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Objective To assess trends in the use of antidepressants among young suicides after the warning that these drugs might increase the risk of suicide. Method Individual data of all 845 suicides in the 10- to 19-year age group in Sweden in the time period 1992-2003 (baseline), and in 2004-2010 (after the warning). Outcome data are prescriptions of antidepressants prior to death and detections of antidepressants in post-mortem toxicology. Results After the warning, suicide in this age group increased for five consecutive years (60.5%). The increase occurred among individuals not treated with antidepressants. Conclusion This study provides further support for the hypothesis that the warning, contrary to its intention, may have increased young suicides by leaving a number of suicidal young persons without treatment with antidepressants. [ABSTRACT FROM AUTHOR]

Many women with typical anginal chest pain have normal coronary angiograms, which may be due to altered endothelial function. We evaluated the endothelial markers cyclic GMP (cGMP) and immunoreactive endothelin (ir-ET) regarding presence of coronary atherosclerosis in women with clinical signs of unstable coronary artery disease (CAD). Plasma levels of cGMP and ir-ET were determined in 118 patients and 84 controls. Ischaemia was evaluated at an exercise test. Of the patients 20% had normal vessels, 14% insignificant CAD and 66% significant stenosis at coronary angiography. Mean (95% CI) concentration of cGMP (nmol/l) was higher in patients than in controls (5.05 (4.53; 5.58) vs. 3.79 (3.34; 4.23)). Separating patients according to daily intake of nitroglycerin, only patients with this medication had significantly higher cGMP level (5.73 (4.88; 6.58)), whereas the difference between those without (4.35 (3.76; 4.94)) and controls disappeared. Patients with ischaemia at exercise test had higher cGMP level than those without (6.01 (5.13; 6.88) vs. 4.30 (3.66; 4.94)), even after adjusting for nitroglycerin treatment. ir-ET (pmol/l) was lower in patients with normal vessels than patients with coronary atherosclerosis (0.83 (0.78; 0.88) vs. 0.98 (0.92; 1.04)) and than the control group (0.91 (0.87; 0.94)). The difference between the control group and patients with atherosclerosis was also significant. Patients with unstable CAD and long-term nitroglycerin treatment have increased cGMP level. Patients with exercise-induced ischaemia have higher cGMP level than those without, irrespective of nitroglycerin treatment, which may reflect a general compensatory mechanism. Patients with normal vessels have low level of ir-ET, indicating different mechanisms for ischaemia/angina in these patients compared with patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

In order to study the relations between plasma cyclic guanosine monophosphate (cGMP) and anthropometric variables, plasma atrial natriuretic factor (ANP) and serum angiotensin-converting enzyme activity (ACE), a population study with random selection of 217 subjects (49% men) 18-69 years old was performed. Venous blood was drawn at 08.00 h and ambulatory blood pressure (ABP) recording was then performed. There was no gender-difference in cGMP levels (men 2.2 ± 1.1 nmol L[sup -1], women 2.2 ± 1.1 nmol L[sup -1]). A weak negative correlation was seen between cGMP and systolic ABP in both genders 20-44 years of age (r = -0.3, p = 0.05 for both), but this correlation did not persist in multivariate analysis with correction for ANP, age and ACE. In women, cGMP correlated positively with ANP (r = 0.27, p = 0.005) independently of ANP, ACE, ABP and age. ACE correlated negatively with cGMP in men (all; r = -0.22, p = 0.03, 45-69 years of age r = -0.49, p = 0.0002) and this correlation was independent of ANP, ACE, ABP and age. ACE catalyses the breakdown of bradykinin, which stimulates the release of NO. As the second messenger of NO is cGMP, the negative correlation between ACE and cGMP in men might be a reflection of reduced production of NO. Our results also suggest that there are gender differences in the stimuli for basal cGMP production. [ABSTRACT FROM AUTHOR]

Objectives: To compare perceived symptoms between patients undergoing antihypertensive therapy and hypertensive patients without drug treatment, and to assess reasons for change of antihypertensive medication in routine clinical practice.Design: Population-based multicentre study. Consecutive patients from a randomized sample of centres were given a standardized questionnaire to assess symptoms as well as opinions about their antihypertensive drugs.Setting: Fifty-five Swedish primary health care centres and 11 clinics of internal medicine.Patients: One thousand and thirteen hypertensive patients on their individually prescribed antihypertensive medication and 13 5 without antihypertensive therapy.Main Outcome Measures: Prevalence and perception of symptoms with and without antihypertensive drug therapy, changes of medication and reasons for this.Results: Amongst the group of patients on antihypertensive medication, 57% spontaneously reported having had symptoms of high blood pressure before they started their drug therapy. Amongst the patients without antihypertensive drugs, 52% reported having such symptoms. When answering direct questions about different symptoms related to current drug treatment or increased blood pressure, patients with and without medication reported symptoms to a similar extent: 80 and 85%, respectively. A majority of patients (64%) had changed their medication during the course of treatment (range 0-61 years). The mean number of changes was 2.4 times over 12 years. The most common reported cause for changing drug treatment was side-effects (42%).Conclusions: The study shows that patients in general perceive symptoms from hypertension. Antihypertensive medication decreases the frequency and intensity of symptoms that might be related to high blood pressure but adds other symptoms linked to the medication. Changes in medication were mostly related to side-effects. The follow-up should pay attention to patients' experience of treatment. A sign of a well-managed hypertension population would be a decrease of symptoms over time. [ABSTRACT FROM AUTHOR]

