Marianne Gex-Fabry

Depression relapse prophylaxis with Mindfulness-Based Cognitive Therapy: replication and extension in the Swiss health care system.

Background Mindfulness-Based Cognitive Therapy (MBCT) is a group intervention that integrates elements of Cognitive Behavioural Therapy (CBT) with components of mindfulness training to prevent depressive relapse. The efficacy of MBCT compared to Treatment As Usual (TAU), shown in two randomized controlled trials indicates a significant decrease in 1-year relapse rates for patients with at least three past depressive episodes. The present study is the first independent replication trial comparing MBCT + TAU to TAU alone across both language and culture (Swiss health care system). Methods Sixty unmedicated patients in remission from recurrent depression (≥ 3 episodes) were randomly assigned to MBCT + TAU or TAU. Relapse rate and time to relapse were measured over a 60 week observation period. The frequency of mindfulness practices during the study was also evaluated. Results Over a 14-month prospective follow-up period, time to relapse was significantly longer with MBCT + TAU than TAU alone (median 204 and 69 days, respectively), although both groups relapsed at similar rates. Analyses of homework adherence revealed that following treatment termination, the frequency of brief and informal mindfulness practice remained unchanged over 14 months, whereas the use of longer formal meditation decreased over time. Limitations Relapse monitoring was 14 months in duration and prospective reporting of mindfulness practice would have yielded more precise frequency estimates compared to the retrospective methods we utilized. Conclusions Further studies are required to determine which patient characteristics, beyond the number of past depressive episodes, may predict differential benefits from this therapeutic approach.

Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication.

Therapeutic drug monitoring (TDM) data for the antipsychotic drug olanzapine were investigated with respect to concentration versus dose relationship, intraindividual versus interindividual variability, and the combined influence of patient characteristics on steady-state concentration. The study included 250 patients, with daily doses ranging from 2.5 to 30 mg. Median concentration to dose ratio was 2.1 (ng/mL)/(mg/d), with 90% of the distribution in a fivefold range. In the first subgroup of patients with two measurements at different doses (n = 21), data were in keeping with linear concentration versus dose relationship. In the second subgroup of patients with repeated measurements at a constant daily dose (n = 40), estimates of within-patient and between-patient variabilities were 30.5% and 49.4%, respectively. In the whole sample, multiple regression analysis of dose-normalized concentration revealed significant effects of time postdose (−18% per 12 hours delay, P < 0.05), age ≥60 years (+27%, P < 0.005), cigarette smoking (−12%, P < 0.05), and comedication with fluvoxamine (+74%, P < 0.001), paroxetine, fluoxetine, or sertraline (considered together, +32%, P < 0.05), venlafaxine (+27%, P < 0.05), and inducers of P450 enzymes (−40%, P < 0.001). The final model included a tendency for higher concentration associated with female gender (+11%, P = 0.07) and accounted for 27% of observed interindividual variability. When considering a worst-case scenario, an elderly, nonsmoking woman prescribed fluvoxamine comedication was predicted to reach a 4.6-fold higher olanzapine concentration than a young male smoker coadministered carbamazepine. The current study suggests that patients characterized by a combination of factors associated with altered metabolism may benefit from olanzapine TDM.

Comparative pharmacokinetic study of a floating multiple-unit capsule, a high-density multiple-unit capsule and an immediate-release tablet containing 25 mg atenolol.

The purpose of this study was to evaluate the possible advantages of floating and high-density dosage forms and their influence on pharmacokinetic parameters. Atenolol was chosen as a model drug because of its poor absorption in the lower gastrointestinal tract. Three formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The two multiple-unit dosage forms were composed of compressed minitablets and had sustained release properties. The bioavailability of the two gastroretentive preparations with sustained release characteristics was significantly decreased when compared to the immediate-release tablet. The floating minitablets seemed to be retained longer in the stomach than the high-density dosage form. The first atenolol concentration detectable in the plasma and the time to peak Tmax were delayed for the floating dosage form. For the parameters Cmax and AUC 0-infinity, the lower limit of the 90% confidence interval was outside the bioequivalence range (0.80-1.25). This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations. Atenolol absorption was delayed and the maximum plasma concentration was diminished.

Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors.

Because of the enormous gap between premarketing studies in physically healthy subjects and clinical practice in patients, the present study reconsidered interindividual variability factors affecting risperidone concentrations under routine therapeutic drug monitoring conditions. The study included 92 patients, 27% of whom were 70 years or older. The patients received risperidone orally (dose range, 0.5-11 mg per day) and had concentrations of risperidone and the active metabolite 9-hydroxyrisperidone measured at steady state by a new, rapid, and sensitive method of high-performance liquid chromatography (HPLC). After normalization to a dose of 4 mg/day, median concentrations were 2.9 ng/ml (80% range, 0.9-27.9 ng/ml) for the parent compound and 24.1 ng/ml (80% range, 12.0-57.6 ng/ml) for the metabolite. When considering linear regression models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite, with age increasing from 20 to 80 years. Body weight provided an additional significant contribution to the variability of 9-hydroxyrisperidone concentration, a 20-kg higher body weight associated with a concentration decrease of 23%. Serotonin-specific reuptake inhibitor (SSRI) comedication (fluoxetine, two patients; citalopram, two patients; paroxetine, one patient; fluvoxamine, one patient) was significantly associated with 4.6-fold higher concentrations of parent compound, in keeping with an inhibitory action on CYP2D6 enzyme. Significantly higher concentrations of 9-hydroxy-risperidone (+ 29%) were also observed in the 17 patients with biperiden comedication. Therapeutic drug monitoring data, collected in patients representative of the population for which the drug was intended, allowed us to quantify the dose reduction needed in elderly patients and thus provided valuable information in addition to the one collected during premarketing studies performed with strict inclusion and exclusion criteria.

CYP2D6 and ABCB1 Genetic Variability : Influence on Paroxetine Plasma Level and Therapeutic Response

Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns. The present study investigates plasma concentration and therapeutic response to paroxetine for the influence of age, sex, and CYP2D6 and ABCB1 polymorphisms, the latter gene encoding for the permeability glycoprotein. Genotyping for CYP2D6 (alleles *3, *4, *5, *6, and *xN) and ABCB1 polymorphisms (61A>G, 2677G>T, and 3435C>T) was performed in 71 depressed patients who started 20 mg paroxetine per day and had plasma concentration measured after 2 weeks at a fixed dose. A dose increase to 30 mg per day was possible starting at week 2. For 63 patients, severity of depression (Montgomery-Åsberg Depression Rating Scale) was assessed at weeks 0, 2, and 4 and every 2 weeks thereafter until discontinuation. Persistent response was defined as 50% improvement from baseline score sustained from the first occurrence to study end point. Paroxetine concentration significantly differed between female and male patients (median, 28 versus 16 ng/mL; P = 0.001). Differences were not significant between CYP2D6 heterozygous and homozygous extensive metabolizers (median, 27 versus 22 ng/mL; P = 0.074) and between ABCB1 genotypes (P > 0.10). When considered in a multivariate model, CYP2D6 heterozygous extensive metabolizer phenotype (P = 0.062) and female gender (P = 0.001) predicted 1.3-fold and 1.6-fold higher paroxetine concentration, respectively, but fraction of explained variability was modest (21%). Frequency of persistent response at study end point did not significantly differ according to CYP2D6 heterozygous extensive metabolizer versus homozygous extensive metabolizer phenotype and ABCB1 polymorphisms in univariate analyses. After adjusting for age, sex, paroxetine concentration at week 2, and daily dose at study end point, ABCB1 genotype contributed to improving the model significantly for 61A>G (P = 0.043), but not 2677G>T (P = 0.068) and 3435C>T (P = 0.11). None of two poor metabolizers and four ultrarapid metabolizers showed persistent response to paroxetine. The hypothesis that permeability glycoprotein activity might be a relevant predictor of therapeutic response deserves to be further investigated while controlling for pharmacokinetic variability.

