Antidepressants and the risk of suicide in young persons--prescription trends and toxicological analyses.

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.

ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram.

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.

Antidepressant medication prevents suicide in depression.

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 in-patients 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.

Evaluating the hip-flask defence using analytical data from ethanol and ethyl glucuronide. A comparison of two models.

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.

Decrease in suicide among the individuals treated with antidepressants: a controlled study of antidepressants in suicide, Sweden 1995-2005.

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.

Relationship between testosterone in serum, saliva and urine during treatment with intramuscular testosterone undecanoate in gender dysphoria and male hypogonadism.

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.

Reference concentrations of antidepressants. A compilation of postmortem and therapeutic levels.

In approximately 95% of all medicolegal autopsies performed in Sweden between 1992 and 2005, femoral blood samples were collected and screened for antidepressant drugs. A total of 8591 cases were identified and used for detailed analysis and interpretation. The present compilation provides information about 15 antidepressant drugs determined in femoral blood from certified fatal intoxications and in postmortem "control cases". The postmortem data were subjected to a previously proposed strategy, based on strictly standardized conditions regarding collection, handling and toxicological analysis of the samples. The postmortem data were compared with a therapeutic drug monitoring material (Group T; n = 16,809). The strict inclusion criteria meant that only 2737 postmortem cases were included in the survey. Accordingly, Group A (n = 330) were certified as deaths involving intoxication with a single antidepressant drug; Group B (n = 864) were deaths involving intoxication with more than one drug and/or with a significant concentration of ethanol; and Group C (n = 1800) were deaths under circumstances not involving incapacitation by drugs. In addition to providing reference levels for each drug, the results may also be used to assess risk of toxicity and supply supplementary information to the standard fatal toxicity index.

Heterogeneity in human soluble guanylate cyclase due to alternative splicing.

Two forms of the smaller subunit of the human soluble guanylate cyclase enzyme have been cloned by using PCR. One of the clones (HSGC-1) is identical to bovine and rat lung smaller subunit cyclase. However, the other (HSGC-2) is lacking 33 amino acids. Comparison of its sequence with published partial genomic sequences of bovine guanylate cyclase indicates that HSGC-2 is formed due to alternative splicing.

Dose-dependent effect of intravenous nitroglycerin on platelet aggregation, and correlation with plasma glyceryl dinitrate concentration in healthy men.

Nitroglycerin has been reported to reduce mortality in patients with acute myocardial infarction. This beneficial effect has been attributed to vasodilation, but it was speculated that part of this effect may be due to altered platelet function. The influence of intravenous nitroglycerin on platelet aggregation was assessed. Eight healthy subjects (aged 22 to 48 years) were studied using filtragometry at baseline, and 3 different nitroglycerin doses. Compared with baseline, aggregation time (which indexes platelet aggregation) increased dose-dependently by 91 +/- 68% (p less than 0.001) at the maximal dose of nitroglycerin (1.1 +/- 0.3 micrograms/kg/min). Plasma concentration-effect relations were observed between nitroglycerin as well as the glyceryl dinitrate metabolites and platelet aggregation (r = 0.6 [p less than 0.002] and r = 0.8 [p less than 0.0001], respectively). It is concluded that increasing doses of intravenous nitroglycerin profoundly and dose-dependently inhibit platelet aggregation. This inhibitory effect correlates with glyceryl dinitrate formation.

In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats.

The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted. By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed. In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg(-1) day(-1) were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions. In the group treated with 100 mg kg(-1) day(-1), the serum and brain total CIT levels were found to be 20 times and 6 - 8 times higher than in the rats treated with 10 or 20 mg kg(-1) day(-1), respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum. In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed. In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

Nitrates. Mode of action at a cellular level.

The nitrates used therapeutically in angina pectoris and congestive heart failure are, from a chemical point of view, organic nitroesters. Their principal pharmacological effect is vascular smooth muscle relaxation, leading to vasodilation, which explains their therapeutic effects. Several mechanisms have been proposed for their mode of action at the cellular level, in order to explain vascular smooth muscle relaxation. Today, there is strong evidence that organic nitroesters stimulate the enzyme guanylate cyclase in the smooth muscle cell. This enzyme produces a cyclic nucleotide, cyclic guanosine-3',5'-monophosphate (cGMP), which in turn eventually lowers the free calcium concentration in the cytosol to induce relaxation. The exact mechanism by which the organic nitroesters stimulate guanylate cyclase is still obscure. Preliminary results from our laboratory indicate that there may be more than one mechanism responsible for the activation of the enzyme. Knowledge of the mode of action at the cellular level is probably important in order to understand the mechanism(s) behind the development of tolerance towards the organic nitroesters.

