: diazepam paracetamol codeine 2 20: paracetamol codeine morphine 2 ------

48 citalopram B-cases ------The data contains 243 cases The data contains 85 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 243, 216, 171 ------Average number of drugs/case = 4 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.30 [µg/g] (max = 78.00, min = 0.50) ------The most common substances in addition to the index-antidepressant 1: ethanol 117 48.15% 2: dextropropoxyphene 87 35.80% 3: paracetamol 76 31.28% 4: propiomazine 64 26.34% 5: diazepam 58 23.87% 6: zopiclone 42 17.28% 7: flunitrazepam 27 11.11% 8: levomepromazine 27 11.11% 9: alimemazine 25 10.29% 10: codeine 22 9.05% 11: nitrazepam 22 9.05% 12: zolpidem 18 7.41% 13: morphine 17 7.00% 14: hydroxyzine 16 6.58% 15: tramadol 16 6.58% ------The most common combinations 1: dextropropoxyphene paracetamol - 45 2: ethanol propiomazine - 36 3: ethanol paracetamol - 34 4: paracetamol diazepam - 28 5: ethanol dextropropoxyphene - 26 6: dextropropoxyphene diazepam - 26 7: ethanol diazepam - 24 8: dextropropoxyphene zopiclone - 17 9: paracetamol propiomazine - 17 10: paracetamol codeine - 17 11: ethanol zopiclone - 16 12: propiomazine diazepam - 16 13: ethanol alimemazine - 13 14: dextropropoxyphene propiomazine - 13 15: paracetamol zopiclone - 13 16: codeine morphine - 13 17: ethanol dextropropoxyphene paracetamol 13 18: dextropropoxyphene paracetamol diazepam 13 19: ethanol tramadol - 12 20: paracetamol tramadol - 12 ------

49 citalopram C-cases ------The data contains 629 cases The data contains 78 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 363, 178, 76 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.30 [µg/g] (max = 1.80, min = 0.05) cases (other substances YES) median = 0.30 [µg/g] (max = 1.80, min = 0.05) cases (other substances NO ) median = 0.30 [µg/g] (max = 1.40, min = 0.05) MMW p value: 0.027 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: ethanol 92 25.34% 2: paracetamol 70 19.28% 3: diazepam 59 16.25% 4: propiomazine 52 14.33% 5: zopiclone 48 13.22% 6: mirtazapine 31 8.54% 7: nitrazepam 28 7.71% 8: dextropropoxyphene 25 6.89% 9: mianserin 25 6.89% 10: alimemazine 21 5.79% 11: flunitrazepam 14 3.86% 12: tramadol 12 3.31% 13: oxazepam 10 2.75% 14: carbamazepine 9 2.48% 15: zolpidem 8 2.20% ------The most common combinations 1: paracetamol dextropropoxyphene - 15 2: ethanol diazepam - 13 3: ethanol paracetamol - 10 4: paracetamol diazepam - 10 5: ethanol zopiclone - 9 6: diazepam propiomazine - 9 7: propiomazine zopiclone - 9 8: ethanol propiomazine - 8 9: paracetamol zopiclone - 7 10: zopiclone mirtazapine - 7 11: ethanol mianserin - 6 12: paracetamol propiomazine - 6 13: propiomazine mirtazapine - 6 14: paracetamol nitrazepam - 5 15: paracetamol tramadol - 5 16: ethanol tramadol - 4 17: ethanol zolpidem - 4 18: ethanol amphetamine - 4 19: paracetamol alimemazine - 4 20: paracetamol flunitrazepam - 4 ------

50 clomipramine B-cases ------The data contains 107 cases The data contains 76 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 107, 87, 68 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.40 [µg/g] (max = 14.00, min = 0.40) ------The most common substances in addition to the index-antidepressant 1: ethanol 43 40.19% 2: paracetamol 33 30.84% 3: dextropropoxyphene 29 27.10% 4: diazepam 25 23.36% 5: flunitrazepam 15 14.02% 6: zopiclone 14 13.08% 7: levomepromazine 13 12.15% 8: codeine 12 11.21% 9: propiomazine 12 11.21% 10: alimemazine 11 10.28% 11: carbamazepine 11 10.28% 12: oxazepam 9 8.41% 13: moclobemide 7 6.54% 14: nortriptyline 7 6.54% 15: citalopram 6 5.61% ------The most common combinations 1: paracetamol dextropropoxyphene - 19 2: ethanol paracetamol - 13 3: ethanol dextropropoxyphene - 10 4: paracetamol codeine - 10 5: dextropropoxyphene diazepam - 10 6: ethanol diazepam - 8 7: paracetamol diazepam - 8 8: ethanol paracetamol dextropropoxyphene 7 9: paracetamol dextropropoxyphene diazepam 7 10: ethanol flunitrazepam - 6 11: ethanol zopiclone - 6 12: paracetamol levomepromazine - 6 13: ethanol codeine - 5 14: ethanol alimemazine - 5 15: ethanol carbamazepine - 5 16: paracetamol flunitrazepam - 5 17: dextropropoxyphene flunitrazepam - 5 18: dextropropoxyphene zopiclone - 5 19: dextropropoxyphene levomepromazine - 5 20: diazepam zopiclone - 5 ------

51 clomipramine C-cases ------The data contains 141 cases The data contains 51 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 84, 42, 17 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.20 [µg/g] (max = 1.00, min = 0.05) cases (other substances YES) median = 0.20 [µg/g] (max = 0.90, min = 0.06) cases (other substances NO ) median = 0.20 [µg/g] (max = 1.00, min = 0.05) MMW p value: 0.369 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: diazepam 24 28.57% 2: ethanol 23 27.38% 3: alimemazine 11 13.10% 4: paracetamol 10 11.90% 5: dextropropoxyphene 6 7.14% 6: promethazine 6 7.14% 7: carbamazepine 5 5.95% 8: flunitrazepam 4 4.76% 9: nitrazepam 4 4.76% 10: zopiclone 4 4.76% 11: citalopram 3 3.57% 12: propiomazine 3 3.57% 13: theophylline 3 3.57% 14: mirtazapine 3 3.57% 15: amitriptyline 2 2.38% ------The most common combinations 1: diazepam ethanol - 6 2: diazepam alimemazine - 3 3: diazepam nitrazepam - 3 4: paracetamol dextropropoxyphene - 3 5: diazepam flunitrazepam - 2 6: ethanol alimemazine - 2 7: ethanol paracetamol - 2 8: ethanol promethazine - 2 9: ethanol propiomazine - 2 10: alimemazine dextropropoxyphene - 2 11: alimemazine promethazine - 2 12: alimemazine carbamazepine - 2 13: alimemazine mirtazapine - 2 14: diazepam paracetamol - 1 15: diazepam dextropropoxyphene - 1 16: diazepam promethazine - 1 17: diazepam carbamazepine - 1 18: diazepam citalopram - 1 19: diazepam thioridazine - 1 20: diazepam sertraline - 1 ------

52 fluoxetine B-cases ------The data contains 36 cases The data contains 50 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 36, 34, 30 ------Average number of drugs/case = 5 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.40 [µg/g] (max = 7.90, min = 0.80) ------The most common substances in addition to the index-antidepressant 1: diazepam 16 44.44% 2: ethanol 15 41.67% 3: dextropropoxyphene 14 38.89% 4: propiomazine 11 30.56% 5: paracetamol 10 27.78% 6: codeine 9 25.00% 7: alimemazine 8 22.22% 8: zopiclone 6 16.67% 9: morphine 5 13.89% 10: promethazine 5 13.89% 11: zolpidem 5 13.89% 12: flunitrazepam 4 11.11% 13: carbamazepine 4 11.11% 14: nitrazepam 4 11.11% 15: alprazolam 3 8.33% ------The most common combinations 1: diazepam ethanol - 9 2: diazepam dextropropoxyphene - 8 3: dextropropoxyphene paracetamol - 8 4: ethanol dextropropoxyphene - 7 5: ethanol propiomazine - 7 6: diazepam codeine - 6 7: diazepam paracetamol - 5 8: dextropropoxyphene codeine - 5 9: paracetamol codeine - 5 10: codeine morphine - 5 11: diazepam morphine - 4 12: ethanol paracetamol - 4 13: ethanol zopiclone - 4 14: propiomazine paracetamol - 4 15: diazepam ethanol dextropropoxyphene 4 16: diazepam dextropropoxyphene paracetamol 4 17: diazepam dextropropoxyphene codeine 4 18: diazepam codeine morphine 4 19: ethanol propiomazine paracetamol 4 20: dextropropoxyphene paracetamol codeine 4 ------

53 fluoxetine C-cases ------The data contains 53 cases The data contains 37 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 42, 23, 10 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.40 [µg/g] (max = 1.60, min = 0.10) cases (other substances YES) median = 0.40 [µg/g] (max = 1.60, min = 0.10) cases (other substances NO ) median = 0.30 [µg/g] (max = 1.30, min = 0.10) MMW p value: 0.807 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: ethanol 19 45.24% 2: diazepam 13 30.95% 3: paracetamol 6 14.29% 4: zopiclone 4 9.52% 5: alimemazine 3 7.14% 6: codeine 3 7.14% 7: mianserin 3 7.14% 8: caffeine 2 4.76% 9: propiomazine 2 4.76% 10: venlafaxine 2 4.76% 11: mirtazapine 2 4.76% 12: alprazolam 1 2.38% 13: amphetamine 1 2.38% 14: amitriptyline 1 2.38% 15: citalopram 1 2.38% ------The most common combinations 1: ethanol diazepam - 6 2: ethanol codeine - 2 3: ethanol caffeine - 2 4: diazepam alimemazine - 2 5: diazepam codeine - 2 6: diazepam caffeine - 2 7: zopiclone venlafaxine - 2 8: ethanol diazepam caffeine 2 9: ethanol paracetamol - 1 10: ethanol zopiclone - 1 11: ethanol mirtazapine - 1 12: ethanol alprazolam - 1 13: ethanol phenazone - 1 14: ethanol carbamazepine - 1 15: ethanol cocaine - 1 16: ethanol benzoylecgonine - 1 17: ethanol carboxyhaemoglobin - 1 18: ethanol promethazine - 1 19: ethanol theophylline - 1 20: ethanol tramadol - 1 ------

54 fluvoxamine B-cases ------The data contains 15 cases The data contains 32 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 15, 14, 13 ------Average number of drugs/case = 5 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 3.50 [µg/g] (max = 14.00, min = 0.90) ------The most common substances in addition to the index-antidepressant 1: paracetamol 6 40.00% 2: flunitrazepam 5 33.33% 3: caffeine 5 33.33% 4: diazepam 4 26.67% 5: ethanol 4 26.67% 6: flecainide 4 26.67% 7: levomepromazine 4 26.67% 8: amitriptyline 3 20.00% 9: dextropropoxyphene 3 20.00% 10: moclobemide 3 20.00% 11: nortriptyline 3 20.00% 12: propiomazine 3 20.00% 13: alprazolam 2 13.33% 14: citalopram 2 13.33% 15: theophylline 2 13.33% ------The most common combinations 1: paracetamol flunitrazepam - 3 2: paracetamol caffeine - 3 3: paracetamol ethanol - 3 4: paracetamol dextropropoxyphene - 3 5: ethanol propiomazine - 3 6: amitriptyline nortriptyline - 3 7: paracetamol diazepam - 2 8: paracetamol flecainide - 2 9: paracetamol propiomazine - 2 10: paracetamol alprazolam - 2 11: flunitrazepam diazepam - 2 12: flunitrazepam ethanol - 2 13: flunitrazepam dextropropoxyphene - 2 14: caffeine diazepam - 2 15: caffeine theophylline - 2 16: flecainide levomepromazine - 2 17: levomepromazine amitriptyline - 2 18: levomepromazine nortriptyline - 2 19: paracetamol flunitrazepam ethanol 2 20: paracetamol flunitrazepam dextropropoxyphene 2 ------

