Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths

ABSTRACT: Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using mediumthroughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths.

Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug induced arrhythmia and sudden unexplained deaths

Abstract Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analyzing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)

Evaluation of periodontitis in hospital outpatients with major depressive disorder.

BACKGROUND AND OBJECTIVE: Major depressive disorder (MDD) has been associated with alterations in the neuroendocrine system and immune function and may be associated with an increased susceptibility to cardiovascular disease, cancer and autoimmune/inflammatory disease. This study was conducted to investigate the relationship between periodontitis and MDD in a convenience sample of hospital outpatients. MATERIAL AND METHODS: The sample consisted of 72 physically healthy subjects (36 outpatients with MDD and 36 age-matched controls [± 3 years]). Patients with bipolar disorder, eating disorders and psychotic disorders were excluded. Probing pocket depth and clinical attachment level were recorded at six sites per tooth. Depression was assessed by means of Structured Clinical Interview for DSM-IV. RESULTS: Extent of clinical attachment level and probing pocket depth were not different between controls and subjects with depression for the following thresholds: ≥ 3 mm (Mann-Whitney, p = 0.927 and 0.756); ≥ 4 mm (Mann-Whitney, p = 0.656 and 0.373); ≥ 5 mm (Mann-Whitney, p = 0.518 and 0.870);, and ≥ 6 mm (Mann-Whitney, p = 0.994 and 0.879). Depression parameters were not associated with clinical attachment level ≥ 5 mm in this sample. Smoking was associated with loss of attachment ≥ 5 mm in the multivariable logistic regression model (odds ratio = 6.99, 95% confidence interval = 2.00-24.43). CONCLUSIONS: In this sample, periodontal clinical parameters were not different between patients with MDD and control subjects. There was no association between depression and periodontitis.

Association of periodontal disease to anxiety and depression symptoms, and psychosocial stress factors.

OBJECTIVE: A cross-sectional study was conducted to investigate if anxiety, depression and hopelessness symptoms are associated with periodontal disease. METHOD: A total of 160 subjects took part in this study. Probing depth and clinical attachment level were recorded at six sites per tooth and the gingival and plaque indices were also recorded. The instruments used to assess the psychological variables (anxiety, depression, stress, psychiatric symptoms and hopelessness) were: the State-Trait Anxiety Inventory, the Beck Depression Inventory, the Life Events Scale modified by Savoia, the Self-Report Screening Questionnaire-20 and the Beck Hopelessness Scale. RESULTS: There was no difference in scale score means between patients with and without established periodontitis. Results of the Ordinal Logistic Regression Analysis model that included age, plaque index, smoking and psychological factors showed that patients with psychiatric symptoms (odds ratio (OR) 1.24, 95% confidence interval (CI) 0.33-4.78), depression symptoms (OR 0.57, 95% CI 0.15-2.21) and with hopelessness (OR 0.70, 95% CI 0.13-3.84) were not at a greater risk of developing established periodontitis. CONCLUSION: In this sample, no evidence was found for an association between depression, hopelessness, psychiatric symptoms and established periodontitis. The association of periodontal disease to depression, anxiety and stress should be investigated in psychiatric populations, especially in those with depression and anxiety disorders.

A dose-finding and discontinuation study of clomipramine in panic disorder.

Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions. Fifty-seven (70.3%) reached operational criteria for full remission in 16.2 +/- 6.5 weeks, with a mean dose of 89.1 +/- 8.2 mg/day. Fifty-four (81%) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4-6 months. No patient relapsed during the clomipramine maintenance phase. Their medication was then tappered and discontinued with placebo substitution under double-blind conditions. Fifty-one (63%) patients were followed-up until relapse or recurrence for up to 3 years, with periodic assessments. Three different outcome groups were identified: the first (n = 19, 19; 37.2%) experienced an early/immediate relapse (5.2 +/- 4.9 weeks after drug discontinuation); the second group (n = 22, 22; 43.1%) experienced recurrence after 42.9 +/- 35 weeks following discontinuation; and the third group (n = 10, 10; 19.6%) remained assymptomatic and functionally well throughout the follow-up. Predictors of early relapse were: (1) higher baseline score in the Beck Depression Inventory; (2) higher global score on the phobic avoidance scale after the full remission criteria; and (3) the need for higher clomipramine doses to reach full remission. The need for long-term or intermittent maintenance for most patients is emphasized.

Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression.

The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs' utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders.

Mood improvement in 'normal' volunteers.

To test the hypothesis that clomipramine is effective in improving subthreshold non-specific symptoms in subjects without any established psychopathology, we conducted a double-blind, cross-over controlled trial of clomipramine (oral doses of 10-40 mg/day) and propanteline (active placebo) for 5 weeks in nine normal volunteers. Four other subjects completed the first part of the trial. These subjects were selected from 275 respondents to newspaper and radio requests for subjects who considered themselves as normal but were unhappy about their usual moods. They did not reach cut-off scores in the Self-Report Questionnaire and did not meet diagnostic criteria for any lifetime or current ICD-10 or DSM-III-R condition, as assessed by an open psychiatric interview and the Schedules for Clinical Assessment in Neuropsychiatry. Despite the small sample and the low level of initial symptomatology, both subjects and observers consistently detected significant improvements with clomipramine in a number of assessments of mood, notably decreased irritability and anxiety. This controlled trial suggests that it is possible to improve subclinical complaints through psychopharmacological agents, raises questions about the mechanisms of their action and discusses their implications.

Alcoholism and phobic anxiety--a clinical-demographic comparison.

The prevalence of anxious and phobic symptoms in 97 alcohol-dependent and alcohol abuse patients, and that of alcohol abuse and dependence in 90 patients with panic/agoraphobia (PAG), were respectively determined in out-patients attending alcoholism and anxiety clinics in a university psychiatric hospital. The clinical and socio-demographic data of both the phobics and non-phobics of the alcoholic sample, and the alcohol dependents and non-dependent of the PAG sample, were compared. Panic attacks and phobias were associated with increased severity and worse prognosis for alcoholism. The infrequent instances of alcohol use to cope with anxiety in the PAG sample were associated with symptoms of social phobia. Alcohol abuse and dependence were more frequent in PAG men who used alcohol to cope with anxiety. Finally, the frequency and intensity of the panic and phobic symptoms of the alcoholic and PAG samples were contrasted. The alcoholism clinic patients with anxiety had less frequent and milder panic attacks. The predominant diagnosis of this group was agoraphobia, which was infrequent in the anxiety disorders clinic.

Clomipramine, a better reference drug for panic/agoraphobia. I. Effectiveness comparison with imipramine.

An 8-week, double-blind, flexible-dose trial comparing low doses of clomipramine (mean=50 mg) with moderate doses of imipramine (mean=113.8 mg and propanteline (active placebo), was carried out in 60 out-patients with panic disorder with or without agoraphobia. Efficacy evaluation included global, anxiety and depression rating scales, and the determination of rates of relapse over up to 10 weeks of single-blind placebo follow-up. Both tricyclics were significantly more effective than propanteline, but clomipramine tended to act faster and more consistently than imipramine on most measures. Given the degree of blindness achieved and the significantly lower doses of clomipramine, this seems a better reference drug than imipramine for clinical trials in panic/agoraphobia.

[Electroencephalographic study of patients with panic disorders]. / Estudo eletroencefalográfico em pacientes com transtorno do pânico.

Electroencephalographic changes were studied in 27 patients with panic disorder and agoraphobia with panic attacks due to some clinical similarities between panic disorder and temporal lobe epilepsy. The EEG records, obtained with sleep deprivation, photostimulation and hyperventilation showed no abnormalities.