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1.
  • Rydberg Sterner, Therese, et al. (author)
  • The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population.
  • 2019
  • In: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 34:2, s. 191-209
  • Journal article (peer-reviewed)abstract
    • To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014-16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n=1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons.
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  • Walz, Lotta, et al. (author)
  • Metformin - Postmortem fatal and non-fatal reference concentrations in femoral blood and risk factors associated with fatal intoxications
  • 2019
  • In: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 303
  • Journal article (peer-reviewed)abstract
    • Background amp; objectives: To improve the interpretation of fatal intoxications by establishing fatal and non-fatal reference concentrations of metformin in postmortem femoral blood and to further evaluate risk factors associated with fatal metformin intoxication. Methods: All forensic autopsies in Sweden where metformin was detected in femoral blood 2011-2016 were identified in the National Board of Forensic Medicine databases (NFMD). The cases were classified as single substance intoxications, A (n = 22), multiple substance intoxications, B (N = 7) and postmortem controls, C (N = 13). The control group consisted of cases where metformin was detected, but the cause of death excluded the incapacitation by metformin or other substances. Strict inclusion criteria were used, and all postmortem cases were assessed by two independent reviewers. All other cases where the inclusion criteria of groups A-C where not met formed group O (N = 78). The forensic findings logged in the NFMD where linked to national registers whereby information on comorbidities, dispensed drugs and clinical data could be obtained. Results: The mean age was 66 +/- 10 years in the total study population and did not differ between the groups. The proportion of men was 64% in group A, 71% in B, 77% in C and 74% in group O. The median values of metformin in group A (48.5 mu g/g; range 13.0-210 mu g/g) and B (21.0 mu g/g; range 4.40-95.0 mu g/g) were significantly (p amp;lt; 0.001 and p = 0.015 respectively) higher than those of the control group C (2.30 mu g/g; range 0.70-21.0 mu g/g). The median concentration of metformin in group A and B was also significantly higher than in group O (4.60 mg/g; range 0.64-54.0 mu g/g) (p amp;lt; 0.001 and p = 0.040 respectively). The results suggest that intoxication with metformin as a cause of death should be considered when the postmortem femoral blood level exceeds about 10 mg/g, although higher levels may be seen in postmortem in cases without incapacitation. The metformin intoxication was confirmed to be intentional in 23% (n = 5) of the single intoxications. Underlying factors identified as important for the remaining fatal metformin intoxications included living alone, any contraindication for the use of metformin, known alcohol abuse and a history of stroke or cardiovascular disease. Conclusions: The reported post mortem femoral blood concentrations of metformin can hopefully contribute to a better interpretation of results in suspected poisonings and obscure cases. Living in a single household, history of cardiovascular disease and contraindications, predominantly alcohol abuse, were associated with fatal metformin intoxication. (C) 2019 Elsevier B.V. All rights reserved.
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3.
  • Ahlner, Johan, et al. (author)
  • Demographics and post-mortem toxicology findings in deaths among people arrested multiple times for use of illicit drugs and/or impaired driving
  • 2016
  • In: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 265, s. 138-143
  • Journal article (peer-reviewed)abstract
    • Background: Multiple arrests for use of illicit drugs and/or impaired driving strongly suggests the existence of a personality disorder and/or a substance abuse problem. Methods: This retrospective study (1993-2010) used a national forensic toxicology database (TOXBASE), and we identified 3943 individuals with two or more arrests for use of illicit drugs and/or impaired driving. These individuals had subsequently died from a fatal drug poisoning or some other cause of death, such as trauma. Results: Of the 3943 repeat offenders 1807 (46%) died from a fatal drug overdose and 2136 (54%) died from other causes (p amp;lt; 0.001). The repeat offenders were predominantly male (90% vs 10%) and mean age of drug poisoning deaths was 5 y younger (mean 35 y) than other causes of death (mean 40 y). Significantly more repeat offenders (46%) died from drug overdose compared with all other forensic autopsies (14%) (p amp;lt; 0.001). Four or more drugs were identified in femoral blood in 44% of deaths from poisoning (drug overdose) compared with 18% of deaths by other causes (p amp;lt; 0.001). The manner of death was considered accidental in 54% of deaths among repeat offenders compared with 28% for other suspicious deaths (p amp;lt; 0.001). The psychoactive substances most commonly identified in autopsy blood from repeat offenders were ethanol, morphine (from heroin), diazepam, amphetamines, cannabis, and various opioids. Conclusions: This study shows that people arrested multiple times for use of illicit drugs and/or impaired driving are more likely to die by accidentally overdosing with drugs. Lives might be saved if repeat offenders were sentenced to treatment and rehabilitation for their drug abuse problem instead of conventional penalties for drug-related crimes. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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6.
  • Ahlner, Johan, et al. (author)
  • Prevalence of alcohol and other drugs and the concentrations in blood of drivers killed in road traffic crashes in Sweden
  • 2014
  • In: Scandinavian Journal of Public Health. - : SAGE Publications (UK and US). - 1403-4948 .- 1651-1905. ; 42:2, s. 177-183
  • Journal article (peer-reviewed)abstract
    • Background: Drunk or drug-impaired drivers represent a major public health and societal problem worldwide. Because over 95% of drivers killed on the roads in Sweden are autopsied, reliable information is available about the use of alcohol and/or other drug before the crash. Methods: This retrospective 4-year study (2008-2011) used a forensic toxicology database (TOXBASE) to evaluate the concentrations of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes. Results: The mean age of all victims (N = 895) was 48 +/- 20 years, and the majority were male (86%). In 504 drivers (56%), the results of toxicological analysis were negative and these victims were older; mean age (+/- SD) 47 +/- 20 years, than alcohol positive cases (35 +/- 14 years) and illicit drug users (34 +/- 15 years). In 21% of fatalities, blood-alcohol concentration (BAC) was above the statutory limit for driving (0.2 g/L), although the median BAC was appreciably higher (1.72 g/L). Illicit drugs (mainly amphetamine and cannabis) were identified in similar to 7% of victims, either alone (2.5%), together with alcohol (1.8%) or a prescription drug (2%). The psychoactive prescription drugs identified were mainly benzodiazepines, z-hypnotics and tramadol, which were found in the blood of 7.6% of crash victims. Conclusions: The high median BAC in fatally-injured drivers speaks strongly towards alcohol-induced impairment as being responsible for the crash. Compared with alcohol, the prevalence of illicit and psychoactive prescription drugs was fairly low despite a dramatic increase in the number of drug-impaired drivers arrested by the police after a zero-tolerance law was introduced in 1999.