55 fluvoxamine C-cases ------The data contains 12 cases The data contains 13 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 9, 6, 4 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.45 [µg/g] (max = 1.20, min = 0.10) cases (other substances YES) median = 0.60 [µg/g] (max = 1.20, min = 0.20) cases (other substances NO ) median = 0.20 [µg/g] (max = 0.30, min = 0.10) MMW p value: 0.045 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: propiomazine 4 44.44% 2: flecainide 3 33.33% 3: nitrazepam 3 33.33% 4: paracetamol 2 22.22% 5: theophylline 2 22.22% 6: alimemazine 1 11.11% 7: diazepam 1 11.11% 8: flunitrazepam 1 11.11% 9: hydroxyzine 1 11.11% 10: caffeine 1 11.11% 11: verapamil 1 11.11% 12: venlafaxine 1 11.11% ------The most common combinations 1: propiomazine nitrazepam - 2 2: propiomazine flecainide - 1 3: propiomazine paracetamol - 1 4: propiomazine theophylline - 1 5: propiomazine diazepam - 1 6: flecainide nitrazepam - 1 7: flecainide paracetamol - 1 8: flecainide flunitrazepam - 1 9: nitrazepam paracetamol - 1 10: paracetamol alimemazine - 1 11: paracetamol hydroxyzine - 1 12: paracetamol venlafaxine - 1 13: theophylline diazepam - 1 14: theophylline caffeine - 1 15: theophylline verapamil - 1 16: alimemazine hydroxyzine - 1 17: alimemazine venlafaxine - 1 18: hydroxyzine venlafaxine - 1 19: caffeine verapamil - 1 20: propiomazine flecainide nitrazepam 1 ------

56 imipramine B-cases ------The data contains 3 cases The data contains 17 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 3, 3, 3 ------Average number of drugs/case = 6 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.10 [µg/g] (max = 4.00, min = 0.60) ------The most common substances in addition to the index-antidepressant 1: ethanol 3 100.00% 2: alimemazine 1 33.33% 3: alprazolam 1 33.33% 4: amitriptyline 1 33.33% 5: fluvoxamine 1 33.33% 6: clomipramine 1 33.33% 7: caffeine 1 33.33% 8: moclobemide 1 33.33% 9: nortriptyline 1 33.33% 10: oxazepam 1 33.33% 11: paroxetine 1 33.33% 12: paracetamol 1 33.33% 13: propiomazine 1 33.33% 14: theophylline 1 33.33% 15: TSH 1 33.33% ------The most common combinations 1: ethanol alimemazine - 1 2: ethanol alprazolam - 1 3: ethanol amitriptyline - 1 4: ethanol fluvoxamine - 1 5: ethanol clomipramine - 1 6: ethanol caffeine - 1 7: ethanol moclobemide - 1 8: ethanol nortriptyline - 1 9: ethanol oxazepam - 1 10: ethanol paroxetine - 1 11: ethanol paracetamol - 1 12: ethanol propiomazine - 1 13: ethanol theophylline - 1 14: ethanol TSH - 1 15: ethanol T3 - 1 16: alimemazine clomipramine - 1 17: alimemazine paroxetine - 1 18: alimemazine TSH - 1 19: alimemazine T3 - 1 20: alprazolam fluvoxamine - 1 ------

57 imipramine C-cases ------The data contains 7 cases The data contains 11 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 6, 3, 1 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.10 [µg/g] (max = 0.70, min = 0.02) cases (other substances YES) median = 0.10 [µg/g] (max = 0.70, min = 0.02) cases (other substances NO ) median = 0.10 [µg/g] (max = 0.10, min = 0.10) MMW p value: 1.000 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: alimemazine 1 16.67% 2: amitriptyline 1 16.67% 3: dextropropoxyphene 1 16.67% 4: diazepam 1 16.67% 5: ethanol 1 16.67% 6: levomepromazine 1 16.67% 7: lidocaine 1 16.67% 8: oxazepam 1 16.67% 9: paracetamol 1 16.67% 10: thiopental 1 16.67% ------The most common combinations 1: amitriptyline levomepromazine - 1 2: amitriptyline thiopental - 1 3: dextropropoxyphene diazepam - 1 4: levomepromazine thiopental - 1 5: lidocaine paracetamol - 1 6: amitriptyline levomepromazine thiopental 1 ------

58 maprotiline B-cases ------The data contains 17 cases The data contains 33 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 17, 15, 9 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 3.10 [µg/g] (max = 9.90, min = 0.50) ------The most common substances in addition to the index-antidepressant 1: ethanol 5 29.41% 2: diazepam 4 23.53% 3: propiomazine 3 17.65% 4: carbamazepine 2 11.76% 5: clomipramine 2 11.76% 6: levomepromazine 2 11.76% 7: mianserin 2 11.76% 8: nitrazepam 2 11.76% 9: paracetamol 2 11.76% 10: zopiclone 2 11.76% 11: alprazolam 1 5.88% 12: amitriptyline 1 5.88% 13: citalopram 1 5.88% 14: dextropropoxyphene 1 5.88% 15: flecainide 1 5.88% ------The most common combinations 1: ethanol zopiclone - 2 2: diazepam propiomazine - 2 3: ethanol carbamazepine - 1 4: ethanol levomepromazine - 1 5: ethanol nitrazepam - 1 6: ethanol amitriptyline - 1 7: ethanol flecainide - 1 8: ethanol moclobemide - 1 9: ethanol remoxipride - 1 10: ethanol buspirone - 1 11: diazepam clomipramine - 1 12: diazepam mianserin - 1 13: diazepam paracetamol - 1 14: diazepam alprazolam - 1 15: diazepam orphenadrine - 1 16: diazepam trimetoprim - 1 17: diazepam sertraline - 1 18: propiomazine paracetamol - 1 19: propiomazine kinin - 1 20: propiomazine orphenadrine - 1 ------

59 maprotiline C-cases ------The data contains 18 cases The data contains 21 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 12, 8, 3 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.20 [µg/g] (max = 1.10, min = 0.10) cases (other substances YES) median = 0.20 [µg/g] (max = 1.10, min = 0.10) cases (other substances NO ) median = 0.20 [µg/g] (max = 0.90, min = 0.10) MMW p value: 0.925 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: diazepam 4 33.33% 2: dextropropoxyphene 2 16.67% 3: flunitrazepam 2 16.67% 4: promethazine 2 16.67% 5: amitriptyline 1 8.33% 6: citalopram 1 8.33% 7: ethanol 1 8.33% 8: glucose 1 8.33% 9: clomipramine 1 8.33% 10: clonazepam 1 8.33% 11: mianserin 1 8.33% 12: nitrazepam 1 8.33% 13: nortriptyline 1 8.33% 14: orphenadrine 1 8.33% 15: paracetamol 1 8.33% ------The most common combinations 1: diazepam promethazine - 1 2: diazepam ethanol - 1 3: diazepam glucose - 1 4: diazepam clomipramine - 1 5: diazepam orphenadrine - 1 6: diazepam tetrahydrocannabinol - 1 7: diazepam zopiclone - 1 8: dextropropoxyphene flunitrazepam - 1 9: dextropropoxyphene paracetamol - 1 10: dextropropoxyphene propiomazine - 1 11: promethazine ethanol - 1 12: promethazine glucose - 1 13: promethazine clomipramine - 1 14: promethazine clonazepam - 1 15: promethazine mianserin - 1 16: promethazine tetrahydrocannabinol - 1 17: amitriptyline nortriptyline - 1 18: citalopram pentobarbital - 1 19: ethanol glucose - 1 20: ethanol clomipramine - 1 ------

60 mianserin B-cases ------The data contains 28 cases The data contains 40 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 28, 27, 20 ------Average number of drugs/case = 4 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.70 [µg/g] (max = 13.00, min = 0.10) ------The most common substances in addition to the index-antidepressant 1: ethanol 12 42.86% 2: paracetamol 10 35.71% 3: citalopram 7 25.00% 4: propiomazine 6 21.43% 5: dextropropoxyphene 5 17.86% 6: flunitrazepam 5 17.86% 7: zopiclone 5 17.86% 8: diazepam 4 14.29% 9: levomepromazine 4 14.29% 10: promethazine 4 14.29% 11: fluoxetine 3 10.71% 12: codeine 3 10.71% 13: nitrazepam 3 10.71% 14: trimipramine 3 10.71% 15: sertraline 3 10.71% ------The most common combinations 1: ethanol paracetamol - 6 2: ethanol citalopram - 3 3: ethanol propiomazine - 3 4: ethanol zopiclone - 3 5: paracetamol propiomazine - 3 6: paracetamol dextropropoxyphene - 3 7: paracetamol flunitrazepam - 3 8: citalopram zopiclone - 3 9: ethanol flunitrazepam - 2 10: ethanol diazepam - 2 11: ethanol promethazine - 2 12: ethanol codeine - 2 13: ethanol trimipramine - 2 14: ethanol sertraline - 2 15: paracetamol promethazine - 2 16: paracetamol fluoxetine - 2 17: paracetamol codeine - 2 18: paracetamol paroxetine - 2 19: citalopram dextropropoxyphene - 2 20: propiomazine flunitrazepam - 2 ------

61 mianserin C-cases ------The data contains 156 cases The data contains 50 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 108, 56, 22 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.09 [µg/g] (max = 0.80, min = 0.03) cases (other substances YES) median = 0.09 [µg/g] (max = 0.80, min = 0.03) cases (other substances NO ) median = 0.09 [µg/g] (max = 0.20, min = 0.03) MMW p value: 0.394 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: citalopram 23 21.30% 2: ethanol 17 15.74% 3: diazepam 15 13.89% 4: sertraline 15 13.89% 5: paracetamol 14 12.96% 6: zopiclone 13 12.04% 7: nitrazepam 11 10.19% 8: propiomazine 8 7.41% 9: alimemazine 6 5.56% 10: paroxetine 6 5.56% 11: dextropropoxyphene 4 3.70% 12: moclobemide 4 3.70% 13: thioridazine 4 3.70% 14: flunitrazepam 3 2.78% 15: fluoxetine 3 2.78% ------The most common combinations 1: citalopram ethanol - 4 2: citalopram propiomazine - 4 3: paracetamol nitrazepam - 4 4: paracetamol dextropropoxyphene - 4 5: citalopram diazepam - 3 6: ethanol zopiclone - 3 7: diazepam sertraline - 3 8: diazepam paracetamol - 3 9: sertraline zopiclone - 3 10: ethanol diazepam - 2 11: ethanol sertraline - 2 12: ethanol alimemazine - 2 13: diazepam zopiclone - 2 14: diazepam nitrazepam - 2 15: diazepam venlafaxine - 2 16: zopiclone promethazine - 2 17: nitrazepam dextropropoxyphene - 2 18: diazepam paracetamol nitrazepam 2 19: paracetamol nitrazepam dextropropoxyphene 2 20: citalopram sertraline - 1 ------

62 mirtazapine B-cases ------The data contains 67 cases The data contains 60 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 67, 63, 59 ------Average number of drugs/case = 5 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.50 [µg/g] (max = 26.00, min = 0.20) ------The most common substances in addition to the index-antidepressant 1: ethanol 33 49.25% 2: propiomazine 23 34.33% 3: zopiclone 23 34.33% 4: dextropropoxyphene 22 32.84% 5: diazepam 20 29.85% 6: paracetamol 20 29.85% 7: alimemazine 16 23.88% 8: codeine 12 17.91% 9: citalopram 11 16.42% 10: venlafaxine 10 14.93% 11: flunitrazepam 7 10.45% 12: morphine 7 10.45% 13: tramadol 7 10.45% 14: hydroxyzine 6 8.96% 15: nitrazepam 6 8.96% ------The most common combinations 1: ethanol zopiclone - 15 2: ethanol propiomazine - 12 3: dextropropoxyphene paracetamol - 12 4: ethanol diazepam - 11 5: ethanol dextropropoxyphene - 10 6: ethanol paracetamol - 10 7: propiomazine zopiclone - 10 8: ethanol alimemazine - 9 9: ethanol citalopram - 8 10: zopiclone dextropropoxyphene - 8 11: zopiclone paracetamol - 8 12: diazepam paracetamol - 8 13: paracetamol codeine - 7 14: ethanol codeine - 6 15: propiomazine dextropropoxyphene - 6 16: propiomazine paracetamol - 6 17: propiomazine citalopram - 6 18: dextropropoxyphene diazepam - 6 19: diazepam alimemazine - 6 20: diazepam codeine - 6 ------