Nitrate tolerance from a biochemical point of view.

Tolerance to nitrate vasodilators appears to be a general phenomenon that encompasses all known drugs belonging to this group, with the possible exception of molsidomine, for which tolerance has not yet been unambiguously proven. The mechanism behind tolerance development is still obscure, although decreased distribution of drug to the target tissue (i.e. the vascular wall) may be important. In addition, the production of cyclic guanosine-3',5'-monophosphate (cGMP) [the alleged mediator of nitrate-induced vascular smooth muscle relaxation] is reduced in tolerant tissue, while its degradation is increased. These changes could be due to a direct effect on the enzymes involved in the formation and degradation of cGMP in the cell, i.e. guanylate cyclase and phosphodiesterase, respectively. Furthermore, there is some evidence that the degradation of organic nitroesters in the vascular wall is reduced in tolerant tissue. This could result in a reduced production of unstable chemical intermediates (e.g. nitrosothiols), which have been suggested to act as mediators of guanylate cyclase.

Glyceryl trinitrate inhibits phosphatidylinositol hydrolysis and protein kinase C activity in bovine mesenteric artery.

The effect of glyceryl trinitrate (GTN) on relaxation, cGMP levels, phosphorylase a activity, phosphatidylinositol hydrolysis and protein kinase C activity was studied on isolated bovine mesenteric arteries (BMA). Two concentrations of GTN were tested, 0.1 nM representing a high affinity component and 1 microM representing a low affinity component of the GTN induced relaxation of BMA, giving a relaxation of 20% and 60% and a 2-fold and 5-fold increase in cGMP, respectively. Phosphatidylinositol hydrolysis and protein kinase C activity were significantly, and to the same extent, reduced at both concentrations tested, whereas the phosphorylase a activity was significantly reduced at the higher concentration only, which might indicate a reduction of the free intracellular Ca2+-concentration at high concentrations of GTN. It is concluded that a therapeutically relevant concentration (0.1 nM) of GTN induces relaxation and an increase in cGMP in bovine mesenteric arteries. The relaxation seems to be associated with an inhibition of phosphatidylinositol hydrolysis and a reduction of the protein kinase C activity.

Effects of pertussis toxin on vasodilation and cyclic GMP in bovine mesenteric arteries and demonstration of a 40 kD soluble protein ribosylation substrate for pertussis toxin.

The inhibitory nucleotide-regulatory protein (Gl) has been shown to lose its adenylate cyclase inhibitory effect upon treatment with pertussis toxin. To find out whether a pertussis sensitive mechanism is involved in the regulation of the cGMP-system, bovine mesenteric arteries were incubated in buffer containing pertussis toxin, and the relaxation and intracellular cGMP accumulation induced by different groups of vasodilating agents were studied. The present results show a pertussis toxin induced decrease in relaxation as well as a decrease in the cGMP-elevation induced by the endothelium dependent vasodilators acetylcholine and calcium ionophore A 23187. Arteries treated with atrial natriuretic peptide showed no alterations in relaxation or cGMP content after incubation with pertussis toxin. A 40 kD soluble ribosylation substrate for pertussis toxin was identified in bovine mesenteric artery. These results suggest that a pertussis toxin sensitive mechanism is involved in the vasodilating mechanism of acetylcholine and calcium ionophore A 23187, while no evidence for such a mechanism could be found regarding the vasodilatory action of atrial natriuretic peptide.

Eosinophil cationic protein (ECP) in saliva: a new marker of disease activity in bronchial asthma.

Eosinophil cells play a crucial role in the pathogenesis of asthma, and concentration of eosinophil cationic protein (ECP) in serum has been used to monitor activity of the disease. Our aim was to determine the feasibility and usefulness of measuring ECP in saliva and to use it as a marker of the disease. Thirty-eight patients with asthma and 16 healthy volunteers were included in this study. Repeatability of measurements of ECP in saliva was acceptable [intra-class correlation coefficients (Ri) = 0.74 and coefficients of repeatability (CR) = 0.37 in five healthy subjects]. Levels of ECP in saliva were higher in asthmatics than in volunteers (P < 0.01). There was a significant inverse association between a surrogate variable reflecting disease activity (i.e. change over a few weeks in dose of inhaled corticosteroid required by a change in clinical status of asthma) and a change over the same time period in salivary ECP in 19 patients with stable asthma (r = -0.64, P = 0.02). Our findings indicate that levels of salivary ECP are elevated in patients with asthma and associated with presumed activity of disease as recorded by alteration of taken dose of inhaled corticosteroid.

Asthma nurse practice--a resource-effective approach in asthma management.