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  • Ahlström, Stina, et al. (author)
  • The Importance of BHB Testing on the Post-Mortem Diagnosis of Ketoacidosis
  • 2022
  • In: Biomolecules. - : MDPI. - 2218-273X. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Although beta-hydroxybutyrate (BHB) analysis has proved its importance in forensic pathology, its effects on cause-of-death diagnostics are unaddressed. Therefore, this study aims at evaluating the effects of BHB analysis on the number of deaths by DKA (diabetes ketoacidosis), AKA (alcoholic ketoacidosis), HHS (hyperosmolar hyperglycaemic state), hypothermia, diabetes, alcoholism, and acidosis NOS (not otherwise specified). All 2900 deaths from 2013 through 2019 in which BHB was analysed at the National Board of Forensic Medicine, and 1069 DKA, AKA, HHS, hypothermia, diabetes, alcoholism, and acidosis cases without BHB analysis were included. The prevalence of BHB-positive cases for each cause of death, and trends and proportions of different BHB concentrations, were investigated. The number of BHB analyses/year increased from 13 to 1417. AKA increased from three to 66 and acidosis from one to 20. The deaths from alcoholism, DKA, and hypothermia remained stable. It is unclear why death from alcoholism remained stable while AKA increased. The increase in unspecific acidosis deaths raises the question why a more specific diagnosis had not been used. In conclusion, BHB analysis is instrumental in detecting AKA and acidosis. The scientific basis for the diagnosis of DKA and hypothermia improved, but the number of cases did not change.
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  • Apelqvist, G, et al. (author)
  • Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy
  • 2000
  • In: Clinical neuropharmacology. - : Ovid Technologies (Wolters Kluwer Health). - 0362-5664 .- 1537-162X. ; 23:6, s. 304-317
  • Journal article (peer-reviewed)abstract
    • Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg ╖ kg-1 ╖ day-1), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCl-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.
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  • Bastami, Salumeh, et al. (author)
  • Influence of UGT2B7, OPRM1 and ABCB1 Gene Polymorphisms on Postoperative Morphine Consumption
  • 2014
  • In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 115:5, s. 423-431
  • Journal article (peer-reviewed)abstract
    • Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in both effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7,OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine-induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsies as morphine is also a very commonly abused drug. Blood samples were collected from 40 patients following abdominal hysterectomy, 24hr after initiation of analgesia through a patient-controlled analgesia (PCA) pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsies found positive for morphine in routine forensic analysis. Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. The dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood. Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients. We conclude that gene polymorphisms contribute significantly to the variation in morphine concentrations observed in individual patients.
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  • Bastami, Salumeh, et al. (author)
  • Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
  • 2013
  • In: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 52:5, s. 1022-1033
  • Journal article (peer-reviewed)abstract
    • Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.
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  • Bastami, Salumeh, 1967- (author)
  • Practical and clinical use of opioids
  • 2013
  • Doctoral thesis (other academic/artistic)abstract
    • Pain is a common symptom of a number of conditions including cancer and one of the most frequent reasons for seeking healthcare. Acute and chronic pain result in considerable discomfort with a detrimental impact on the quality of life. Opioids are the mainstay of pain management for many patients with severe pain. Opioids are, unfortunately, also commonly abused drugs, and are well-represented in forensic toxicology investigations.Side effects related to the central nervous system are the major reasons fordiscontinuation of opioid treatment. In this thesis, we tested the hypothesis that local analgesic treatment by opioids, without the usual opioid-related side effects, could be a potential alternative to systemic opioid treatment. We examined the analgesic effect of topically applied morphine in a randomized, double blind, cross over study in patients with painful leg ulcers. Significant reduction of pain was obtained after application of both morphine and placebo gel. Morphine reduced pain more than placebo but the difference was not statistically significant. However, morphine could reduce pain considerably more than placebo in those cases where VAS (Visual analog scale) was higher initially.Another issue with opioid therapy is the substantial individual variability in response to opioids including morphine and tramadol. We investigated the significance of UGT2B7, CYP2D6, OPRM1 and ABCB1 polymorphisms for pharmacokinetic and pharmacodynamic properties of morphine and tramadol. We showed that genetic variants in CYP2D6 and UGT2B7 have an important role in the metabolism of tramadol and morphine respectively. While the role of SNPs in ABCB1 remained unclear, genetic variants in OPRM1 gene were correlated with the required dose of morphine. Taken together, these findings suggest that genotypes should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results.Opioids, besides their analgesic properties, have other pharmacological effects including effects on immune system. We evaluated potential differences between commonly used opiates with regard to their effect on the immune system. We found an inhibition of cytokine release, in the order of potency as follows: tramadol > ketobemidone >morphine >fentanyl. All opioids with the exception of fentanyl were capable of inhibiting production of mRNAs for TNF-alpha and IL-8. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of opioids and to improve opioid treatment strategies in patients with cancer.Here, we have found that individual genotype matters and affects the individual response. Further research is warranted to tailor individualized treatment. Personalized medicine has increased in importance and will hopefully in the near future become standard procedure to improve and predict the outcome of treatment by opioids.
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  • Bastami, Salumeh, et al. (author)
  • Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial : a pilot study
  • 2012
  • In: International Wound Journal. - : Blackwell Publishing. - 1742-4801 .- 1742-481X. ; 9:4, s. 419-427
  • Journal article (peer-reviewed)abstract
    • Chronic painful wounds, a major health problem, have a detrimental impact on the quality of life due to associated pain. Some clinical reports have suggested that local administration of morphine could be beneficial. The aim of this study was to evaluate the analgesic effect of topically applied morphine on chronic painful leg ulcers. Twenty-one patients were randomly assigned to receive either morphine or placebo in a randomised, placebo-controlled, crossover pilot study. Each patient was treated four times in total. Pain was measured by the visual analogue score (VAS) before application of gel, directly after and after 2, 6, 12 and 24 hours. Although an overall, clinically relevant, reduction of pain was observed upon treatment with morphine, the difference was not statistically significant. Morphine reduced pain scores more than placebo on treatment occasions 1 and 2. The difference was statistically significant only 2 hours after dressing on the first treatment occasion. Thus, our study did not demonstrate a consistent and globally significant difference in nociception in patients treated with morphine. However, the relatively small number of patients included in our study and other methodological limitations makes it difficult for us to draw general conclusions regarding efficacy of topically applied morphine as an effective treatment for some painful ulcers. Further studies are warranted to evaluate the value of topically applied morphine in the treatment of patients with chronic painful leg ulcers.
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  • Boiso, Samuel, et al. (author)
  • ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
  • 2013
  • In: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:9, s. 463-469
  • Journal article (peer-reviewed)abstract
    • Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.