63 mirtazapine C-cases ------The data contains 237 cases The data contains 48 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 162, 86, 34 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.10 [µg/g] (max = 1.50, min = 0.09) cases (other substances YES) median = 0.10 [µg/g] (max = 1.50, min = 0.10) cases (other substances NO ) median = 0.10 [µg/g] (max = 0.50, min = 0.09) MMW p value: 0.010 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: zopiclone 36 22.22% 2: diazepam 31 19.14% 3: citalopram 23 14.20% 4: ethanol 23 14.20% 5: paracetamol 23 14.20% 6: propiomazine 23 14.20% 7: alimemazine 19 11.73% 8: sertraline 15 9.26% 9: venlafaxine 12 7.41% 10: dextropropoxyphene 7 4.32% 11: olanzapine 7 4.32% 12: nitrazepam 6 3.70% 13: zolpidem 6 3.70% 14: hydroxyzine 5 3.09% 15: orphenadrine 5 3.09% ------The most common combinations 1: zopiclone citalopram - 5 2: zopiclone paracetamol - 5 3: zopiclone propiomazine - 5 4: citalopram propiomazine - 5 5: ethanol propiomazine - 5 6: paracetamol propiomazine - 5 7: alimemazine sertraline - 5 8: diazepam citalopram - 4 9: paracetamol dextropropoxyphene - 4 10: zopiclone diazepam - 3 11: zopiclone ethanol - 3 12: diazepam ethanol - 3 13: diazepam paracetamol - 3 14: diazepam propiomazine - 3 15: diazepam alimemazine - 3 16: diazepam sertraline - 3 17: citalopram nitrazepam - 3 18: ethanol paracetamol - 3 19: alimemazine hydroxyzine - 3 20: zopiclone alimemazine - 2 ------

64 moclobemide B-cases ------The data contains 30 cases The data contains 46 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 30, 24, 19 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 28.50 [µg/g] (max = 300.00, min = 3.60) ------The most common substances in addition to the index-antidepressant 1: ethanol 10 33.33% 2: propiomazine 8 26.67% 3: clomipramine 6 20.00% 4: paracetamol 6 20.00% 5: zopiclone 5 16.67% 6: citalopram 4 13.33% 7: diazepam 4 13.33% 8: sertraline 4 13.33% 9: dextropropoxyphene 3 10.00% 10: fluvoxamine 3 10.00% 11: fluoxetine 3 10.00% 12: oxazepam 3 10.00% 13: venlafaxine 3 10.00% 14: alimemazine 2 6.67% 15: chlordiazepoxide 2 6.67% ------The most common combinations 1: ethanol propiomazine - 3 2: propiomazine zopiclone - 3 3: paracetamol dextropropoxyphene - 3 4: ethanol clomipramine - 2 5: ethanol paracetamol - 2 6: ethanol zopiclone - 2 7: ethanol citalopram - 2 8: ethanol sertraline - 2 9: ethanol oxazepam - 2 10: ethanol mianserin - 2 11: propiomazine paracetamol - 2 12: propiomazine citalopram - 2 13: propiomazine fluoxetine - 2 14: clomipramine zopiclone - 2 15: clomipramine diazepam - 2 16: paracetamol citalopram - 2 17: zopiclone sertraline - 2 18: ethanol diazepam - 1 19: ethanol fluvoxamine - 1 20: ethanol alprazolam - 1 ------

65 moclobemide C-cases ------The data contains 45 cases The data contains 23 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 29, 16, 5 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.60 [µg/g] (max = 5.00, min = 0.10) cases (other substances YES) median = 0.60 [µg/g] (max = 2.70, min = 0.10) cases (other substances NO ) median = 0.65 [µg/g] (max = 5.00, min = 0.20) MMW p value: 0.784 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: nitrazepam 7 24.14% 2: propiomazine 7 24.14% 3: ethanol 5 17.24% 4: dextropropoxyphene 4 13.79% 5: diazepam 4 13.79% 6: mianserin 4 13.79% 7: paracetamol 4 13.79% 8: oxazepam 3 10.34% 9: zopiclone 3 10.34% 10: levomepromazine 2 6.90% 11: alimemazine 1 3.45% 12: amitriptyline 1 3.45% 13: citalopram 1 3.45% 14: dixyrazine 1 3.45% 15: diltiazem 1 3.45% ------The most common combinations 1: dextropropoxyphene paracetamol - 3 2: nitrazepam ethanol - 2 3: ethanol diazepam - 2 4: oxazepam zopiclone - 2 5: nitrazepam propiomazine - 1 6: nitrazepam alimemazine - 1 7: nitrazepam metronidazoel - 1 8: propiomazine mianserin - 1 9: propiomazine paracetamol - 1 10: propiomazine oxazepam - 1 11: propiomazine zopiclone - 1 12: propiomazine chlorpromazine - 1 13: propiomazine promethazine - 1 14: ethanol dextropropoxyphene - 1 15: ethanol paracetamol - 1 16: ethanol levomepromazine - 1 17: ethanol alimemazine - 1 18: ethanol citalopram - 1 19: ethanol zolpidem - 1 20: ethanol tramadol - 1 ------

66 nortriptyline B-cases ------The data contains 22 cases The data contains 32 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 22, 18, 16 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 2.65 [µg/g] (max = 9.20, min = 0.80) ------The most common substances in addition to the index-antidepressant 1: ethanol 9 40.91% 2: diazepam 6 27.27% 3: paracetamol 6 27.27% 4: dextropropoxyphene 5 22.73% 5: flunitrazepam 4 18.18% 6: nitrazepam 4 18.18% 7: citalopram 3 13.64% 8: carbamazepine 2 9.09% 9: carisoprodol 2 9.09% 10: clomipramine 2 9.09% 11: levomepromazine 2 9.09% 12: meprobamate 2 9.09% 13: oxazepam 2 9.09% 14: paroxetine 2 9.09% 15: promethazine 2 9.09% ------The most common combinations 1: diazepam flunitrazepam - 3 2: paracetamol dextropropoxyphene - 3 3: diazepam paracetamol - 2 4: diazepam dextropropoxyphene - 2 5: diazepam zopiclone - 2 6: paracetamol flunitrazepam - 2 7: paracetamol nitrazepam - 2 8: dextropropoxyphene flunitrazepam - 2 9: dextropropoxyphene carbamazepine - 2 10: carisoprodol meprobamate - 2 11: paracetamol dextropropoxyphene flunitrazepam 2 12: ethanol diazepam - 1 13: ethanol paracetamol - 1 14: ethanol dextropropoxyphene - 1 15: ethanol nitrazepam - 1 16: ethanol citalopram - 1 17: ethanol carbamazepine - 1 18: ethanol carisoprodol - 1 19: ethanol meprobamate - 1 20: ethanol promethazine - 1 ------

67 nortriptyline C-cases ------The data contains 11 cases The data contains 8 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 6, 3, 1 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.30 [µg/g] (max = 1.10, min = 0.10) cases (other substances YES) median = 0.35 [µg/g] (max = 1.10, min = 0.10) cases (other substances NO ) median = 0.20 [µg/g] (max = 0.70, min = 0.10) MMW p value: 0.753 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: citalopram 2 33.33% 2: dextropropoxyphene 2 33.33% 3: diazepam 2 33.33% 4: paracetamol 2 33.33% 5: amitriptyline 1 16.67% 6: orphenadrine 1 16.67% 7: mirtazapine 1 16.67% ------The most common combinations 1: diazepam paracetamol - 2 2: citalopram dextropropoxyphene - 1 3: citalopram diazepam - 1 4: citalopram paracetamol - 1 5: citalopram mirtazapine - 1 6: diazepam mirtazapine - 1 7: paracetamol mirtazapine - 1 8: citalopram diazepam paracetamol 1 9: citalopram diazepam mirtazapine 1 10: citalopram paracetamol mirtazapine 1 11: diazepam paracetamol mirtazapine 1 ------

68 paroxetine B-cases ------The data contains 31 cases The data contains 41 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 31, 29, 24 ------Average number of drugs/case = 4 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.80 [µg/g] (max = 5.70, min = 0.30) ------The most common substances in addition to the index-antidepressant 1: paracetamol 15 48.39% 2: dextropropoxyphene 11 35.48% 3: ethanol 10 32.26% 4: propiomazine 9 29.03% 5: alprazolam 5 16.13% 6: flunitrazepam 5 16.13% 7: diazepam 4 12.90% 8: nitrazepam 4 12.90% 9: oxazepam 4 12.90% 10: zopiclone 4 12.90% 11: codeine 3 9.68% 12: citalopram 2 6.45% 13: clonazepam 2 6.45% 14: metoprolol 2 6.45% 15: moclobemide 2 6.45% ------The most common combinations 1: paracetamol dextropropoxyphene - 9 2: paracetamol ethanol - 4 3: paracetamol propiomazine - 4 4: paracetamol flunitrazepam - 3 5: paracetamol codeine - 3 6: dextropropoxyphene ethanol - 3 7: dextropropoxyphene propiomazine - 3 8: ethanol propiomazine - 3 9: paracetamol dextropropoxyphene ethanol 3 10: paracetamol oxazepam - 2 11: paracetamol zopiclone - 2 12: paracetamol mianserin - 2 13: dextropropoxyphene alprazolam - 2 14: dextropropoxyphene flunitrazepam - 2 15: dextropropoxyphene nitrazepam - 2 16: dextropropoxyphene oxazepam - 2 17: dextropropoxyphene zopiclone - 2 18: dextropropoxyphene codeine - 2 19: ethanol alprazolam - 2 20: ethanol flunitrazepam - 2 ------

69 paroxetine C-cases ------The data contains 49 cases The data contains 24 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 34, 15, 6 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.20 [µg/g] (max = 1.00, min = 0.08) cases (other substances YES) median = 0.25 [µg/g] (max = 0.90, min = 0.08) cases (other substances NO ) median = 0.20 [µg/g] (max = 1.00, min = 0.09) MMW p value: 0.651 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: ethanol 10 29.41% 2: mianserin 7 20.59% 3: propiomazine 6 17.65% 4: zopiclone 5 14.71% 5: alprazolam 4 11.76% 6: diazepam 4 11.76% 7: nitrazepam 3 8.82% 8: venlafaxine 2 5.88% 9: mirtazapine 2 5.88% 10: alimemazine 1 2.94% 11: amitriptyline 1 2.94% 12: dextropropoxyphene 1 2.94% 13: carbamazepine 1 2.94% 14: clomipramine 1 2.94% 15: caffeine 1 2.94% ------The most common combinations 1: ethanol propiomazine - 3 2: ethanol alprazolam - 2 3: ethanol diazepam - 1 4: ethanol nitrazepam - 1 5: ethanol mirtazapine - 1 6: ethanol caffeine - 1 7: ethanol promethazine - 1 8: ethanol salicylicacid - 1 9: mianserin propiomazine - 1 10: mianserin zopiclone - 1 11: mianserin venlafaxine - 1 12: mianserin melperone - 1 13: propiomazine nitrazepam - 1 14: propiomazine mirtazapine - 1 15: propiomazine paracetamol - 1 16: propiomazine promethazine - 1 17: propiomazine salicylicacid - 1 18: zopiclone alprazolam - 1 19: zopiclone diazepam - 1 20: zopiclone venlafaxine - 1 ------

