Johan Ahlner

Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14 857 suicides

Objective:  To test the hypothesis that selective serotonin reuptake inhibitor (SSRI) antidepressants may have a suicide emergent effect, particularly in children and adolescents.

High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases.

In Sweden, about 550 individuals die every year of drug intoxication. Many of these drugs are metabolized by CYP enzymes such as CYP2D6 and CYP2C19. A lack of these enzymes, resulting in poor metabolism, can lead to adverse reactions and even to fatality. On the other hand, an ultrarapid metabolism can lead to insufficient drug plasma concentration, resulting in failure of treatment, or it can lead to high concentrations of active/toxic metabolites. The aim of this project was to study the genetic profile of individuals with regard to the presence of CYP2D6 and CYP2C19 genes, in cases of fatal intoxication (242), suicide (intoxications excluded) (262), and natural death (212). PCR, followed by pyrosequencing, was used for all the analyses. We found that, among those who died of suicide (suicide cases), there was a higher number carrying more than two active CYP2D6 genes (corresponding to the phenotype of ultrarapid metabolizer) as compared with those who died of natural causes (natural‐death cases) (P = 0.007).

Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers

Abstract.Objective: This study was performed to assess whether coadminstration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine).Methods:Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study.Results:When amlodipine was coadministered with grapefruit juice, Cmax was 115% and AUC(0–72 h) was 116% compared with water, but tmax was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4–8 h after drug administration, coinciding with Cmax, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study.Conclusion:An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR.The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects.

Serum concentrations of antidepressant drugs in a naturalistic setting: compilation based on a large therapeutic drug monitoring database.

A compilation of therapeutic drug monitoring data for 15 antidepressant drugs in a naturalistic routine clinical setting is presented. A substantial number of serum concentrations, at different daily doses, are outlined, and the intraindividual and overall serum concentration coefficient of variation for a respective substance is presented. Also, concentration comparisons between women and men, and patients older or younger than 65 years are made. The drugs included are amitriptyline (n = 394), citalopram (n = 5457), clomipramine (n = 400), escitalopram (n = 3066), fluoxetine (n = 793), fluvoxamine (n = 165), mianserin (n = 1063), mirtazapine (n = 1427), moclobemide (n = 200), nortriptyline (n = 206), paroxetine (n = 1677), reboxetine (n = 85), sertraline (n = 2998), trimipramine (n = 158), and venlafaxine (n = 1781). Of the 9 drugs exhibiting linear (first order) kinetics, all but reboxetine gave a significant negative dose-to-dose-normalized correlation with concentrations, that is an increased clearance with higher dose. When dose was correlated to the metabolite:parent substance ratio for drugs exhibiting linear kinetics, citalopram and mianserin gave a positive slope, contrary to a negative slope shown for sertraline and venlafaxine. The intraindividual variations of the serum concentrations were lower than the overall variations, and the intraindividual variation of the metabolite:parent substance ratio was lower than the intraindividual variation of respective parent substance (except clomipramine and mianserin). Women had significantly higher serum concentrations than men (significant for citalopram, escitalopram, mianserin, mirtazapine, and venlafaxine), and patients older than 65 years had higher serum concentrations than the younger ones for all drugs except amitriptyline, moclobemide, and trimipramine. By presenting a comprehensive compilation of therapeutic drug monitoring data for each drug, a reference tool is created, in addition to improved pharmacokinetic knowledge of 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.

Perceived symptoms amongst hypertensive patients in routine clinical practice – a population‐based study

Kjellgren KI, Ahlner J, Dahlöf B, Gill H, Hedner T, Säljö R (Faculty of Health Sciences, Linköping; Sahlgrenska University Hospital, Göteborg; and Linköping University, Linköping, Sweden). Perceived symptoms amongst hypertensive patients in routine clinical practice – a population‐based study. J Intern Med 1998; 244: 325–332.

Five-year update on the occurrence of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes in Sweden

According to statistics provided by the Swedish National Road Administration (Vägverket), a total of 1403 drivers were killed in road-traffic crashes in Sweden between 2003 and 2007. Forensic autopsies were performed in approximately 97% of all deaths and specimens of blood and urine were sent for toxicological analysis. In 60% of cases (N=835) the toxicology results were negative and 83% of these victims were men. The blood-alcohol concentration (BAC) was above the legal limit for driving (>0.2g/L) in 22% of cases (N=315) at mean, median and highest concentrations of 1.7 g/L, 1.7 g/L and 4.9 g/L, respectively. The proportions of male to female drivers with BAC>0.2g/L were 93% vs 7% compared with 83% vs 17% for those with drugs other than alcohol in blood. Drivers with a punishable BAC were over-represented in single vehicle crashes compared with multiple vehicle crashes (67% vs 33%). The opposite held for drivers who had taken a prescription drug (39% vs 61%) and also for drug-negative cases (31% vs 69%). Drugs other than alcohol were identified in 253 cases (18%); illicit drugs only in 39 cases (2.8%), both licit and illicit in 28 cases (2.0%) and in 186 cases (13.3%) one or more therapeutic drugs were present. Amphetamine was the most common illicit drug identified at mean, median and highest concentrations of 1.5mg/L, 1.1mg/L and 5.0mg/L, respectively (N=39). Blood specimens contained a wide spectrum of pharmaceutical products (mean 2.4 drugs/person), comprising sedative-hypnotics (N=93), opiates/opioids (N=69) as well non-scheduled substances, such as paracetamol (N=78) and antidepressants (N=93). The concentrations of these substances in blood were mostly in the therapeutic range. Despite an appreciable increase (12-fold) in number of arrests made by the police for drug-impaired driving after a zero-tolerance law was introduced (July 1999), alcohol still remains the psychoactive substance most frequently identified in the blood of drivers killed in road-traffic crashes.

Stability of drugs in stored postmortem femoral blood and vitreous humor

The stability of 46 drugs in postmortem femoral blood stored for one year at -20 degrees 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.

Flunitrazepam: an evaluation of use, abuse and toxicity

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 concomitant 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.

To follow or not to follow dermatological treatment : A review of the literature

Creams, ointments and solutions applied to the skin surface by patients as part of a daily routine might be expected to provide a more variable dosage than do standard tablets. However, adherence to treatment in dermatology has been little studied. This article reviews recent publications in the field. These are dominated by questionnaire-based studies, which tend to over-estimate adherence. Reduced adherence to dermatological treatment is noted in 34-45% of patients. It is likely that the percentage of patients who practice truly optimal treatment in their daily life is even lower considering the variable practice of self-treatment. Self-reported psychiatric morbidity contributes to poor adherence to dermatological treatment, while a well-functioning doctor-patient interaction is a major determinant of good adherence, as is patient satisfaction. In conclusion, adherence to dermatological treatment is unsatisfactory and there is a need for intervention and change in clinical routines. The therapeutic and economic benefits may be considerable. The immediate challenge is to stimulate a change in patient behaviour and improve self-treatment at home.