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  • Carlsson, Björn, et al. (author)
  • Enantioselective analysis of citalopram and escitalopram in postmortem blood together with genotyping for CYP2D6 and CYP2C19
  • 2009
  • In: Journal of Analytical Toxicology. - 0146-4760. ; 33:2, s. 65-76
  • Journal article (peer-reviewed)abstract
    • Citalopram is marketed as a racemate (50:50) mixture of the S(+)-enantiomer and R(-)-enantiomer and the active S(+)-enantiomer (escitalopram) that possess inhibitory effects. Citalopram was introduced in Sweden in 1992 and is the most frequently used antidepressant to date in Sweden. In 2002, escitalopram was introduced onto the Swedish market for treatment of depression and anxiety disorders. The main objective of this study was to investigate S(+)-citalopram [i.e., the racemic drug (citalopram) or the enantiomer (escitalopram)] present in forensic autopsy cases positive for the presence of citalopram in routine screening using a non-enantioselective bioanalytical method. Fifty out of the 270 samples found positive by gas chromatography-nitrogen-phosphorus detection were further analyzed using enantioselective high-performance liquid chromatography. The 50 cases were genotyped for CYP2D6 and CYP2C19, as these isoenzymes are implicated in the metabolism of citalopram and escitalopram. In samples positive for racemic citalopram using the screening method for forensic autopsy cases, up to 20% would have been misinterpreted in the absence of an enantioselective method. An enantioselective method is thus necessary for correct interpretation of autopsy cases, after the enantiomer has been introduced onto the market. The percentage of poor metabolizers was 6% for CYP2D6 and 8% for CYP2C19.
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  • Carlsson, Björn, et al. (author)
  • Enantioselective Analysis of Citalopram and Metabolites in Adolescents
  • 2001
  • In: Therapeutic drug monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356. ; 23, s. 658-
  • Journal article (peer-reviewed)abstract
    • Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.
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  • Chermá Yeste, Maria Dolores, 1961-, et al. (author)
  • Concentration of Antidepressant Drugs in Children and Adolescents: a naturalistic clinical study
  • Other publication (other academic/artistic)abstract
    • Objective: The aims of this study were to evaluate the pharmacokinetics (PKs) of antidepressant agents, in terms of steady-state and trough values, in a heterogeneous cohort of patients and to describe the utilisation of antidepressant drugs (ATDs) in Child and Adolescent Psychiatry in the south- east of Sweden. Method: Patients from Child and Adolescent Psychiatry centres in the counties of Östergötland, Jönköping and Kalmar (Sweden) to be prescribed an antidepressant drug, were studied between 2002 and 2004. The blood concentration of ATDs and, in some cases, also CYP2D6 were determined and relevant clinical information provided. Results: Two hundred and eleven children: 64 % girls and 36 % boys, between the ages of 8 and 20 were evaluated. The concentrations of drugs in the patient evaluated (PE) population were as expected from the dose administered in 63 % of this population, higher than expected in 26 % and lower than expected in 11 %. Dose-concentration relationships for sertraline (rs=0.48, p<0.001) and metabolite desmethylsertraline (rs=0.5, p<0.001) were seen. No relationship was found between dose and ratio desmethylsertraline-to-sertraline. CYP2D6*4 was the most common poor metabolizer (PM) allele. The primary indication for the antidepressant treatment was depression in 69 % of subjects. Suspected adverse drug reactions were spontaneously reported in 31 %. Monotherapy was indicated in 49 % of request forms. The most common drug combinations with the antidepressant drug were oral anticontraceptives and anxiolytics/sedatives/hypnotic drugs. Conclusion: the most prescribed antidepressant drug in children and adolescents in the present study was sertraline. The pharmacokinetic outcomes of serum concentration of sertraline, as well as daily doses administered were similar to the referenced data for adults. Antidepressant drug monotherapy was most common. No serious adverse side effects were spontaneously reported. TDM may provide support to the prescribing physicians to individual dose optimising and to assess drug compliance, above all when the antidepressant drugs are not well studied in pediatric patients before approval for general prescription. Further clinical trials, as well as naturalistic studies are necessary to ensure that children are not exposed to unnecessary risk and to determine the most appropriate dose in children of different ages.
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  • Chermá Yeste, Maria Dolores, 1961- (author)
  • Therapeutic Drug Monitoring in Psychiatry : Some aspects of utility in clinical practice and research
  • 2009
  • Doctoral thesis (other academic/artistic)abstract
    • Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described.Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study.The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype.The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug.Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.
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  • Cherma Yeste, Maria Dolores, et al. (author)
  • Use of Lisdexamfetamine or Amphetamine? Interpretation of Chiral Amphetamine Analyses
  • 2022
  • In: Journal of Analytical Toxicology. - : OXFORD UNIV PRESS INC. - 0146-4760 .- 1945-2403. ; 46:1, s. 10-16
  • Journal article (peer-reviewed)abstract
    • Amphetamine is frequently detected in forensic toxicological cases. Differentiating between the two isomers of amphetamine (d-amphetamine and l-amphetamine) and determining their relative proportion are fundamental to correctly interpret the results of toxicological analyses. The aim of this study was to examine the profile of amphetamine as well as storage stability of the isomers in authentic samples from patients chronically treated with lisdexamfetamine (LDX), the most prescribed medical amphetamine product in Sweden. Blood and urine samples were collected from 18 patients. The samples were analyzed with an achiral (racemate) method for quantification of amphetamine and with a chiral method to determine the proportion of each isomer of amphetamine. The median daily dose of LDX was 40 mg (range, 20-70 mg). The median amphetamine concentration was 0.06 mu g/g (range, 0.02-0.15 mu g/g) in blood and 6 mu g/mL (range, 1-22 mu g/mL) in urine. Only d-amphetamine was found in the blood and urine samples from the included patients. Furthermore, no formation of l-amphetamine occurred during the storage for 3 months at 4 degrees C, 9 months at -20 degrees C and three freeze-thaw cycles. The results from this study may be helpful in the interpretation of whether the source of identified amphetamine in biological samples is from LDX drug intake or not.
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22.
  • D Cherma, Maria, et al. (author)
  • Antidepressant Drugs in Children and Adolescents Analytical and Demographic Data in a Naturalistic, Clinical Study
  • 2011
  • In: JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY. - : Williams andamp; Wilkins. - 0271-0749. ; 31:1, s. 98-102
  • Journal article (peer-reviewed)abstract
    • Pharmacokinetics of antidepressant drugs (ATDs), in terms of steady-state and trough values, in patients from Child and Adolescent Psychiatry centers in the midsouth-eastern part of Sweden, were evaluated, and the use of ATDs in this population were described. Patients to be prescribed an ATD were studied between 2002 and 2004. Two hundred eleven children, 64% girls and 36% boys (ages 8-20 years) were evaluated. The primary indication for the antidepressant treatment was depression in 69% of subjects. The median body mass index was 20.2 kg/m(2) (range, 12.4-38.6 kg/m(2)). Suspected adverse drug reactions were spontaneously reported in 31% (no serious). Monotherapy was indicated in 49% of request forms. The most common drug combination with the ATD was oral contraceptives. The concentrations of drugs in the patient evaluated population to referenced data for adults from the dose administered were as expected in 63%, higher than expected in 26% and lower than expected in 11%. The most prescribed ATD was sertraline (SERT). Dose-concentration relationships for SERT and metabolite desmethylsertraline (DSERT) were seen, r(s) = 0.48 and r(s) = 0.5, respectively. No relationship was found between dose and ratio DSERT/SERT. The median daily dose was 50 mg (range, 12.5-150 mg), SERT concentration 16 ng/mL (range, 3-88 ng/mL), and DSERT 33 ng/mL (range, 0-253 ng/mL). CYP2D6*4 was the most common poor metabolizer allele. Therapeutic drug monitoring may provide support to prescribing physicians to individual dose optimizing and to assess drug compliance, above all when ATDs are not well studied in pediatric patients before approval for general prescription.