70 sertraline B-cases ------The data contains 46 cases The data contains 52 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 46, 42, 37 ------Average number of drugs/case = 4 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.35 [µg/g] (max = 14.00, min = 0.50) ------The most common substances in addition to the index-antidepressant 1: ethanol 19 41.30% 2: dextropropoxyphene 12 26.09% 3: paracetamol 12 26.09% 4: propiomazine 10 21.74% 5: citalopram 8 17.39% 6: diazepam 8 17.39% 7: zopiclone 8 17.39% 8: codeine 7 15.22% 9: zolpidem 7 15.22% 10: caffeine 6 13.04% 11: nitrazepam 5 10.87% 12: alimemazine 4 8.70% 13: morphine 4 8.70% 14: moclobemide 4 8.70% 15: oxazepam 4 8.70% ------The most common combinations 1: dextropropoxyphene paracetamol - 7 2: ethanol paracetamol - 6 3: ethanol propiomazine - 6 4: ethanol zopiclone - 5 5: paracetamol diazepam - 5 6: ethanol citalopram - 4 7: ethanol nitrazepam - 4 8: dextropropoxyphene diazepam - 4 9: propiomazine zopiclone - 4 10: codeine morphine - 4 11: dextropropoxyphene paracetamol diazepam 4 12: ethanol dextropropoxyphene - 3 13: ethanol diazepam - 3 14: ethanol zolpidem - 3 15: ethanol caffeine - 3 16: ethanol moclobemide - 3 17: ethanol hydroxyzine - 3 18: dextropropoxyphene propiomazine - 3 19: dextropropoxyphene citalopram - 3 20: paracetamol citalopram - 3 ------

71 sertraline C-cases ------The data contains 196 cases The data contains 40 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 124, 65, 20 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.10 [µg/g] (max = 1.20, min = 0.05) cases (other substances YES) median = 0.10 [µg/g] (max = 0.70, min = 0.05) cases (other substances NO ) median = 0.10 [µg/g] (max = 1.20, min = 0.05) MMW p value: 0.277 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: ethanol 33 26.61% 2: diazepam 24 19.35% 3: zopiclone 22 17.74% 4: paracetamol 18 14.52% 5: mirtazapine 16 12.90% 6: propiomazine 14 11.29% 7: mianserin 13 10.48% 8: alimemazine 10 8.06% 9: dextropropoxyphene 7 5.65% 10: nitrazepam 5 4.03% 11: citalopram 3 2.42% 12: diltiazem 3 2.42% 13: flunitrazepam 3 2.42% 14: hydroxyzine 3 2.42% 15: promethazine 3 2.42% ------The most common combinations 1: diazepam zopiclone - 7 2: ethanol paracetamol - 5 3: paracetamol dextropropoxyphene - 5 4: mirtazapine alimemazine - 5 5: ethanol zopiclone - 4 6: ethanol diazepam - 3 7: ethanol dextropropoxyphene - 3 8: diazepam mirtazapine - 3 9: diazepam nitrazepam - 3 10: zopiclone mianserin - 3 11: ethanol mianserin - 2 12: ethanol zolpidem - 2 13: diazepam propiomazine - 2 14: diazepam mianserin - 2 15: diazepam alimemazine - 2 16: zopiclone paracetamol - 2 17: zopiclone alimemazine - 2 18: paracetamol propiomazine - 2 19: mirtazapine propiomazine - 2 20: propiomazine citalopram - 2 ------

72 trimipramine B-cases ------The data contains 44 cases The data contains 39 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 44, 37, 28 ------Average number of drugs/case = 3 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 1.60 [µg/g] (max = 25.00, min = 0.50) ------The most common substances in addition to the index-antidepressant 1: ethanol 26 59.09% 2: paracetamol 13 29.55% 3: propiomazine 11 25.00% 4: dextropropoxyphene 8 18.18% 5: diazepam 8 18.18% 6: flunitrazepam 7 15.91% 7: oxazepam 5 11.36% 8: codeine 4 9.09% 9: mianserin 4 9.09% 10: zopiclone 4 9.09% 11: alimemazine 3 6.82% 12: alprazolam 3 6.82% 13: morphine 3 6.82% 14: mirtazapine 3 6.82% 15: tramadol 3 6.82% ------The most common combinations 1: ethanol paracetamol - 6 2: paracetamol dextropropoxyphene - 6 3: ethanol dextropropoxyphene - 5 4: ethanol propiomazine - 4 5: ethanol diazepam - 4 6: paracetamol propiomazine - 4 7: paracetamol diazepam - 4 8: propiomazine flunitrazepam - 4 9: ethanol flunitrazepam - 3 10: ethanol oxazepam - 3 11: paracetamol flunitrazepam - 3 12: paracetamol tramadol - 3 13: propiomazine diazepam - 3 14: diazepam flunitrazepam - 3 15: codeine morphine - 3 16: ethanol paracetamol dextropropoxyphene 3 17: ethanol codeine - 2 18: ethanol zopiclone - 2 19: ethanol alimemazine - 2 20: ethanol alprazolam - 2 ------

73 trimipramine C-cases ------The data contains 13 cases The data contains 21 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 13, 7, 2 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.20 [µg/g] (max = 0.80, min = 0.06) ------The most common substances in addition to the index-antidepressant 1: ethanol 3 23.08% 2: diazepam 2 15.38% 3: flunitrazepam 2 15.38% 4: paracetamol 2 15.38% 5: propiomazine 2 15.38% 6: alimemazine 1 7.69% 7: dextropropoxyphene 1 7.69% 8: diphenhydramine 1 7.69% 9: clomipramine 1 7.69% 10: clonazepam 1 7.69% 11: melperone 1 7.69% 12: orphenadrine 1 7.69% 13: propranolol 1 7.69% 14: remoxipride 1 7.69% 15: thioridazine 1 7.69% ------The most common combinations 1: ethanol diazepam - 1 2: ethanol flunitrazepam - 1 3: ethanol paracetamol - 1 4: ethanol diphenhydramine - 1 5: ethanol zopiclone - 1 6: ethanol zolpidem - 1 7: ethanol mirtazapine - 1 8: diazepam melperone - 1 9: flunitrazepam paracetamol - 1 10: flunitrazepam diphenhydramine - 1 11: flunitrazepam zopiclone - 1 12: flunitrazepam zolpidem - 1 13: flunitrazepam mirtazapine - 1 14: paracetamol dextropropoxyphene - 1 15: paracetamol diphenhydramine - 1 16: paracetamol clonazepam - 1 17: paracetamol zopiclone - 1 18: paracetamol zolpidem - 1 19: paracetamol mirtazapine - 1 20: propiomazine propranolol - 1 ------

74 venlafaxine B-cases ------The data contains 54 cases The data contains 51 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 54, 53, 45 ------Average number of drugs/case = 4 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 4.05 [µg/g] (max = 113.00, min = 1.10) ------The most common substances in addition to the index-antidepressant 1: propiomazine 22 40.74% 2: paracetamol 18 33.33% 3: ethanol 17 31.48% 4: zopiclone 17 31.48% 5: alimemazine 16 29.63% 6: dextropropoxyphene 13 24.07% 7: diazepam 11 20.37% 8: codeine 10 18.52% 9: citalopram 8 14.81% 10: nortriptyline 7 12.96% 11: mirtazapine 7 12.96% 12: alprazolam 6 11.11% 13: amitriptyline 6 11.11% 14: flunitrazepam 6 11.11% 15: carbamazepine 5 9.26% ------The most common combinations 1: paracetamol dextropropoxyphene - 11 2: propiomazine zopiclone - 9 3: propiomazine alimemazine - 8 4: propiomazine paracetamol - 7 5: paracetamol codeine - 7 6: ethanol alimemazine - 7 7: propiomazine ethanol - 6 8: paracetamol ethanol - 6 9: paracetamol zopiclone - 6 10: zopiclone alimemazine - 6 11: nortriptyline amitriptyline - 6 12: paracetamol alimemazine - 5 13: ethanol zopiclone - 5 14: ethanol dextropropoxyphene - 5 15: zopiclone dextropropoxyphene - 5 16: paracetamol ethanol dextropropoxyphene 5 17: ethanol diazepam - 4 18: ethanol codeine - 4 19: zopiclone mirtazapine - 4 20: alimemazine diazepam - 4 ------

75 venlafaxine C-cases ------The data contains 142 cases The data contains 37 different substances in addition to the index-antidepressant ------Cases with at least 1, 2, 3, substances in addition to the index-antidepressant number of such cases 86, 41, 19 ------Average number of drugs/case = 2 (cases with at least one substances in addition to the index-antidepressant) ------median concentration of the index-antidepressant all cases median = 0.30 [µg/g] (max = 3.00, min = 0.05) cases (other substances YES) median = 0.35 [µg/g] (max = 3.00, min = 0.05) cases (other substances NO ) median = 0.30 [µg/g] (max = 2.30, min = 0.06) MMW p value: 0.382 with other substance against no other substance ------The most common substances in addition to the index-antidepressant 1: ethanol 25 29.07% 2: diazepam 18 20.93% 3: paracetamol 14 16.28% 4: zopiclone 14 16.28% 5: propiomazine 11 12.79% 6: mirtazapine 11 12.79% 7: alimemazine 9 10.47% 8: olanzapine 8 9.30% 9: nitrazepam 4 4.65% 10: citalopram 3 3.49% 11: codeine 3 3.49% 12: mianserin 3 3.49% 13: tramadol 3 3.49% 14: alprazolam 2 2.33% 15: amphetamine 2 2.33% ------The most common combinations 1: diazepam paracetamol - 6 2: ethanol diazepam - 5 3: ethanol zopiclone - 4 4: diazepam zopiclone - 4 5: diazepam alimemazine - 3 6: diazepam codeine - 3 7: ethanol paracetamol - 2 8: ethanol propiomazine - 2 9: ethanol olanzapine - 2 10: paracetamol zopiclone - 2 11: paracetamol codeine - 2 12: zopiclone fluoxetine - 2 13: alimemazine hydroxyzine - 2 14: diazepam paracetamol codeine 2 15: ethanol mirtazapine - 1 16: ethanol alimemazine - 1 17: ethanol citalopram - 1 18: ethanol codeine - 1 19: ethanol tramadol - 1 20: ethanol alprazolam - 1 ------

Appendix IV – Statistical data Statistical data listed on the next coming pages for all comparisons of the most common concomitant drugs for B-case groups against respective C-case. The concomitant drug in question is shown together with a, b, c, d, n (number of concomitant drugs tested for this group), i (which test it is in the order, for the Benjamini-Hochberg procedure), Benjamini-Hochberg value, p-values (from Fisher’s exact test, has to be lower than Benjamini-Hochberg value for being significant), and odds ratio, relative risk and their corresponding 95% confidence intervals are also sown.

If concomitant drugs were significantly more common in B-cases than in C-cases, or reversed, tests on concentration differences were made. Significant concentration differences of the index-antidepressants were listed. The tests were made within the B-case group and within the C-case group respectively. Cases that had the concomitant drug in question were compared against cases without the very same drug. If any p-values were < 0.05 the median concentration of the index-antidepressant is listed both for cases with the concomitant drug and for cases without the concomitant drug. The p-value from the test is also displayed.