Abstract: The concentration of free-morphine was determined in peripheral (femoral) blood from heroin-related deaths and compared with the concentration in venous blood from impaired drivers. The presence of 6-MAM in blood or urine served as a biomarker for recent use of heroin. Males dominated over females (p <0.001) in both the autopsy cases (88%) and the drivers (91%), although their mean age was about the same 33–35 y (p >0.05). Concentrations of free-morphine in blood were not associated with age of heroin users in Sweden (p >0.05). The median concentration of free-morphine was higher in autopsy cases (0.24mg/L, N =766) compared with apprehended drivers with 6-MAM in blood (0.15mg/L, N =124, p <0.05), and appreciably higher than in drivers with 6-MAM in urine but not in blood (0.03mg/L, N =1823, p <0.001). The free-morphine concentration was above 0.20mg/L in 65% of autopsy cases, 36% of drivers with 6-MAM in blood but only 1.4% of drivers with 6-MAM in urine. Poly-drug deaths had about the same concentrations of free-morphine in blood (0.24mg/L, N =703) as heroin-only deaths (0.25mg/L, N =63). The concentration of morphine in drug overdose deaths (median 0.25mg/L, N =669) was about the same as in traumatic deaths among heroin users (0.23mg/L, N =97). However, the concentration of morphine was lower when the deceased had consumed alcohol (0.18mg/L, N =104) compared with taking a benzodiazepine (0.32mg/L, N =94). The concentration distributions of free-morphine in blood in heroin-related deaths overlapped with the concentrations in impaired drivers, which makes the interpretation of toxicology results difficult without knowledge about tolerance to opiates in any individual case. [Copyright &y& Elsevier]

The article focuses on antidepressant drugs and their possible intoxication with the femoral blood that may lead to death. Between 1992-2005, approximately 95 percent of the autopsies done in Sweden were screened to have antidepressant drugs on their femoral blood samples. In addition, levels for each drug should be provided and the results should be assessed to determine the risk of toxicity and be able to come up with counter-measures.

Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14 857 suicides.Acta Psychiatr Scand 2005: 1–5.© Blackwell Munksgaard 2005.To test the hypothesis that selective serotonin reuptake inhibitor (SSRI) antidepressants may have a suicide emergent effect, particularly in children and adolescents.Detections of different antidepressants in the forensic toxicological screening of 14 857 suicides were compared with those in 26 422 cases of deaths by accident or natural causes in Sweden 1992–2000.There were 3411 detections of antidepressants in the suicides and 1538 in the controls. SSRIs had lower odds ratios than the other antidepressants. In the 52 suicides under 15 years, no SSRIs were detected. In 15–19-year age group, SSRIs had lower relative risk in suicides compared with non-SSRIs.The hypothesis that treatment of depressed individuals with SSRIs leads to an increased risk of suicide was not supported by this analysis of the total suicidal outcome of the nationwide use of SSRIs in Sweden over a period of 9 years, either in adults or in children or adolescents. [ABSTRACT FROM AUTHOR]

Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000 mg testosterone undecanoate ( TU) every 12th week during 1 year. This was an observational study. Males with primary and secondary hypogonadism ( HG; n = 23), subjects with gender dysphoria ( GD FtM; n = 15) and a healthy control group of men ( n = 32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics® enzyme immunoassay, S-T with Roche Elecsys® testosterone II assay and U-T by gas chromatography-mass spectrometry. Sal-T correlated significantly with S-T and calculated free testosterone in both controls and patients ( HG men and GD FtM), while Sal-T to U-T showed weaker correlations. Trough values of Sal-T after 12 months were significantly higher in the GD FtM group (0.77 ± 0.35 nmol/L) compared to HG men (0.53 ± 0.22 nmol/L) and controls (0.46 ± 0.15 nmol/L), while no differences between S-T and U-T trough values were found. Markedly elevated concentrations of salivary testosterone, 7-14 days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal-T might be a useful clinical tool to monitor long-term testosterone replacement therapy and might give additional information in forensic cases. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp), encoded by the ABCB1/ MDR1 gene, is a drug transporter at the blood-brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases. [ABSTRACT FROM AUTHOR]

We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most likely due to a poisoning with a combination of VEN, oxycodone and ethanol, and the manner of death was considered to be an accident. The blood concentration of VEN was high (4.5 mg/kg), and the ratio of the VEN metabolite O-desmethylvenlafaxine (ODV) to VEN was exceptionally low (0.006). Mechanistic pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations combined with genotyping were considered very useful in this fatal drug poisoning case. [ABSTRACT FROM AUTHOR]