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23.
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24.
  • Dolores Cherma Yeste, Maria, et al. (author)
  • Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
  • 2008
  • In: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 30:6, s. 682-688
  • Journal article (peer-reviewed)abstract
    • There is limited information on the pharmacokinetics of ziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linkoping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20-320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L-1 mg(-1) d(-1)) for ZIP and SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively, with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.
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25.
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26.
  • Druid, H., et al. (author)
  • Flunitrazepam : An evaluation of use, abuse and toxicity
  • 2001
  • In: Forensic Science International. - 0379-0738 .- 1872-6283. ; 122:2-3, s. 136-141
  • Journal article (peer-reviewed)abstract
    • The benzodiazepine flunitrazepam is extensively prescribed to patients with insomnia in many countries, but has also become popular among alcohol- and drug abusers. Several reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. Furthermore, flunitrazepam is involved in many fatal intoxications in Sweden. This study was designed and conducted to explore the negative consequences of flunitrazepam abuse in Sweden, and to assess the trends in its use and abuse. The occurrence of flunitrazepam in cases referred to the Department of Forensic Chemistry in Linköping, Sweden 1992-1998, was investigated in detail. The detections were studied separately for different groups, medicolegal death investigations, drug abuse cases, driving under influence cases, and other medicolegal cases. These data were further compared with the sales, and seizures by the Swedish Customs and the Swedish Police. During 1992-1998, 641 fatalities occurred, where the cause of death was attributed to intoxication with flunitrazepam solely (130) or in combination with other drugs, or concomittant conditions (511). In 78% of all driving under influence cases, where flunitrazepam was detected, the analyses also disclosed the presence of illicit drugs. A similar association was seen in drug abuse cases. The seizures reported by the Swedish Customs revealed a substantial and increasing illegal trade. Cases, where flunitrazepam seemingly induced violent behavior were identified, and one of these is described in some detail. It is concluded that the abuse pattern and the toxicity of flunitrazepam should be kept in mind by forensic investigators and that this panorama also should be considered when decisions about the registration and classification of flunitrazepam are made in different countries. Copyright © 2001 Elsevier Science Ireland Ltd.
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27.
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28.
  • Fazel, S., et al. (author)
  • Suicides by violent means in individuals taking SSRIs and other antidepressants : A postmortem study in Sweden, 1992-2004
  • 2007
  • In: Journal of Clinical Psychopharmacology. - : Ovid Technologies (Wolters Kluwer Health). - 0271-0749 .- 1533-712X. ; 27:5, s. 503-506
  • Journal article (peer-reviewed)abstract
    • A number of reports have linked consumption of selective serotonin reuptake inhibitors (SSRIs) with suicide by violent methods. We aimed to determine whether suicides with postmortem evidence of SSRI consumption are more likely to have used violent methods compared with suicides with no detectable antidepressants. Blood samples from all suicides in Sweden during 1992-2004 were examined. Suicides were classified into those who died by violence and nonviolent (self-poisoning) methods using information from police records and autopsy. In addition, we investigated proportions of violent suicide in individuals who died with detectable levels of tricyclic and other antidepressants.The sample consisted of 14,691 suicides. Of the 1958 suicides with detectable levels of SSRIs, 1247 were by violent means (63.7%) compared with 7835 of 11,045 suicides (70.9%) in antidepressant-free group (?1 = 7.6, P < 0.01). We found no significant differences in the proportion of violent suicides in the SSRI group compared with the antidepressant-free group by sex or age band (15-24, 25-39, and over 40 years). When subdivided by gender and age-bands, we found specific groups with significantly lower proportions of violent suicides compared with the antidepressants-free group, including men aged 15-24 years. © 2007 Lippincott Williams & Wilkins, Inc.
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29.
  • Fazel, Seena, et al. (author)
  • "Suicides by violent means in individuals taking SSRIs and other antidepressants: A postmortem study in Sweden, 1992-2004" : Erratum
  • 2008
  • In: Journal of Clinical Psychopharmacology. - 0271-0749. ; 28:1, s. 123-
  • Journal article (peer-reviewed)abstract
    • Reports an error in "Suicides by violent means in individuals taking SSRIs and other antidepressants: A postmortem study in Sweden, 1992-2004" by Seena Fazel, Martin Grann, Johan Ahlner and Guy Goodwin (Journal of Clinical Psychopharmacology, 2007[Oct], Vol 27[5], 503-506). In the article, the entire second to the last sentence in the abstract on page 503 should have been deleted. (The following abstract of the original article appeared in record 2007-14520-014). A number of reports have linked consumption of selective serotonin reuptake inhibitors (SSRIs) with suicide by violent methods. We aimed to determine whether suicides with postmortem evidence of SSRI consumption are more likely to have used violent methods compared with suicides with no detectable antidepressants. Blood samples from all suicides in Sweden during 1992-2004 were examined. Suicides were classified into those who died by violence and nonviolent (self-poisoning) methods using information from police records and autopsy. In addition, we investigated proportions of violent suicide in individuals who died with detectable levels of tricyclic and other antidepressants. The sample consisted of 14,691 suicides. Of the 1958 suicides with detectable levels of SSRIs, 1247 were by violent means (63.7%) compared with 7835 of 11,045 suicides (70.9%) in antidepressant-free group (χ◊-sub-1 = 7.6; P < 0.01). We found no significant differences in the proportion of violent suicides in the SSRI group compared with the antidepressant-free group by sex or age band (15-24, 25-39, and over 40 years). When subdivided by gender and age-bands, we found specific groups with significantly lower proportions of violent suicides compared with the antidepressants-free group, including men aged 15-24 years.
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30.