77 all B-cases against all C-cases significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 222 514 67 855 9 1 0.0056 Fisher's exact test p = 0.0000 odds ratio with 95%CI 4.11 < 5.51 < 7.40 relative risk with 95%CI 1.90 < 2.05 < 2.17 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 349 387 248 674 9 2 0.0111 Fisher's exact test p = 0.0000 odds ratio with 95%CI 2.00 < 2.45 < 3.01 relative risk with 95%CI 1.46 < 1.60 < 1.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 81 655 18 904 9 3 0.0167 Fisher's exact test p = 0.0000 odds ratio with 95%CI 3.69 < 6.21 < 10.45 relative risk with 95%CI 1.73 < 1.95 < 2.10 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 92 644 33 889 9 4 0.0222 Fisher's exact test p = 0.0000 odds ratio with 95%CI 2.55 < 3.85 < 5.80 relative risk with 95%CI 1.55 < 1.75 < 1.92 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 234 502 165 757 9 5 0.0278 Fisher's exact test p = 0.0000 odds ratio with 95%CI 1.70 < 2.14 < 2.69 relative risk with 95%CI 1.33 < 1.47 < 1.61 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 176 560 118 804 9 6 0.0333 Fisher's exact test p = 0.0000 odds ratio with 95%CI 1.66 < 2.14 < 2.77 relative risk with 95%CI 1.30 < 1.46 < 1.60 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 86 650 77 845 9 7 0.0389 Fisher's exact test p = 0.0251 odds ratio with 95%CI 1.05 < 1.45 < 2.01 relative risk with 95%CI 1.03 < 1.21 < 1.40 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 175 561 201 721 9 8 0.0444 Fisher's exact test p = 0.3455 odds ratio with 95%CI 0.89 < 1.12 < 1.41 relative risk with 95%CI 0.93 < 1.06 < 1.20 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 121 615 136 786 9 9 0.0500 Fisher's exact test p = 0.3747 odds ratio with 95%CI 0.87 < 1.14 < 1.48 relative risk with 95%CI 0.92 < 1.07 < 1.22

AMITRIPTYLINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 67 52 11 44 9 1 0.0056 Fisher's exact test p = 0.0000 odds ratio with 95%CI 2.43 < 5.15 < 10.95 relative risk with 95%CI 1.37 < 1.59 < 1.71 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 21 98 2 53 9 2 0.0111 Fisher's exact test p = 0.0142 odds ratio with 95%CI 1.28 < 5.68 < 25.16 relative risk with 95%CI 1.08 < 1.41 < 1.51 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 17 102 2 53 9 3 0.0167 Fisher's exact test p = 0.0383 odds ratio with 95%CI 0.98 < 4.42 < 19.84 relative risk with 95%CI 0.99 < 1.36 < 1.48 ------SUBSTANCE a c b d n i Benjamini–Hochberg carbamazepine 7 112 7 48 9 4 0.0222 Fisher's exact test p = 0.1401 odds ratio with 95%CI 0.14 < 0.43 < 1.29 relative risk with 95%CI 0.36 < 0.71 < 1.07 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 27 92 18 37 9 5 0.0278 Fisher's exact test p = 0.1929 odds ratio with 95%CI 0.30 < 0.60 < 1.22 relative risk with 95%CI 0.60 < 0.84 < 1.06 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 12 107 2 53 9 6 0.0333 Fisher's exact test p = 0.2303 odds ratio with 95%CI 0.64 < 2.97 < 13.76 relative risk with 95%CI 0.84 < 1.28 < 1.44 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 30 89 9 46 9 7 0.0389 Fisher's exact test p = 0.2421 odds ratio with 95%CI 0.75 < 1.72 < 3.93 relative risk with 95%CI 0.90 < 1.17 < 1.34 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 33 86 12 43 9 8 0.0444 Fisher's exact test p = 0.4603 odds ratio with 95%CI 0.65 < 1.38 < 2.93 relative risk with 95%CI 0.85 < 1.10 < 1.28 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 14 105 5 50 9 9 0.0500 Fisher's exact test p = 0.7947 odds ratio with 95%CI 0.45 < 1.33 < 3.91 relative risk with 95%CI 0.72 < 1.09 < 1.32 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

CITALOPRAM significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 87 156 25 338 9 1 0.0056 Fisher's exact test p = 0.0000 odds ratio with 95%CI 4.65 < 7.54 < 12.23 relative risk with 95%CI 2.16 < 2.46 < 2.69 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 117 126 92 271 9 2 0.0111 Fisher's exact test p = 0.0000 odds ratio with 95%CI 1.94 < 2.74 < 3.86 relative risk with 95%CI 1.49 < 1.76 < 2.02 ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 27 216 5 358 9 3 0.0167 Fisher's exact test p = 0.0000 odds ratio with 95%CI 3.40 < 8.95 < 23.59 relative risk with 95%CI 1.79 < 2.24 < 2.48 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 64 179 52 311 9 4 0.0222 Fisher's exact test p = 0.0003 odds ratio with 95%CI 1.42 < 2.14 < 3.22 relative risk with 95%CI 1.23 < 1.51 < 1.78 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 27 216 14 349 9 5 0.0278 Fisher's exact test p = 0.0008 odds ratio with 95%CI 1.60 < 3.12 < 6.07 relative risk with 95%CI 1.30 < 1.72 < 2.07 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 76 167 70 293 9 6 0.0333 Fisher's exact test p = 0.0009 odds ratio with 95%CI 1.31 < 1.90 < 2.77 relative risk with 95%CI 1.18 < 1.43 < 1.69 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 58 185 59 304 9 7 0.0389 Fisher's exact test p = 0.0212 odds ratio with 95%CI 1.08 < 1.62 < 2.42 relative risk with 95%CI 1.05 < 1.31 < 1.58 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 25 218 21 342 9 8 0.0444 Fisher's exact test p = 0.0431 odds ratio with 95%CI 1.02 < 1.87 < 3.42 relative risk with 95%CI 1.01 < 1.40 < 1.76 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 42 201 48 315 9 9 0.0500 Fisher's exact test p = 0.1997 odds ratio with 95%CI 0.87 < 1.37 < 2.15 relative risk with 95%CI 0.92 < 1.20 < 1.49 ------

CLOMIPRAMINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 29 78 6 78 11 1 0.0045 Fisher's exact test p = 0.0003 odds ratio with 95%CI 1.90 < 4.83 < 12.29 relative risk with 95%CI 1.31 < 1.66 < 1.85 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 33 74 10 74 11 2 0.0091 Fisher's exact test p = 0.0027 odds ratio with 95%CI 1.52 < 3.30 < 7.18 relative risk with 95%CI 1.21 < 1.53 < 1.76 ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 13 94 2 82 11 3 0.0136 Fisher's exact test p = 0.0141 odds ratio with 95%CI 1.24 < 5.67 < 25.87 relative risk with 95%CI 1.10 < 1.62 < 1.81 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 12 95 2 82 11 4 0.0182 Fisher's exact test p = 0.0242 odds ratio with 95%CI 1.13 < 5.18 < 23.82 relative risk with 95%CI 1.05 < 1.60 < 1.80 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 15 92 4 80 11 5 0.0227 Fisher's exact test p = 0.0494 odds ratio with 95%CI 1.04 < 3.26 < 10.23 relative risk with 95%CI 1.02 < 1.48 < 1.72 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 12 95 3 81 11 6 0.0273 Fisher's exact test p = 0.0605 odds ratio with 95%CI 0.93 < 3.41 < 12.51 relative risk with 95%CI 0.97 < 1.48 < 1.73 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 43 64 23 61 11 7 0.0318 Fisher's exact test p = 0.0683 odds ratio with 95%CI 0.96 < 1.78 < 3.30 relative risk with 95%CI 0.98 < 1.27 < 1.52 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 14 93 4 80 11 8 0.0364 Fisher's exact test p = 0.0785 odds ratio with 95%CI 0.95 < 3.01 < 9.52 relative risk with 95%CI 0.98 < 1.45 < 1.71 ------SUBSTANCE a c b d n i Benjamini–Hochberg carbamazepine 11 96 5 79 11 9 0.0409 Fisher's exact test p = 0.3087 odds ratio with 95%CI 0.60 < 1.81 < 5.43 relative risk with 95%CI 0.77 < 1.25 < 1.58 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 25 82 24 60 11 10 0.0455 Fisher's exact test p = 0.5047 odds ratio with 95%CI 0.40 < 0.76 < 1.46 relative risk with 95%CI 0.61 < 0.88 < 1.15 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 11 96 11 73 11 11 0.0500 Fisher's exact test p = 0.6493 odds ratio with 95%CI 0.31 < 0.76 < 1.85 relative risk with 95%CI 0.51 < 0.88 < 1.25 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

FLUOXETINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 14 22 1 41 14 1 0.0036 Fisher's exact test p = 0.0001 odds ratio with 95%CI 3.21 < 26.09 < 211.75 relative risk with 95%CI 1.81 < 2.67 < 2.84 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 11 25 2 40 14 2 0.0071 Fisher's exact test p = 0.0045 odds ratio with 95%CI 1.80 < 8.80 < 43.04 relative risk with 95%CI 1.38 < 2.20 < 2.51 ------SUBSTANCE a c b d n i Benjamini–Hochberg morphine 5 31 0 42 14 3 0.0107 Fisher's exact test p = 0.0179 odds ratio with 95%CI 0.79 < 14.84 < 278.36 relative risk with 95%CI 0.87 < 2.16 < 2.34 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 9 27 3 39 14 4 0.0143 Fisher's exact test p = 0.0557 odds ratio with 95%CI 1.07 < 4.33 < 17.50 relative risk with 95%CI 1.04 < 1.83 < 2.26 ------SUBSTANCE a c b d n i Benjamini–Hochberg promethazine 5 31 1 41 14 5 0.0179 Fisher's exact test p = 0.0897 odds ratio with 95%CI 0.73 < 6.61 < 59.51 relative risk with 95%CI 0.83 < 1.94 < 2.27 ------SUBSTANCE a c b d n i Benjamini–Hochberg zolpidem 5 31 1 41 14 6 0.0214 Fisher's exact test p = 0.0897 odds ratio with 95%CI 0.73 < 6.61 < 59.51 relative risk with 95%CI 0.83 < 1.94 < 2.27 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 8 28 3 39 14 7 0.0250 Fisher's exact test p = 0.1000 odds ratio with 95%CI 0.90 < 3.71 < 15.26 relative risk with 95%CI 0.94 < 1.74 < 2.19 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 10 26 6 36 14 8 0.0286 Fisher's exact test p = 0.1678 odds ratio with 95%CI 0.74 < 2.31 < 7.15 relative risk with 95%CI 0.83 < 1.49 < 2.00 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 4 32 1 41 14 9 0.0321 Fisher's exact test p = 0.1753 odds ratio with 95%CI 0.55 < 5.13 < 48.12 relative risk with 95%CI 0.68 < 1.83 < 2.22 ------SUBSTANCE a c b d n i Benjamini–Hochberg carbamazepine 4 32 1 41 14 10 0.0357 Fisher's exact test p = 0.1753 odds ratio with 95%CI 0.55 < 5.13 < 48.12 relative risk with 95%CI 0.68 < 1.83 < 2.22 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 4 32 1 41 14 11 0.0393 Fisher's exact test p = 0.1753 odds ratio with 95%CI 0.55 < 5.13 < 48.12 relative risk with 95%CI 0.68 < 1.83 < 2.22 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 16 20 13 29 14 12 0.0429 Fisher's exact test p = 0.2473 odds ratio with 95%CI 0.71 < 1.78 < 4.51 relative risk with 95%CI 0.80 < 1.35 < 1.85 ------

SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 6 30 4 38 14 13 0.0464 Fisher's exact test p = 0.4996 odds ratio with 95%CI 0.49 < 1.90 < 7.35 relative risk with 95%CI 0.63 < 1.36 < 1.93 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 15 21 19 23 14 14 0.0500 Fisher's exact test p = 0.8209 odds ratio with 95%CI 0.35 < 0.86 < 2.12 relative risk with 95%CI 0.51 < 0.92 < 1.38 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------dextropropoxyphene with without | with without median concentration [µg/g] 1.20 1.90 | 0.10 0.40 MMW p values: 0.020 | 0.112 ------

FLUVOXAMINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 1 14 3 6 21 1 0.0024 Fisher's exact test p = 0.1304 odds ratio with 95%CI 0.01 < 0.14 < 1.67 relative risk with 95%CI 0.04 < 0.36 < 1.14 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 4 11 0 9 21 2 0.0048 Fisher's exact test p = 0.2589 odds ratio with 95%CI 0.35 < 7.43 < 156.28 relative risk with 95%CI 0.55 < 1.64 < 1.81 ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 4 11 0 9 21 3 0.0071 Fisher's exact test p = 0.2589 odds ratio with 95%CI 0.35 < 7.43 < 156.28 relative risk with 95%CI 0.55 < 1.64 < 1.81 ------SUBSTANCE a c b d n i Benjamini–Hochberg amitriptyline 3 12 0 9 21 4 0.0095 Fisher's exact test p = 0.2663 odds ratio with 95%CI 0.24 < 5.32 < 115.86 relative risk with 95%CI 0.43 < 1.53 < 1.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 3 12 0 9 21 5 0.0119 Fisher's exact test p = 0.2663 odds ratio with 95%CI 0.24 < 5.32 < 115.86 relative risk with 95%CI 0.43 < 1.53 < 1.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg moclobemide 3 12 0 9 21 6 0.0143 Fisher's exact test p = 0.2663 odds ratio with 95%CI 0.24 < 5.32 < 115.86 relative risk with 95%CI 0.43 < 1.53 < 1.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg nortriptyline 3 12 0 9 21 7 0.0167 Fisher's exact test p = 0.2663 odds ratio with 95%CI 0.24 < 5.32 < 115.86 relative risk with 95%CI 0.43 < 1.53 < 1.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 5 10 1 8 21 8 0.0190 Fisher's exact test p = 0.3509 odds ratio with 95%CI 0.39 < 4.00 < 41.51 relative risk with 95%CI 0.59 < 1.50 < 1.77 ------SUBSTANCE a c b d n i Benjamini–Hochberg caffeine 5 10 1 8 21 9 0.0214 Fisher's exact test p = 0.3509 odds ratio with 95%CI 0.39 < 4.00 < 41.51 relative risk with 95%CI 0.59 < 1.50 < 1.77 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 3 12 4 5 21 10 0.0238 Fisher's exact test p = 0.3564 odds ratio with 95%CI 0.05 < 0.31 < 1.94 relative risk with 95%CI 0.15 < 0.61 < 1.17 ------SUBSTANCE a c b d n i Benjamini–Hochberg verapamil 0 15 1 8 21 11 0.0262 Fisher's exact test p = 0.3750 odds ratio with 95%CI 0.01 < 0.18 < 5.00 relative risk with 95%CI 0.02 < 0.39 < 1.39 ------SUBSTANCE a c b d n i Benjamini–Hochberg venlafaxine 0 15 1 8 21 12 0.0286 Fisher's exact test p = 0.3750 odds ratio with 95%CI 0.01 < 0.18 < 5.00 relative risk with 95%CI 0.02 < 0.39 < 1.39 ------

SUBSTANCE a c b d n i Benjamini–Hochberg alprazolam 2 13 0 9 21 13 0.0310 Fisher's exact test p = 0.5109 odds ratio with 95%CI 0.15 < 3.52 < 81.92 relative risk with 95%CI 0.30 < 1.41 < 1.68 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 2 13 0 9 21 14 0.0333 Fisher's exact test p = 0.5109 odds ratio with 95%CI 0.15 < 3.52 < 81.92 relative risk with 95%CI 0.30 < 1.41 < 1.68 ------SUBSTANCE a c b d n i Benjamini–Hochberg trimipramine 2 13 0 9 21 15 0.0357 Fisher's exact test p = 0.5109 odds ratio with 95%CI 0.15 < 3.52 < 81.92 relative risk with 95%CI 0.30 < 1.41 < 1.68 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 4 11 1 8 21 16 0.0381 Fisher's exact test p = 0.6146 odds ratio with 95%CI 0.27 < 2.91 < 31.21 relative risk with 95%CI 0.47 < 1.38 < 1.69 ------SUBSTANCE a c b d n i Benjamini–Hochberg theophylline 2 13 2 7 21 17 0.0405 Fisher's exact test p = 0.6146 odds ratio with 95%CI 0.06 < 0.54 < 4.69 relative risk with 95%CI 0.16 < 0.77 < 1.38 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 6 9 2 7 21 18 0.0429 Fisher's exact test p = 0.6570 odds ratio with 95%CI 0.36 < 2.33 < 15.30 relative risk with 95%CI 0.56 < 1.33 < 1.69 ------SUBSTANCE a c b d n i Benjamini–Hochberg flecainide 4 11 3 6 21 19 0.0452 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 0.73 < 4.39 relative risk with 95%CI 0.28 < 0.88 < 1.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 1 14 1 8 21 20 0.0476 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.03 < 0.57 < 10.43 relative risk with 95%CI 0.08 < 0.79 < 1.49 ------SUBSTANCE a c b d n i Benjamini–Hochberg hydroxyzine 1 14 1 8 21 21 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.03 < 0.57 < 10.43 relative risk with 95%CI 0.08 < 0.79 < 1.49 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

IMIPRAMINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 3 0 1 5 21 1 0.0024 Fisher's exact test p = 0.0476 odds ratio with 95%CI 0.80 < 25.67 < 824.72 relative risk with 95%CI 0.80 < 25.67 < 824.72 ------SUBSTANCE a c b d n i Benjamini–Hochberg alprazolam 1 2 0 6 21 2 0.0048 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg fluvoxamine 1 2 0 6 21 3 0.0071 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg clomipramine 1 2 0 6 21 4 0.0095 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg caffeine 1 2 0 6 21 5 0.0119 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg moclobemide 1 2 0 6 21 6 0.0143 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg nortriptyline 1 2 0 6 21 7 0.0167 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg paroxetine 1 2 0 6 21 8 0.0190 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 1 2 0 6 21 9 0.0214 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg theophylline 1 2 0 6 21 10 0.0238 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg TSH 1 2 0 6 21 11 0.0262 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg T3 1 2 0 6 21 12 0.0286 Fisher's exact test p = 0.3333 odds ratio with 95%CI 0.23 < 7.80 < 262.81 relative risk with 95%CI 0.29 < 2.89 < 3.95 ------

SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 1 2 1 5 21 13 0.0310 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.10 < 2.50 < 62.60 relative risk with 95%CI 0.13 < 1.75 < 3.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg amitriptyline 1 2 1 5 21 14 0.0333 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.10 < 2.50 < 62.60 relative risk with 95%CI 0.13 < 1.75 < 3.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg oxazepam 1 2 1 5 21 15 0.0357 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.10 < 2.50 < 62.60 relative risk with 95%CI 0.13 < 1.75 < 3.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 1 2 1 5 21 16 0.0381 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.10 < 2.50 < 62.60 relative risk with 95%CI 0.13 < 1.75 < 3.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 0 3 1 5 21 17 0.0405 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.02 < 0.52 < 16.83 relative risk with 95%CI 0.03 < 0.64 < 2.43 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 0 3 1 5 21 18 0.0429 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.02 < 0.52 < 16.83 relative risk with 95%CI 0.03 < 0.64 < 2.43 ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 0 3 1 5 21 19 0.0452 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.02 < 0.52 < 16.83 relative risk with 95%CI 0.03 < 0.64 < 2.43 ------SUBSTANCE a c b d n i Benjamini–Hochberg lidocaine 0 3 1 5 21 20 0.0476 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.02 < 0.52 < 16.83 relative risk with 95%CI 0.03 < 0.64 < 2.43 ------SUBSTANCE a c b d n i Benjamini–Hochberg thiopental 0 3 1 5 21 21 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.02 < 0.52 < 16.83 relative risk with 95%CI 0.03 < 0.64 < 2.43 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

MAPROTILINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 5 12 1 11 13 1 0.0038 Fisher's exact test p = 0.3544 odds ratio with 95%CI 0.46 < 4.58 < 45.61 relative risk with 95%CI 0.64 < 1.60 < 1.88 ------SUBSTANCE a c b d n i Benjamini–Hochberg carbamazepine 2 15 0 12 13 2 0.0077 Fisher's exact test p = 0.4975 odds ratio with 95%CI 0.18 < 4.03 < 91.91 relative risk with 95%CI 0.33 < 1.50 < 1.78 ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 2 15 0 12 13 3 0.0115 Fisher's exact test p = 0.4975 odds ratio with 95%CI 0.18 < 4.03 < 91.91 relative risk with 95%CI 0.33 < 1.50 < 1.78 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 1 16 2 10 13 4 0.0154 Fisher's exact test p = 0.5534 odds ratio with 95%CI 0.02 < 0.31 < 3.91 relative risk with 95%CI 0.06 < 0.54 < 1.40 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 1 16 2 10 13 5 0.0192 Fisher's exact test p = 0.5534 odds ratio with 95%CI 0.02 < 0.31 < 3.91 relative risk with 95%CI 0.06 < 0.54 < 1.40 ------SUBSTANCE a c b d n i Benjamini–Hochberg promethazine 1 16 2 10 13 6 0.0231 Fisher's exact test p = 0.5534 odds ratio with 95%CI 0.02 < 0.31 < 3.91 relative risk with 95%CI 0.06 < 0.54 < 1.40 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 3 14 1 11 13 7 0.0269 Fisher's exact test p = 0.6221 odds ratio with 95%CI 0.21 < 2.36 < 25.91 relative risk with 95%CI 0.38 < 1.34 < 1.73 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 4 13 4 8 13 8 0.0308 Fisher's exact test p = 0.6828 odds ratio with 95%CI 0.12 < 0.62 < 3.18 relative risk with 95%CI 0.26 < 0.81 < 1.35 ------SUBSTANCE a c b d n i Benjamini–Hochberg clomipramine 2 15 1 11 13 9 0.0346 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 1.47 < 18.29 relative risk with 95%CI 0.24 < 1.16 < 1.67 ------SUBSTANCE a c b d n i Benjamini–Hochberg mianserin 2 15 1 11 13 10 0.0385 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 1.47 < 18.29 relative risk with 95%CI 0.24 < 1.16 < 1.67 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 2 15 1 11 13 11 0.0423 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 1.47 < 18.29 relative risk with 95%CI 0.24 < 1.16 < 1.67 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 2 15 1 11 13 12 0.0462 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 1.47 < 18.29 relative risk with 95%CI 0.24 < 1.16 < 1.67 ------

SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 2 15 1 11 13 13 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.12 < 1.47 < 18.29 relative risk with 95%CI 0.24 < 1.16 < 1.67 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