Abstract: Over a 10-year period (1998–2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N =6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N =2288 (33%), undetermined N =2260 (33%) and accidental N =2346 (34%). The average age (±SD) of all victims was 49.1±15.9 years and men 47.4±15.6 years were 5-year younger than women 52.2±15.8 years (p <0.01). Most of the deceased (78%) were poly-drug users although a single drug (mono-intoxications) was found in 22% of all poisoning deaths (p <0.001). The number of drugs in blood samples varied from 1 to 12 with a median of 3–4 per case. Mono-intoxication deaths were mostly ethanol-related (N =976) and the mean and median blood-alcohol concentration (BAC) was 3.06g/L and 3.10g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15g/L with one drug to 1.25g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N =93) 0.5mg/L (0.2mg/L), amphetamine (N =39) 2.0mg/L (1.2mg/L), dextropropoxyphene (N =33) 3.9mg/L (2.9mg/L), dihydro-propiomazine (N =32) 1.6mg/L (1.0mg/L) and 7-amino-flunitrazepam (N =28), 0.4mg/L (0.3mg/L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined. [Copyright &y& Elsevier]

Isacsson G, Reutfors J, Papadopoulos FC, Ösby U, Ahlner J. Antidepressant medication prevents suicide in depression. 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. 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. 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 in-patients but excluding those who had been in-patients for the treatment of depression. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Management of dermatological self-treatment is demanding. Imperfect application of creams and ointments and poor adherence to topical treatment are common, resulting in unsatisfactory treatment outcome. Objectives To assess the technique and precision of test subjects’ self-application of a test cream. Treated and neglected skin sites were measured after intended widespread single application of a fluorescent test cream. Methods Twenty healthy volunteers (10 women, 10 men) were included. They were asked to treat their whole skin surface with the fluorescent test cream, except the head and neck and skin covered by underwear. Treated and untreated sites were subsequently measured under Wood's ultraviolet radiation. Results Thirty-one per cent of the skin surface that was a target for application did not show any fluorescence and thus was assumed to have been untreated. Typical neglected sites included the central back, the upper breast, the axilla with surrounding skin, the legs and the feet, particularly the sole. The posterior aspect of both trunk and extremities, not easily inspected, was more often neglected. In the treated sites the fluorescence was typically uneven. Conclusions Qualified and motivated persons with no obvious physical limitations practised imperfect self-application of a test cream mimicking a therapeutic cream product. As much as 31% of the skin surface was neglected. Sites especially prone to nonapplication were identified. This might imply that dermatological patients on long-term self-treatment may practise local application very poorly, a problem of major therapeutic and economic importance. A fluorescent test cream can be used for research, and as an educational tool in the training of dermatological patients on how to apply local treatment. [ABSTRACT FROM AUTHOR]

Background It 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. Objective The 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. Methods Analysis 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 outpatient clinics of gynecology in Sweden. Results Four distinctively different interpretations of risk, depending on whether or not benefits were discussed in the same context, emerged from the analysis. On average, five advantages (range 0-11) and two (0-3) disadvantages were mentioned during the consultations. In the interviews, the women expressed on average four advantages (0-7) and one disadvantage (0-3). There were major variations between advantages and disadvantages expressed in the consultation and the following interview. Conclusion Even 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-taking. [ABSTRACT FROM AUTHOR]

Objective: Many commonly used pharmaceuticals, such as antidepressants and neuroleptics as well as some illegal drugs, are metabolised by the cytochrome P 450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Of Caucasians, 7-10% lack this enzyme, which can, upon administration of drugs in normal therapeutic doses, lead to adverse reactions and unexpected intoxication, leading in turn even to a fatal outcome in some cases. Methods: Individuals (n = 242) who had died due to intoxication by pharmaceuticals were genotyped for CYP2D6 and CYP2C19 and compared with a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. Four CYP2C19 alleles *1 (wt), *2, *3 and *4 were also identified by SNP analysis. Results: The prevalence of the CYP2D6 poor metaboliser (PM) genotypes in individuals with fatal intoxication was lower (4.7%) than expected from the frequencies of these genotypes in the blood donors (8.5%). A significantly lower frequency Pc 0.005 (0.03 with correction according to Bonferroni) was found for the CYP2D6*4 allele among the fatal intoxication cases. The CYP2C19 genotype analyses showed the same results for the fatal intoxication cases and for the blood donors. Conclusions: The findings in this study confirm our earlier observations of a lower frequency of CYP2D6 PM genotypes in cases of fatal intoxication. To our knowledge, it has not been shown previously that intoxication victims might have a lower frequency of PMs than the general population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Many commonly used pharmaceuticals such as antidepressants and neuroleptics as well as some illegal drugs are metabolised by the Cytochrome P450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Seven to ten percent of Caucasians lack this enzyme which can lead to adverse reactions and in some cases to unexpected intoxication even with fatal outcome, upon administration of drugs in normal therapeutic doses. 236 individuals who had died due to intoxication of pharmaceuticals were genotyped for CYP2D6 and compared to a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. The prevalence of the CYP2D6 PM genotype in the fatal intoxications was lower (4.7%) compared to the blood donors (8.5%). A significant decrease (p<0.005) was found in the CYP2D6*4 allele frequency among the fatal intoxications. [Copyright &y& Elsevier]