  • Forsman, Jonas, et al. (author)
  • Selective serotonin re-uptake inhibitors and the risk of violent suicide: a nationwide postmortem study
  • 2019
  • In: European Journal of Clinical Pharmacology. - : SPRINGER HEIDELBERG. - 0031-6970 .- 1432-1041. ; 75:3, s. 393-400
  • Journal article (peer-reviewed)abstract
    • PurposeWe endeavored to investigate whether previous findings of an association between antemortem exposure to selective serotonin re-uptake inhibitors (SSRI) and method of suicide could be replicated.MethodsUsing the Swedish National Board of Forensic Medicines toxicology database and the Swedish National Board of Health and Welfares national registries of causes of death and prescriptions, 10,002 incidents of suicide were retrieved. Risks of violent suicide conferred by SSRIs, expressed as odds ratios (ORs) with 95% confidence intervals (CIs), were estimated using logistic regression. In accordance with previous work, suicide by violent meanscaseswere defined as death attributable to causes designated by ICD-10 codes X70-X83 and Y20-Y33; and suicide by non-violent meanscontrolsby codes X60-X69 and Y10-Y19.ResultsOur results imply that SSRI exposure confers a risk of violent suicide for shorter treatment durations; and that antemortem exposure to other substances (including illegal drugs) confounds estimates of risk. After adjustment for age, sex, and other substances, SSRIs treatment not exceeding 28days conferred an almost fourfold risk of violent suicide (OR 3.6 [95% CI 1.9-6.8]), a finding partly in line with a recent Swedish study that employed a case-crossover design.ConclusionsAlthough risks associated with shorter treatment duration may reflect latencies to onset of therapeutic effect, it is unclear how latencies would influence the choice of suicide method, unless conditions for which SSRIs are prescribed are themselves associated with violent suicide. Finally, in the total dataset, SSRIs were not associated with an increased risk of violent suicide; however, by adjusting for other substances, we avoided the spurious conclusion that the effect of medications in this regard is protective.
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31.
  • Forsman, M., et al. (author)
  • Urinary detection times and excretion patterns of flunitrazepam and its metabolites after a single oral dose
  • 2009
  • In: Journal of Analytical Toxicology. - 0146-4760 .- 1945-2403. ; 33:8, s. 491-501
  • Journal article (peer-reviewed)abstract
    • We investigated the excretion profiles of flunitrazepam metabolites in urine after a single dose. Sixteen volunteers received either 0.5 or 2.0 mg flunitrazepam. Urine samples were collected after 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 240, and 336 h. Samples were screened using CEDIA (300 µg/L cutoff) and quantitated using liquid chromatography-tandem mass spectrometry. The cutoff was 0.5 µg/L for flunitrazepam, N-desmethylflunitrazepam, 7-aminoflunitrazepam, 7-aminodesmethylflunitrazepam, 7-acetamidoflunitrazepam, and 7-acetamidodesmethylflunitrazepam. None of the subjects receiving 0.5 mg were screened positive, and only 23 of 102 samples from the subjects given 2.0 mg were positive with CEDIA. The predominant metabolites were 7-aminoflunitrazepam and 7-aminodesmethylflunitrazepam. For all subjects given the low dose, 7-aminoflunitrazepam was detected up to 120 h, and for two subjects for more than 240 h. Seven subjects given the high dose were positive up to 240 h for 7-aminoflunitrazepam. We conclude that the ratio 7-aminodesmethylflunitrazepam to 7-aminoflunitrazepam increased with time, independent of dose, and may be used to estimate the time of intake. For some low-dose subjects, the metabolite concentrations in the early samples were low and a chromatographic method may fail to detect the intake. We think laboratories should consider this when advising police and hospitals about sampling as well as when they set up strategies for analysis.
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32.
  • Fugelstad, A, et al. (author)
  • Use of morphine and 6-monoacetylmorphine in blood for the evaluation of possible risk factors for sudden death in 192 heroin users
  • 2003
  • In: Addiction. - : Wiley. - 0965-2140 .- 1360-0443. ; 98:4, s. 463-470
  • Journal article (peer-reviewed)abstract
    • Aims: To detect risk factors for sudden death from heroin injection. Design: Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. Setting: Stockholm, Sweden. Measurements: Autopsy investigation and toxicological analysis of blood and urine: and police reports. Findings: In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. Conclusions: We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors.
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33.
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34.
  • Hedlund, Jonatan, et al. (author)
  • A population-based study on toxicological findings in Swedish homicide victims and offenders from 2007 to 2009
  • 2014
  • In: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 244, s. 25-29
  • Journal article (peer-reviewed)abstract
    • Background and objectives: Previous research on the toxicology of homicide has shown that about half of offenders and victims have psychoactive substances in their blood. The purpose of this study was to examine this topic in a Swedish setting. Methods: Toxicological data were sought in a database for all victims (n = 273) and perpetrators (n = 257) of homicide in Sweden from 2007 to 2009. Sufficient tests were identified for 97.1% of all victims (n = 265) and 46.7% of all offenders (n = 120). Additional information was obtained from court records and police reports. Results: A majority of individuals involved in homicides displayed positive toxicology (57.0% of victims and 62.5% of offenders). The most commonly detected substances, in both victims and offenders, were ethanol (44.9% vs. 40.8%) and benzodiazepines (8.3% vs. 19.2%). The difference between offenders and victims concerning benzodiazepines was statistically significant (OR 2.6; p = 0.002). Perpetrators of homicide-suicide had a lower prevalence of positive toxicology (30.8%) than other homicide offenders (66.4%; p = 0.04) and victims in unsolved cases more often exhibited positive drug toxicology compared to victims in solved cases (36.1% vs. 8.3%; p less than 0.001). Conclusions: The results of the study support the notion that substance abuse is firmly linked to committing homicide and to becoming a victim thereof.
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35.
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36.
  • Hoffmann, Mikael, et al. (author)
  • Do patients or their physicians more accurately assess long-term risk associated with hypertension? A population-based study
  • 2020
  • In: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 38:2, s. 166-175
  • Journal article (peer-reviewed)abstract
    • Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better (p < 0.001) than their physicians in estimating the average probability of heart failure compared with actual outcome data (14% vs. 24%, outcome 15%), AMI (16% vs. 26%, outcome 8%), and stroke (15% vs. 25%, outcome 11%). Patients were significantly worse (p < 0.001) at estimating the average probability of death (10% vs. 18%, actual outcome 20%). Neither the patients nor the physicians were able to distinguish reliably between low-risk and high-risk patients after adjustment for age and sex. Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patient’s risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.Key points •Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. •Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient’s risk of cardiovascular morbidity. •Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. •The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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37.