MIANSERIN significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg levomepromazine 4 24 0 108 15 1 0.0033 Fisher's exact test p = 0.0015 odds ratio with 95%CI 2.08 < 39.86 < 764.90 relative risk with 95%CI 1.74 < 4.94 < 5.47 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 12 16 17 91 15 2 0.0067 Fisher's exact test p = 0.0037 odds ratio with 95%CI 1.62 < 4.01 < 9.98 relative risk with 95%CI 1.48 < 2.77 < 4.26 ------SUBSTANCE a c b d n i Benjamini–Hochberg trimipramine 3 25 0 108 15 3 0.0100 Fisher's exact test p = 0.0080 odds ratio with 95%CI 1.49 < 29.78 < 594.90 relative risk with 95%CI 1.37 < 4.65 < 5.28 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 5 23 3 105 15 4 0.0133 Fisher's exact test p = 0.0095 odds ratio with 95%CI 1.70 < 7.61 < 34.13 relative risk with 95%CI 1.51 < 3.48 < 4.91 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 10 18 14 94 15 5 0.0167 Fisher's exact test p = 0.0101 odds ratio with 95%CI 1.43 < 3.73 < 9.70 relative risk with 95%CI 1.34 < 2.59 < 4.04 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 5 23 4 104 15 6 0.0200 Fisher's exact test p = 0.0182 odds ratio with 95%CI 1.41 < 5.65 < 22.70 relative risk with 95%CI 1.31 < 3.07 < 4.60 ------SUBSTANCE a c b d n i Benjamini–Hochberg promethazine 4 24 3 105 15 7 0.0233 Fisher's exact test p = 0.0328 odds ratio with 95%CI 1.22 < 5.83 < 27.79 relative risk with 95%CI 1.18 < 3.07 < 4.64 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 6 22 8 100 15 8 0.0267 Fisher's exact test p = 0.0406 odds ratio with 95%CI 1.07 < 3.41 < 10.82 relative risk with 95%CI 1.06 < 2.38 < 3.90 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 3 25 2 106 15 9 0.0300 Fisher's exact test p = 0.0590 odds ratio with 95%CI 1.01 < 6.36 < 40.11 relative risk with 95%CI 1.01 < 3.14 < 4.74 ------SUBSTANCE a c b d n i Benjamini–Hochberg fluoxetine 3 25 3 105 15 10 0.0333 Fisher's exact test p = 0.1016 odds ratio with 95%CI 0.80 < 4.20 < 22.06 relative risk with 95%CI 0.83 < 2.60 < 4.37 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 5 23 13 95 15 11 0.0367 Fisher's exact test p = 0.5303 odds ratio with 95%CI 0.51 < 1.59 < 4.91 relative risk with 95%CI 0.57 < 1.43 < 2.79 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 7 21 23 85 15 12 0.0400 Fisher's exact test p = 0.7983 odds ratio with 95%CI 0.47 < 1.23 < 3.25 relative risk with 95%CI 0.52 < 1.18 < 2.25 ------

SUBSTANCE a c b d n i Benjamini–Hochberg sertraline 3 25 15 93 15 13 0.0433 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.20 < 0.74 < 2.77 relative risk with 95%CI 0.24 < 0.79 < 2.02 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 4 24 15 93 15 14 0.0467 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.31 < 1.03 < 3.40 relative risk with 95%CI 0.37 < 1.03 < 2.28 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 3 25 11 97 15 15 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.27 < 1.06 < 4.08 relative risk with 95%CI 0.32 < 1.05 < 2.50 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

MIRTAZAPINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 22 45 7 155 13 1 0.0038 Fisher's exact test p = 0.0000 odds ratio with 95%CI 4.34 < 10.83 < 26.97 relative risk with 95%CI 2.48 < 3.37 < 3.94 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 33 34 23 139 13 2 0.0077 Fisher's exact test p = 0.0000 odds ratio with 95%CI 3.06 < 5.87 < 11.25 relative risk with 95%CI 2.18 < 3.00 < 3.73 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 12 55 0 162 13 3 0.0115 Fisher's exact test p = 0.0000 odds ratio with 95%CI 4.26 < 73.20 < 1256.70 relative risk with 95%CI 2.33 < 3.79 < 3.94 ------SUBSTANCE a c b d n i Benjamini–Hochberg morphine 7 60 0 162 13 4 0.0154 Fisher's exact test p = 0.0001 odds ratio with 95%CI 2.27 < 40.29 < 716.21 relative risk with 95%CI 1.69 < 3.47 < 3.69 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 23 44 23 139 13 5 0.0192 Fisher's exact test p = 0.0010 odds ratio with 95%CI 1.62 < 3.16 < 6.17 relative risk with 95%CI 1.41 < 2.08 < 2.75 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 7 60 3 159 13 6 0.0231 Fisher's exact test p = 0.0078 odds ratio with 95%CI 1.55 < 6.18 < 24.69 relative risk with 95%CI 1.35 < 2.55 < 3.30 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 20 47 23 139 13 7 0.0269 Fisher's exact test p = 0.0087 odds ratio with 95%CI 1.30 < 2.57 < 5.10 relative risk with 95%CI 1.21 < 1.84 < 2.50 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 16 51 19 143 13 8 0.0308 Fisher's exact test p = 0.0263 odds ratio with 95%CI 1.13 < 2.36 < 4.94 relative risk with 95%CI 1.09 < 1.74 < 2.43 ------SUBSTANCE a c b d n i Benjamini–Hochberg tramadol 7 60 5 157 13 9 0.0346 Fisher's exact test p = 0.0439 odds ratio with 95%CI 1.12 < 3.66 < 11.99 relative risk with 95%CI 1.08 < 2.11 < 2.97 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 23 44 36 126 13 10 0.0385 Fisher's exact test p = 0.0680 odds ratio with 95%CI 0.98 < 1.83 < 3.42 relative risk with 95%CI 0.98 < 1.51 < 2.10 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 20 47 31 131 13 11 0.0423 Fisher's exact test p = 0.0831 odds ratio with 95%CI 0.94 < 1.80 < 3.46 relative risk with 95%CI 0.95 < 1.49 < 2.10 ------SUBSTANCE a c b d n i Benjamini–Hochberg venlafaxine 10 57 12 150 13 12 0.0462 Fisher's exact test p = 0.0885 odds ratio with 95%CI 0.90 < 2.19 < 5.36 relative risk with 95%CI 0.92 < 1.65 < 2.44 ------

SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 11 56 23 139 13 13 0.0500 Fisher's exact test p = 0.6854 odds ratio with 95%CI 0.54 < 1.19 < 2.60 relative risk with 95%CI 0.62 < 1.13 < 1.78 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------dextropropoxyphene with without | with without median concentration [µg/g] 0.40 0.60 | 0.10 0.10 MMW p values: 0.014 | 0.921 ------propiomazine with without | with without median concentration [µg/g] 0.50 0.50 | 0.20 0.10 MMW p values: 0.666 | 0.001 ------

MOCLOBEMIDE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg clomipramine 6 24 0 29 15 1 0.0033 Fisher's exact test p = 0.0237 odds ratio with 95%CI 0.84 < 15.65 < 291.95 relative risk with 95%CI 0.91 < 2.05 < 2.20 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 2 28 7 22 15 2 0.0067 Fisher's exact test p = 0.0797 odds ratio with 95%CI 0.04 < 0.22 < 1.19 relative risk with 95%CI 0.09 < 0.40 < 1.08 ------SUBSTANCE a c b d n i Benjamini–Hochberg sertraline 4 26 0 29 15 3 0.0100 Fisher's exact test p = 0.1124 odds ratio with 95%CI 0.51 < 10.02 < 194.99 relative risk with 95%CI 0.67 < 1.90 < 2.10 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 10 20 5 24 15 4 0.0133 Fisher's exact test p = 0.2326 odds ratio with 95%CI 0.70 < 2.40 < 8.18 relative risk with 95%CI 0.81 < 1.47 < 1.92 ------SUBSTANCE a c b d n i Benjamini–Hochberg fluvoxamine 3 27 0 29 15 5 0.0167 Fisher's exact test p = 0.2373 odds ratio with 95%CI 0.37 < 7.51 < 152.09 relative risk with 95%CI 0.53 < 1.81 < 2.06 ------SUBSTANCE a c b d n i Benjamini–Hochberg fluoxetine 3 27 0 29 15 6 0.0200 Fisher's exact test p = 0.2373 odds ratio with 95%CI 0.37 < 7.51 < 152.09 relative risk with 95%CI 0.53 < 1.81 < 2.06 ------SUBSTANCE a c b d n i Benjamini–Hochberg venlafaxine 3 27 0 29 15 7 0.0233 Fisher's exact test p = 0.2373 odds ratio with 95%CI 0.37 < 7.51 < 152.09 relative risk with 95%CI 0.53 < 1.81 < 2.06 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 4 26 1 28 15 8 0.0267 Fisher's exact test p = 0.3533 odds ratio with 95%CI 0.45 < 4.31 < 41.09 relative risk with 95%CI 0.61 < 1.66 < 2.02 ------SUBSTANCE a c b d n i Benjamini–Hochberg mianserin 2 28 4 25 15 9 0.0300 Fisher's exact test p = 0.4238 odds ratio with 95%CI 0.08 < 0.45 < 2.65 relative risk with 95%CI 0.15 < 0.63 < 1.42 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 3 27 4 25 15 10 0.0333 Fisher's exact test p = 0.7065 odds ratio with 95%CI 0.14 < 0.69 < 3.41 relative risk with 95%CI 0.25 < 0.83 < 1.52 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 5 25 3 26 15 11 0.0367 Fisher's exact test p = 0.7065 odds ratio with 95%CI 0.37 < 1.73 < 8.03 relative risk with 95%CI 0.54 < 1.27 < 1.81 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 6 24 4 25 15 12 0.0400 Fisher's exact test p = 0.7306 odds ratio with 95%CI 0.39 < 1.56 < 6.23 relative risk with 95%CI 0.56 < 1.23 < 1.75 ------

SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 8 22 7 22 15 13 0.0433 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.35 < 1.14 < 3.70 relative risk with 95%CI 0.52 < 1.07 < 1.57 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 4 26 4 25 15 14 0.0467 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.22 < 0.96 < 4.27 relative risk with 95%CI 0.36 < 0.98 < 1.60 ------SUBSTANCE a c b d n i Benjamini–Hochberg oxazepam 3 27 3 26 15 15 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.18 < 0.96 < 5.21 relative risk with 95%CI 0.31 < 0.98 < 1.66 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

NORTRIPTYLINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 9 13 0 6 10 1 0.0050 Fisher's exact test p = 0.1358 odds ratio with 95%CI 0.46 < 9.15 < 182.61 relative risk with 95%CI 0.73 < 1.39 < 1.46 ------SUBSTANCE a c b d n i Benjamini–Hochberg amitriptyline 0 22 1 5 10 2 0.0100 Fisher's exact test p = 0.2143 odds ratio with 95%CI 0.00 < 0.08 < 2.28 relative risk with 95%CI 0.02 < 0.32 < 1.12 ------SUBSTANCE a c b d n i Benjamini–Hochberg orphenadrine 0 22 1 5 10 3 0.0150 Fisher's exact test p = 0.2143 odds ratio with 95%CI 0.00 < 0.08 < 2.28 relative risk with 95%CI 0.02 < 0.32 < 1.12 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 3 19 2 4 10 4 0.0200 Fisher's exact test p = 0.2855 odds ratio with 95%CI 0.04 < 0.32 < 2.55 relative risk with 95%CI 0.19 < 0.73 < 1.12 ------SUBSTANCE a c b d n i Benjamini–Hochberg mirtazapine 1 21 1 5 10 5 0.0250 Fisher's exact test p = 0.3889 odds ratio with 95%CI 0.01 < 0.24 < 4.50 relative risk with 95%CI 0.06 < 0.62 < 1.18 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 4 18 0 6 10 6 0.0300 Fisher's exact test p = 0.5487 odds ratio with 95%CI 0.15 < 3.16 < 67.13 relative risk with 95%CI 0.41 < 1.21 < 1.33 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 4 18 0 6 10 7 0.0350 Fisher's exact test p = 0.5487 odds ratio with 95%CI 0.15 < 3.16 < 67.13 relative risk with 95%CI 0.41 < 1.21 < 1.33 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 5 17 2 4 10 8 0.0400 Fisher's exact test p = 0.6219 odds ratio with 95%CI 0.08 < 0.59 < 4.21 relative risk with 95%CI 0.32 < 0.88 < 1.17 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 6 16 2 4 10 9 0.0450 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.11 < 0.75 < 5.22 relative risk with 95%CI 0.38 < 0.94 < 1.19 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 6 16 2 4 10 10 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.11 < 0.75 < 5.22 relative risk with 95%CI 0.38 < 0.94 < 1.19 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

PAROXETINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 15 16 1 33 11 1 0.0045 Fisher's exact test p = 0.0000 odds ratio with 95%CI 3.75 < 30.94 < 255.30 relative risk with 95%CI 1.98 < 2.87 < 3.04 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 11 20 1 33 11 2 0.0091 Fisher's exact test p = 0.0009 odds ratio with 95%CI 2.18 < 18.15 < 151.38 relative risk with 95%CI 1.51 < 2.43 < 2.62 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 5 26 0 34 11 3 0.0136 Fisher's exact test p = 0.0206 odds ratio with 95%CI 0.76 < 14.32 < 270.62 relative risk with 95%CI 0.85 < 2.11 < 2.30 ------SUBSTANCE a c b d n i Benjamini–Hochberg oxazepam 4 27 0 34 11 4 0.0182 Fisher's exact test p = 0.0465 odds ratio with 95%CI 0.58 < 11.29 < 218.85 relative risk with 95%CI 0.71 < 2.03 < 2.25 ------SUBSTANCE a c b d n i Benjamini–Hochberg mianserin 2 29 7 27 11 5 0.0227 Fisher's exact test p = 0.1527 odds ratio with 95%CI 0.05 < 0.27 < 1.39 relative risk with 95%CI 0.10 < 0.43 < 1.16 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 9 22 6 28 11 6 0.0273 Fisher's exact test p = 0.3789 odds ratio with 95%CI 0.59 < 1.91 < 6.18 relative risk with 95%CI 0.72 < 1.36 < 1.88 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 4 27 3 31 11 7 0.0318 Fisher's exact test p = 0.7006 odds ratio with 95%CI 0.31 < 1.53 < 7.46 relative risk with 95%CI 0.46 < 1.23 < 1.86 ------SUBSTANCE a c b d n i Benjamini–Hochberg alprazolam 5 26 4 30 11 8 0.0364 Fisher's exact test p = 0.7261 odds ratio with 95%CI 0.35 < 1.44 < 5.94 relative risk with 95%CI 0.50 < 1.20 < 1.80 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 4 27 4 30 11 9 0.0409 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.25 < 1.11 < 4.88 relative risk with 95%CI 0.39 < 1.06 < 1.72 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 4 27 5 29 11 10 0.0455 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.21 < 0.86 < 3.54 relative risk with 95%CI 0.34 < 0.92 < 1.59 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 10 21 10 24 11 11 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.40 < 1.14 < 3.28 relative risk with 95%CI 0.55 < 1.07 < 1.59 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

SERTRALINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 7 39 0 124 13 1 0.0038 Fisher's exact test p = 0.0001 odds ratio with 95%CI 2.64 < 47.28 < 846.45 relative risk with 95%CI 1.90 < 3.92 < 4.16 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 12 34 7 117 13 2 0.0077 Fisher's exact test p = 0.0005 odds ratio with 95%CI 2.15 < 5.90 < 16.15 relative risk with 95%CI 1.71 < 2.80 < 3.66 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 8 38 3 121 13 3 0.0115 Fisher's exact test p = 0.0015 odds ratio with 95%CI 2.14 < 8.49 < 33.62 relative risk with 95%CI 1.68 < 3.04 < 3.82 ------SUBSTANCE a c b d n i Benjamini–Hochberg caffeine 6 40 1 123 13 4 0.0154 Fisher's exact test p = 0.0017 odds ratio with 95%CI 2.16 < 18.45 < 157.89 relative risk with 95%CI 1.68 < 3.49 < 4.00 ------SUBSTANCE a c b d n i Benjamini–Hochberg zolpidem 7 39 3 121 13 5 0.0192 Fisher's exact test p = 0.0044 odds ratio with 95%CI 1.79 < 7.24 < 29.35 relative risk with 95%CI 1.50 < 2.87 < 3.71 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 10 36 14 110 13 6 0.0231 Fisher's exact test p = 0.0890 odds ratio with 95%CI 0.89 < 2.18 < 5.34 relative risk with 95%CI 0.92 < 1.69 < 2.58 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 19 27 33 91 13 7 0.0269 Fisher's exact test p = 0.0909 odds ratio with 95%CI 0.95 < 1.94 < 3.94 relative risk with 95%CI 0.96 < 1.60 < 2.36 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 12 34 18 106 13 8 0.0308 Fisher's exact test p = 0.1112 odds ratio with 95%CI 0.91 < 2.08 < 4.75 relative risk with 95%CI 0.93 < 1.65 < 2.49 ------SUBSTANCE a c b d n i Benjamini–Hochberg nitrazepam 5 41 5 119 13 9 0.0346 Fisher's exact test p = 0.1364 odds ratio with 95%CI 0.80 < 2.90 < 10.54 relative risk with 95%CI 0.84 < 1.95 < 3.06 ------SUBSTANCE a c b d n i Benjamini–Hochberg mianserin 3 43 13 111 13 10 0.0385 Fisher's exact test p = 0.5620 odds ratio with 95%CI 0.16 < 0.60 < 2.19 relative risk with 95%CI 0.21 < 0.67 < 1.65 ------SUBSTANCE a c b d n i Benjamini–Hochberg mirtazapine 4 42 16 108 13 11 0.0423 Fisher's exact test p = 0.5954 odds ratio with 95%CI 0.20 < 0.64 < 2.03 relative risk with 95%CI 0.26 < 0.71 < 1.58 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 8 38 24 100 13 12 0.0462 Fisher's exact test p = 0.8292 odds ratio with 95%CI 0.36 < 0.88 < 2.12 relative risk with 95%CI 0.44 < 0.91 < 1.62 ------

SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 8 38 22 102 13 13 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.40 < 0.98 < 2.38 relative risk with 95%CI 0.48 < 0.98 < 1.73 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------citalopram with without | with without median concentration [µg/g] 2.45 1.25 | 0.30 0.10 MMW p values: 0.033 | 0.418 ------caffeine with without | with without median concentration [µg/g] 0.75 1.50 | 0.09 0.10 MMW p values: 0.050 | 0.258 ------

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TRIMIPRAMINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 26 18 3 10 7 1 0.0071 Fisher's exact test p = 0.0295 odds ratio with 95%CI 1.16 < 4.81 < 19.99 relative risk with 95%CI 1.05 < 1.39 < 1.51 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 13 31 2 11 7 2 0.0143 Fisher's exact test p = 0.4779 odds ratio with 95%CI 0.45 < 2.31 < 11.89 relative risk with 95%CI 0.76 < 1.17 < 1.32 ------SUBSTANCE a c b d n i Benjamini–Hochberg oxazepam 5 39 0 13 7 3 0.0214 Fisher's exact test p = 0.5785 odds ratio with 95%CI 0.19 < 3.76 < 72.57 relative risk with 95%CI 0.49 < 1.22 < 1.33 ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 8 36 1 12 7 4 0.0286 Fisher's exact test p = 0.6678 odds ratio with 95%CI 0.30 < 2.67 < 23.57 relative risk with 95%CI 0.63 < 1.19 < 1.31 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 11 33 2 11 7 5 0.0357 Fisher's exact test p = 0.7101 odds ratio with 95%CI 0.35 < 1.83 < 9.58 relative risk with 95%CI 0.68 < 1.13 < 1.29 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 7 37 2 11 7 6 0.0429 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.19 < 1.04 < 5.75 relative risk with 95%CI 0.50 < 1.01 < 1.23 ------SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 8 36 2 11 7 7 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.23 < 1.22 < 6.63 relative risk with 95%CI 0.55 < 1.04 < 1.25 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------There were no significant differences in concentration------

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VENLAFAXINE significant substances p ≤ Benjamini–Hochberg correction is considered significant this is calculated by using the Benjamini–Hochberg procedure ------SUBSTANCE a c b d n i Benjamini–Hochberg dextropropoxyphene 13 41 2 84 14 1 0.0036 Fisher's exact test p = 0.0001 odds ratio with 95%CI 2.87 < 13.32 < 61.80 relative risk with 95%CI 1.78 < 2.64 < 2.95 ------SUBSTANCE a c b d n i Benjamini–Hochberg propiomazine 22 32 11 75 14 2 0.0071 Fisher's exact test p = 0.0002 odds ratio with 95%CI 2.04 < 4.69 < 10.79 relative risk with 95%CI 1.55 < 2.23 < 2.75 ------SUBSTANCE a c b d n i Benjamini–Hochberg nortriptyline 7 47 0 86 14 3 0.0107 Fisher's exact test p = 0.0010 odds ratio with 95%CI 1.53 < 27.32 < 488.81 relative risk with 95%CI 1.29 < 2.65 < 2.82 ------SUBSTANCE a c b d n i Benjamini–Hochberg codeine 10 44 3 83 14 4 0.0143 Fisher's exact test p = 0.0052 odds ratio with 95%CI 1.64 < 6.29 < 24.04 relative risk with 95%CI 1.34 < 2.22 < 2.68 ------SUBSTANCE a c b d n i Benjamini–Hochberg alimemazine 16 38 9 77 14 5 0.0179 Fisher's exact test p = 0.0060 odds ratio with 95%CI 1.46 < 3.60 < 8.90 relative risk with 95%CI 1.27 < 1.94 < 2.47 ------SUBSTANCE a c b d n i Benjamini–Hochberg amitriptyline 6 48 1 85 14 6 0.0214 Fisher's exact test p = 0.0134 odds ratio with 95%CI 1.24 < 10.63 < 90.88 relative risk with 95%CI 1.14 < 2.38 < 2.72 ------SUBSTANCE a c b d n i Benjamini–Hochberg flunitrazepam 6 48 1 85 14 7 0.0250 Fisher's exact test p = 0.0134 odds ratio with 95%CI 1.24 < 10.63 < 90.88 relative risk with 95%CI 1.14 < 2.38 < 2.72 ------SUBSTANCE a c b d n i Benjamini–Hochberg citalopram 8 46 3 83 14 8 0.0286 Fisher's exact test p = 0.0225 odds ratio with 95%CI 1.22 < 4.81 < 19.03 relative risk with 95%CI 1.13 < 2.04 < 2.56 ------SUBSTANCE a c b d n i Benjamini–Hochberg paracetamol 18 36 14 72 14 9 0.0321 Fisher's exact test p = 0.0237 odds ratio with 95%CI 1.15 < 2.57 < 5.75 relative risk with 95%CI 1.10 < 1.69 < 2.23 ------SUBSTANCE a c b d n i Benjamini–Hochberg zopiclone 17 37 14 72 14 10 0.0357 Fisher's exact test p = 0.0392 odds ratio with 95%CI 1.05 < 2.36 < 5.32 relative risk with 95%CI 1.03 < 1.62 < 2.16 ------SUBSTANCE a c b d n i Benjamini–Hochberg alprazolam 6 48 2 84 14 11 0.0393 Fisher's exact test p = 0.0548 odds ratio with 95%CI 1.02 < 5.25 < 27.04 relative risk with 95%CI 1.01 < 2.06 < 2.58 ------SUBSTANCE a c b d n i Benjamini–Hochberg ethanol 17 37 25 61 14 12 0.0429 Fisher's exact test p = 0.8502 odds ratio with 95%CI 0.54 < 1.12 < 2.35 relative risk with 95%CI 0.65 < 1.07 < 1.56 ------

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SUBSTANCE a c b d n i Benjamini–Hochberg diazepam 11 43 18 68 14 13 0.0464 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.42 < 0.97 < 2.24 relative risk with 95%CI 0.54 < 0.98 < 1.51 ------SUBSTANCE a c b d n i Benjamini–Hochberg mirtazapine 7 47 11 75 14 14 0.0500 Fisher's exact test p = 1.0000 odds ratio with 95%CI 0.37 < 1.02 < 2.80 relative risk with 95%CI 0.49 < 1.01 < 1.65 ------SUBSTANCE b-cases: with vs without | c-cases: with vs without ------propiomazine with without | with without median concentration [µg/g] 4.45 3.50 | 0.60 0.30 MMW p values: 0.199 | 0.005 ------codeine with without | with without median concentration [µg/g] 2.00 4.35 | 0.50 0.30 MMW p values: 0.050 | 0.191 ------alimemazine with without | with without median concentration [µg/g] 2.80 4.35 | 0.80 0.30 MMW p values: 0.329 | 0.007 ------

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