The objective of this study was to evaluate the efficacy of an Asthma Nurse Practice (ANP) in primary health care. A 12-month (September 1994-August 1995) open, prospective intervention study with pre- and post-test comparisons was performed on patients with asthma treated at a primary care centre in Sweden. Sixty-three patients with mild or moderate asthma participated and medication, structured follow-up and education in self-management at an ANP were assessed over a 12-month period. The main outcome measures assessed were pulmonary function, eosinophil cationic protein (ECP) in serum, respiratory symptoms, patient knowledge of asthma and emergency visits. ANP in primary health care increased patient knowledge of asthma and medication. The number of patients with nocturnal symptoms decreased significantly. Pulmonary function was improved: vital capacity (VC) 98-106, forced expiratory volume in 1 sec (FEV1) 93-100 and peak expiratory flow (PEF) 98-115% of predicted (P < 0.001). Variation in PEF fell from 21 to 12% (P < 0.001). ECP was significantly reduced. Visits to the emergency room were 60% fewer during the year of intervention (P < 0.01). In conclusion, patients attending an Asthma Nurse Practice, comprising a structured programme for asthma management, improve their knowledge and asthma control.

Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy.

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 x kg(-1) x 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 KCI-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.

Pharmacokinetic and pharmacodynamic responses to chronic administration of the selective serotonin reuptake inhibitor citalopram in rats.

The number of drugs used to treat affective disorders such as depression is rapidly increasing. Citalopram (CIT), an antidepressant, is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In the present study, rats were treated with 10 mg/kg/d racemic CIT for two weeks with use of osmotic pumps, and the following were monitored: open-field behavior, racemic and enantioselective concentrations of CIT and metabolites in blood, brain parenchyma, and extracellular space, and the brain extracellular monoamine levels. The racemic CIT concentration in serum was estimated about tenfold lower than in brain parenchyma but much higher than in brain extracellular fluid. The major CIT metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were 20% and 30%, respectively, of the amounts of CIT in serum and even lower in the brain parenchyma. The S-enantiomer/R-enantiomer ratios for CIT and DCIT were about 1.01 and 0.31, respectively, in blood and brain. There was a clear correlation between the different drug components within and between blood and brain compartments. Citalopram had no measured effect on open-field behavior, but it elevated extracellular 5-HT and decreased 5-HIAA levels. No correlations between any of the drug components and the brain monoamines were found. In summary, the drug components after chronic dosing correlated well between the periphery and the brain, but not with the brain monoamine concentrations. Further studies investigating the combined pharmacokinetic/dynamic effects could take advantage of blood drug monitoring for the commonly used novel antidepressant drugs.

Taking antihypertensive medication--controlling or co-operating with patients?

Low compliance with antihypertensive drug regimens has been a well documented reason for inadequate control of hypertension. We assessed recent literature regarding compliance from different disciplines to clarify the nature of reported problems on low compliance to prescribed antihypertensive medication. Much research focuses on primary factors for compliance, methods to monitor and measure individual rates and patterns of compliance. From a behavioural oriented point of view, the focus is on understanding why patients act as they do. This review indicates that there is an almost complete lack of knowledge about how the decision making in the clinical practice is organized when prescribing antihypertensive medication and/or when following up treatment from patients already taking such drugs. Since the concrete communication and collaboration between patient and physician in the clinical setting are of prime significance for patient adherence to drug regimens, it is important to shed light on what happens in this critical situation.

Reasons for adherence with antihypertensive medication.

BACKGROUND: Hypertension is often insufficiently controlled in clinical practice, a prominent reason for this being poor patient adherence with therapy. Little is known about the underlying reasons for poor adherence. We set out to investigate hypertensive patients' self-reported reasons for adhering to or ignoring medical advice regarding antihypertensive medication. METHODS: Qualitative analysis of semi-structured interviews with 33 hypertensive patients in a general-practice centre and a specialist hypertension unit in Southern Sweden. Blood-pressure measurements and laboratory measurements of antihypertensive medication were performed. RESULTS: Nineteen out of 33 patients were classified as adherent. Adherence was a function of faith in the physician, fear of complications of hypertension, and a desire to control blood pressure. Non-adherence was an active decision, partly based on misunderstandings of the condition and general disapproval of medication, but mostly taken in order to facilitate daily life or minimize adverse effects. Adherent patients gave less evidence of involvement in care than non-adherent patients. There was no obvious relation between reported adherence, laboratory markers of adherence and blood-pressure levels. CONCLUSIONS: The interview is a powerful tool for ascertaining patients' concepts and behaviour. To optimize treatment of hypertension, it is important to form a therapeutic alliance in which patients' doubts and difficulties with therapy can be detected and addressed. For this, effective patient-physician communication is of vital importance.