  • Hoffmann, Mikael, et al. (author)
  • Hormone replacement therapy in the menopause - structure and content of risk talk
  • 2005
  • In: Maturitas. - : Elsevier BV. - 0378-5122 .- 1873-4111. ; 50:1, s. 8-18
  • Journal article (peer-reviewed)abstract
    • Objective: To investigate how risks and benefits of hormone replacement therapy (HRT) are communicated to women in clinical practice. To evaluate the usefulness of a risk classification based on context framing, i.e. whether the risk is discussed for one or several alternative treatments, and/or in the same context as possible benefits. Design: Analysis of structure and content of transcribed consultations (n=20) from first-time visits for discussion of climacteric discomfort and/or HRT with five physicians at three different out-patient clinics of gynecology. Results: All women received a prescription of HRT. An alternative to HRT was discussed in seven of the consultations. No decision aids were used. Risk discussion was dominated by the physicians giving information about long-time risk and benefits. The decision to prescribe was made either before the risk discussion was initiated, or before it was finished, in 8 of the 18 consultations where risk discussion was present. Risk classification according to context framing was performed and indicated use of different communication strategies by the physicians.Conclusions: The perspective of the physicians was mainly on prevention while the women were more focused on symptom alleviation. Each physician had a strategy of his/her own for the risk discussion. Thus, the major differences found between the consultations were between physicians, and not between the women. Risk discussion seemed to be aimed at motivating the woman to follow the physician’s decision rather than to help her participate in the decision-making process.
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38.
  • Hoffmann, Mikael, et al. (author)
  • Risk communication in consultations about hormone therapy in the menopause – concordance in risk assessment and framing due to the context
  • 2006
  • In: Climacteric. - : Informa UK Limited. - 1369-7137 .- 1473-0804. ; 9:5, s. 347-354
  • Journal article (peer-reviewed)abstract
    • BackgroundIt is important for the physician and the patient to have a mutual understanding of the possible consequences of different treatment alternatives in order to achieve a partnership in decision making.ObjectiveThe aim of this study was to explore to which degree first-time consultations for discussion of climacteric discomfort achieved shared understanding of the risks and benefits associated with hormone therapy in the menopausal transition (HT).MethodsAnalysis of structure and content of transcribed consultations (n=20), and follow-up interviews of the women (n=19 pairs of consultations and interviews), from first-time visits for discussion of climacteric discomfort and/or HT with five physicians at three different out-patient clinics of gynaecology in Sweden.ResultsFour distinctively different interpretations of risk, depending on whether or not benefits were discussed in the same context, emerged from the analysis. On average 5 advantages (range 0-11) and 2 (0-3) disadvantages were mentioned during the consultations. In the interviews the women expressed on average 4 advantages (0-7) and 1 disadvantage (0-3). There were major variations between advantages and disadvantages expressed in the consultation and the following interview.ConclusionEven though the consultations scored high in patient involvement, the information in most consultations was not structured in a way that made it possible to achieve a shared or an informed decision making.
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39.
  • Hoffmann, Mikael (author)
  • Risk Talk : On Communicating Benefits and Harms in Health Care
  • 2006
  • Doctoral thesis (other academic/artistic)abstract
    • One of the most critical elements in empowering the patient, and ensuring concordance, is communication of the possible benefits and harms of different actions in health care. Risk assessment is a complex task due both to the different interpretations of the concept of risk, and the common lack of hard facts. Hormone, or hormone replacement, therapy (HT) is used by many women in, and after, the menopause. The benefits and possible harms associated with short and long term treatment with HT have been extensively discussed the last decade and the use of HT has decreased dramatically internationally the last few years.The aims of this thesis were to study the interaction between patient and physician when discussing risks and benefits of different treatment alternatives, and to suggest strategies to improve risk communication in clinical practice. The studies have focused on how risks and benefits with HT were communicated between women and physicians during firsttime consultations in 1999- 2000 on this subject (20 women, 5 gynaecologists), and through questionnaires how attitudes towards HT have changed between 1999 (n=1,760) and 2003 (n=1,733) among women entering the menopause (53-54 years).Through a qualitative analysis of the risk communication in the consultations a system was constructed to classify how risk is communicated in relation to benefits. This was used to assess and present differences in risk communication in the consultations. Different rhetorical strategies by the physicians were identified and the dominating tendency was a move from the woman’s current problems to the long-term effects of HT.The questionnaires showed a marked difference in attitudes towards HT between the years. In 2003 women perceived HT to be associated with higher risk and less benefits than in 1999. This correlated to a drastic reduction in the use of HT over the same period. Media was the most frequent source of information about HT during the last twelve months before the questionnaire in 2003.Possible explanations for the different attitudes towards HT between women entering the menopause and gynaecologist; how this difference might have influenced the results; and how they may have implications for future communication strategies are discussed. This thesis illustrates the importance of a deeper understanding in health care of the concept of risk in order to achieve an adequate communication of risk. This is important both in consultations and in campaigns to educate and inform the public.
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40.
  • Hoiseth, G., et al. (author)
  • Evaluating the hip-flask defence using analytical data from ethanol and ethyl glucuronide. A comparison of two models
  • 2020
  • In: Forensic Science International. - : ELSEVIER IRELAND LTD. - 0379-0738 .- 1872-6283. ; 316
  • Journal article (peer-reviewed)abstract
    • Aim: Claimed intake of alcohol after a traffic incident, called the hip-flask defence, can be objectively assessed by different methods. One of them is the use of two consecutive ethanol concentrations in urine and the ratio between ethanol concentrations in urine and blood. Another one is the concentrations of ethyl glucuronide (EtG) and ethyl sulphate (EtS) in blood and their ratio to ethanol. The experimental basis for both these models is from single dose studies only. The aim of this study was therefore to describe the kinetics of ethanol, EtG and EtS after ingestion of two repeated doses of ethanol and to investigate the usefulness of the different models for the assessment of the hip-flask defence. Methods: Thirty-five subjects ingested a first dose of 0.51 g of ethanol per kilo body weight, and two hours later a second dose (the hip-flask drink) of 0.25, 0.51 or 0.85 g of ethanol per kilo body weight. Ten urine and 17 blood samples were collected and analysed for ethanol, EtG and EtS using fully validated methods. It was investigated if all subjects fulfilled the criteria for recent drinking, according to the two different models, when using the samples collected 180-240 minutes after start of first dose drinking. According to the first model, increase in urinary ethanol concentrations and a ratio UAC/BAC below 1.3 indicated recent drinking. According to the second model, increase in blood EtG concentrations and a ratio ethanol (g/kg)/EtG (mg/L) above 1 indicated recent drinking. Results: All subjects in the high dose group fulfilled all criteria for recent drinking. One subject in the medium dose group and nine subjects in the low dose group failed to show increasing UAC and/or a UAC/ BAC ratio below 1.3. One subject in the low dose group failed to show increasing concentrations of blood EtG, but all subjects showed a ratio ethanol/EtG above 1. Conclusions: The present study showed, by the use of experimental data, that both two models used to investigate the hip-flask defence can be used, but only when the hip-flask dose is sufficiently high. (C) 2020 The Author(s). Published by Elsevier B.V.
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41.
  • Holmgren, Anita, et al. (author)
  • High re-arrest rates among drug-impaired drivers despite zero-tolerance legislation
  • 2008
  • In: Accident Analysis and Prevention. - : Elsevier BV. - 0001-4575 .- 1879-2057. ; 40:2, s. 534-540
  • Journal article (peer-reviewed)abstract
    • Background: A zero-tolerance law for driving under the influence of drugs (DUID) in Sweden led to a 10-fold increase in the number of cases submitted by the police for toxicological analysis. The statutory blood-alcohol concentration (BAC) limit for driving is 0.2 mg/g (∼0.02 g%). Methods: An in-house database (TOXBASE) was used to investigate re-arrests for impaired driving over 4 years (2001-2004), which comprised 36,799 cases. The age, gender, re-arrest rate of the offenders and the concentrations of ethanol and amphetamine in blood samples were evaluated. Results: We found that 44% of individuals (N = 16,277) re-offended 3.2 times on average (range 1-23 arrests). Between 85 and 89% of first-time offenders were men and there was also a male dominance among the recidivists (88-93%). The mean age of drunken drivers was ∼40 years compared with ∼35 years for driving under the influence of amphetamine, which was the drug identified in 50-60% of DUID cases, either alone or together with other licit or illicit drugs. The median BAC was 1.5 mg/g (∼0.15 g%), which suggests a dominance of heavy drinkers. The median BAC was even higher in recidivists (1.6-1.7 mg/g). The median concentration of amphetamine in blood was 1.0 mg/L in recidivists compared with 0.5 mg/L in the first-time offenders. About 14% of drunken drivers re-offended 1-10 times compared with 68% of DUID suspects, who were re-arrested 1-23 times. People with only a scheduled prescription drug in blood were re-arrested much less frequently (∼17%) compared with those taking illicit drugs (68%). Conclusions: The appreciable increase in number of arrests for DUID after a zero-tolerance law might reflect a heightened enthusiasm by the police authorities armed with knowledge that a prosecution is easier to obtain. Zero-tolerance laws do not deter people from impaired driving judging by the high re-arrest rates. During the sentencing of hardcore offenders, the courts should give more consideration to the underlying substance abuse problem. © 2007 Elsevier Ltd. All rights reserved.
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42.
  • Holmgren, A, et al. (author)
  • Predominance of illicit drugs and poly-drug use among drug-impaired drivers in Sweden
  • 2007
  • In: Traffic Injury Prevention. - : Informa UK Limited. - 1538-9588 .- 1538-957X. ; 8:4, s. 361-367
  • Journal article (peer-reviewed)abstract
    • Objective. After Sweden's zero-tolerance law came into force (1 July 1999), the number of cases of driving under the influence of drugs (DUID) submitted by the police for toxicological analysis increased more than 10-fold. This prompted an in-depth investigation into the kinds of drugs used by DUID offenders, whether licit or illicit, and the frequency of their occurrence. Methods. All blood samples from DUID suspects sent by the police for toxicological analysis over a 4-year period (2001-2004) were investigated (N = 22,777 cases). Specimens of blood or urine were subjected to a broad screening analysis by immunoassay methods aimed at detecting amphetamines, cannabis, opiates, cocaine metabolite, and the major benzodiazepines. All positive results from the screening stage were verified by use of more specific analytical methods (e.g., GC-MS, LC-MS, GC-FID, and GC-NPD). Results. Between 80 and 85% of all the blood samples contained at least one banned substance and many contained two or more therapeutic and/or illicit drugs. About 15% of cases were negative for drugs, although these frequently (30-50%) contained ethanol above the legal limit for driving in Sweden, which is 0.20 mg/g (0.02 g%). Amphetamine was the most prominent illicit drug seen in 55-60% of cases either alone or together with other drugs of abuse. Stimulants like cocaine and/or its metabolite were infrequently encountered (1.2% of cases). The next most prevalent illicit drug was cannabis, with positive results for tetrahydrocannabinol (THC) in blood either alone (4%) or together with other psychoactive substances (20%). Morphine, codeine, and/or 6-acetyl morphine were identified in 2% of all DUID suspects, being indicative of heroin abuse. The major prescription drugs identified in blood were benzodiazepines (10%) as exemplified by diazepam, alprazolam, nitrazepam, and flunitrazepam. Drugs for treating insomnia, zolpidem and zopiclone, were also identified in blood samples from DUID suspects over the study period. Other therapeutic agents were encountered in only 1-2% of all cases. Conclusions. The dramatic increase in DUID after the zero-tolerance law came into force probably reflects enhanced police activity and more enthusiasm to apprehend and charge individuals for this offence. Illicit drugs, particularly amphetamine and cannabis, and poly-drug use were predominant compared with use of scheduled prescription drugs. The typical DUID offender in Sweden abuses central stimulants, particularly amphetamine, and has probably done so over many years. Options for treating offenders for their underlying substance abuse problem should be considered instead of the more conventional penalties for drug-impaired driving.
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43.
  • Holmgren, Per, et al. (author)
  • Alcohol and drugs in drivers fatally injured in traffic accidents in Sweden during the years 2000-2002
  • 2005
  • In: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 151:1, s. 11-17
  • Journal article (peer-reviewed)abstract
    • During the years 2000-2002, alcohol, pharmaceuticals and illicit drugs were analysed in blood samples from fatally injured drivers in Sweden. The total number of drivers was 920 and in 855 of these, corresponding to 93%, a toxicological investigation was performed. About 85% of the drivers were men and 15% were women. All but three women (96%) were car drivers while the corresponding figure for men was about 78% and about 13% were motorcyclists. The number of positive cases increased from 38.9% in year 2000 to 45.9% in year 2002 and alcohol was the most common drug with frequencies of 19.8%, 25.0% and 21.8% for the studied years 2000, 2001 and 2002, respectively. The median blood alcohol concentration ranged from 1.6 to 2.0 mg/mL for men and from 1.2 to 1.8 mg/mL for women. There was a decrease in cases where alcohol was the only drug detected, from 52 out of 58 cases (90%) in year 2000 to 41 out of 61 cases (67%) in 2002. At the same time there was an increase, from 5.4% to 10.0% of illicit drugs, mainly amphetamine, and the cases with multiple drug intake increased from 10% to 26%. The prevalence of pharmaceuticals as the only drug or drugs detected decreased from 14.0% to 10.4% and in the majority of these cases the drug concentrations were within the therapeutic range.
  •  
44.
  • Holmgren, Per, et al. (author)
  • Caffeine fatalities - four case reports
  • 2004
  • In: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 139:1, s. 71-73
  • Journal article (peer-reviewed)abstract
    • Four cases of fatal intoxications with caffeine are described. Caffeine is widely available in beverages and in different OTC-products, in many of them in combinations with other drugs like ephedrine. Caffeine is not as harmless as one might believe. An overdose of caffeine alone, intentional or not, might be deadly. It seems to be warranted to include caffeine in the drug-screening of forensic autopsy cases. It is not motivated from a medical point of view to sell pure caffeine over the counter.
  •  
45.
  • Holmgren, Per, et al. (author)
  • Drug interactions : a challenge in interpreting postmortem toxicology results and a problem in the clinical practice
  • Other publication (other academic/artistic)abstract
    • Objective: Multiple drug intake is a problem in tbe clinical setting with potential to adverse drug reactions and certainly a problem in interpretation of forensic toxicology results. The aims of this investigation were to study the incidence of concomitant drugs in autopsy cases where citalopram or zopiclone were detected in femoral blood and to evaluate the potential of drug interactions.Methods: All medico-legal autopsy cases in Sweden during 1992 to 2003 where citalopram or zopiclone were detected in femoral blood at the toxicological analyses were selected. The number and occurrences of concomitant drugs were recorded together with the concentrations as well as the cause of death.Results: In the 2405 cases with citalopram, 123 different drugs, metabolites excluded, were detected 4679 times giving an average of 1.9 concomitant drugs and 1099 different dmg combinations were identified. The corresponding figures for the cases with zopiclone were 1557 cases, 118 different drugs detected 3984 times giving an average of 2.6 concomitant drugs and 977 different combinations. We found a strong positive correlation between the number of drugs detected and the frequency of cases judged to be intoxication.Conclusions: Pharmacokinetic and pharmacodynamic interactions are a potential problem when interpreting forensic toxicological results and the conclusions about the cause and manner of death in the single case must be based on all available information from the investigation and tbe autopsy and on tbe knowledge of tbe pharmacology of included drugs. A better control of prescriptions of what different drugs an individual is given together with a comprehensive therapy control may reduce the risks of adverse drug reactions and unintended or accidental intoxications.
  •  
46.
  • Holmgren, Per, et al. (author)
  • Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19
  • 2004
  • In: Journal of Analytical Toxicology. - : Oxford University Press (OUP). - 0146-4760 .- 1945-2403. ; 28:2, s. 94-104
  • Journal article (peer-reviewed)abstract
    • Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (± standard deviation) S/R ratio for citalopram was 0.67 ± 0.25 and for desmethylcitalopram, 0.68 ± 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.
  •  
47.
  • Holmgren, Per, et al. (author)
  • Stability of drugs in stored postmortem femoral blood and vitreous humor
  • 2004
  • In: Journal of Forensic Sciences. - 0022-1198 .- 1556-4029. ; 49:4, s. 820-825
  • Journal article (peer-reviewed)abstract
    • The stability of 46 drugs in postmortem femoral blood stored for one year at -20°C was investigated. The drugs included benzodiazepines, antidepressants, analgetics and hypnotics. For seven drugs we found a significant change in the concentration between the first and second analysis. Five substances; ethanol, desmethylmianserin, 7-amino-nitrazepam, THC and zopiclone showed a decrease in the concentration whereas the concentrations of two substances; ketobemidone and thioridazine increased. However, the changes observed were not of such an order that it would affect the interpretation in normal forensic casework. We also investigated the possible influence of potassium fluoride on the concentrations of the 46 drugs in vitreous humor after storage for one year. For two substances, ethanol and zopiclone, there were significantly lower concentrations in the samples without potassium fluoride. Furthermore, we also studied the correlation between the concentrations in femoral blood and vitreous humor. For 23 substances there was a significant difference between the concentrations in the vitreous humor and femoral blood. Significant correlations between the concentrations in these two specimens were found for 23 substances, indicating that vitreous humor can be an alternative specimen when blood samples are not available, provided that such correlation exists for the particular substance. Statistical analysis also revealed a correlation between the degree of protein binding of the different drugs and percentage of vitreous/femoral blood concentrations.
  •  
48.
  • Hägg, Staffan, et al. (author)
  • Current Evidence on Abuse and Misuse of Gabapentinoids
  • 2020
  • In: Drug Safety. - : ADIS INT LTD. - 0114-5916 .- 1179-1942. ; 43, s. 1235-1254
  • Research review (peer-reviewed)abstract
    • This review summarizes current evidence on the abuse and misuse of the gabapentinoids pregabalin and gabapentin. Pharmacovigilance studies, register-based studies, surveys, clinical toxicology studies, and forensic toxicology studies were identified and scrutinized with the goal to define the problem, identify risk factors, and discuss possible methods to reduce the potential for abuse and misuse. Studies found that gabapentinoids are abused and misused and that individuals with a history of psychiatric disorders or substance use disorder seem to be at high risk. Moreover, some evidence supports the notion that patients with opioid use disorders may be at an increased risk of abusing gabapentinoids. Available evidence also suggests that abuse and misuse are more frequent in users of pregabalin compared with users of gabapentin. Health professionals and prescribers should be aware of the risk for misuse of pregabalin and gabapentin, which eventually could lead to abuse, substance dependence, and intoxications. Prescribing to patients belonging to risk populations such as those with psychiatric disorders or substance use disorder should be avoided if possible and, if prescribed, signs of misuse and abuse should be monitored.
  •  
49.
  • Isacsson, G., et al. (author)
  • Antidepressant medication prevents suicide in depression
  • 2010
  • In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 122:6, s. 454-460
  • Journal article (peer-reviewed)abstract
    • Objective: Ecological studies have demonstrated a substantial decrease in suicide in parallel with an increasing use of antidepressants. To investigate on the individual level the hypothesis that antidepressant medication was a causal factor. Method: Data on the toxicological detection of antidepressants in 18 922 suicides in Sweden 1992-2003 were linked to registers of psychiatric hospitalization as well as registers with sociodemographic data. Results: The probability for the toxicological detection of an antidepressant was lowest in the non-suicide controls, higher in suicides, and even higher in suicides that had been psychiatric inpatients but excluding those who had been in-patients for the treatment of depression. Conclusion: The finding that in-patient care for depression did not increase the probability of the detection of antidepressants in suicides is difficult to explain other than by the assumption that a substantial number of depressed individuals were saved from suicide by postdischarge treatment with antidepressant medication.
  •  
50.
  • Isacsson, G., et al. (author)
  • Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005
  • 2009
  • In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 120:1, s. 37-44
  • Journal article (peer-reviewed)abstract
    • Objective: Ecological studies have demonstrated a substantial decrease in suicide in parallel with an increase in the use of antidepressants. Causality cannot, however, be inferred from such studies. The aim of this study was to test on the individual level the hypothesis that treatment with antidepressant medication has been a substantially contributing cause of the decrease in suicide. Method: Time trends in the detection of antidepressants and five control medications in the forensic toxicological screening of 16 937 suicides and 33 426 controls in Sweden 1995-2005. Results: The expected number of antidepressant-positive suicides in 2005 was 409 if the hypothesis was true and 603 if it was false. The observed number in 2005 was 420. The control medications were detected to the extent that was expected if not preventing suicide. Conclusion: The observed trend in the number of suicides with antidepressants was well predicted by the hypothesis that the increased use of antidepressants has been a substantially contributing cause of the decrease in suicide.
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