Clinical Pharmacokinetics of Clomipramine

SummaryClomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its pharmacokinetics have been studied essentially in healthy volunteers. By combining published information obtained during observational studies, it has been possible to derive a fairly precise picture of the behaviour of both parent compound and main metabolite (demethyl-clomipramine) in humans.Clomipramine can be compared with amitriptyline or imipramine so far as its physicochemical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract, but undergoes an important first-pass metabolism to demethyl-clomipramine which is pharmacologically active and participates in both therapeutic and unwanted effects. Protein binding is high, and the apparent volume of distribution is very large (i.e. < 1000L). After reaching the systemic circulation, clomipramine is further biotransformed into demethyl-clomipramine, and both active principles are hydroxylated to metabolites which are further conjugated before being excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination half-life of clomipramine is about 24h and that of demethyl-clomipramine, 96h. Accordingly, the time to reach steady-state for both active moieties is in general around 3 weeks.Various pathological or environmental factors influence the behaviour of clomipramine and demethyl-clomipramine. Patients genetically deficient in hydroxylation accumulate demethylclomipramine at high concentrations that can produce serious side effects and/or nonresponse. The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking induces demethylation, whereas long term alcohol intake appears to reduce this metabolic pathway. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower daily dose of clomipramine in most elderly patients.Studies relating blood concentrations of clomipramine and demethyl-clomipramine are conflicting. However, analysis of the available information indicates that blood concentrations lower than 150 µg/L are usually associated with nonresponse, whereas those above 450 µg/L seldom lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined with a high interindividual variability, makes this class of drugs ideal candidates for blood concentration monitoring.

Clomipramine Metabolism Model-Based Analysis of Variability Factors from Drug Monitoring Data

SummaryA steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations.Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steadystate, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed.Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.

Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone

Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady‐state pharmacokinetics of methadone.

Drug-Induced Long QT in Adult Psychiatric Inpatients: The 5-Year Cross-Sectional ECG Screening Outcome in Psychiatry Study

OBJECTIVE The authors aimed to determine the prevalence of drug-induced long QT at admission to a public psychiatric hospital and to document the associated factors using a cross-sectional approach. METHOD All ECG recordings over a 5-year period were reviewed for drug-induced long QT (heart-rate corrected QT ≥500 ms and certain or probable drug imputability) and associated conditions. Patients with drug-induced long QT (N=62) were compared with a sample of patients with normal ECG (N=143). RESULTS Among 6,790 inpatients, 27.3% had abnormal ECG, 1.6% had long QT, and 0.9% qualified as drug-induced long QT case subjects. Sudden cardiac death was recorded in five patients, and torsade de pointes was recorded in seven other patients. Relative to comparison subjects, patients with drug-induced long QT had significantly higher frequencies of hypokalemia, hepatitis C virus (HCV) infection, HIV infection, and abnormal T wave morphology. Haloperidol, sertindole, clotiapine, phenothiazines, fluoxetine, citalopram (including escitalopram), and methadone were significantly more frequent in patients with drug-induced long QT. After adjustment for hypokalemia, HCV infection, HIV infection, and abnormal T wave morphology, the effects of haloperidol, clotiapine, phenothiazines, and citalopram (including escitalopram) remained statistically significant. Receiver operating characteristic curve analysis based on the number of endorsed factors per patient indicated that 85.5% of drug-induced long QT patients had two or more factors, whereas 81.1% of patients with normal ECG had fewer than two factors. CONCLUSIONS Drug-induced long QT and arrhythmia propensity substantially increase when specific psychotropic drugs are administered to patients with hypokalemia, abnormal T wave morphology, HCV infection, and HIV infection.

Determinants of postconflict symptoms in Albanian Kosovars.

During the period from 1998 to 1999, more than 1 million civilians from the province of Kosovo in the Balkans were displaced as a consequence of organized violence and war. The aim of the present study was to determine the prevalence of posttraumatic stress disorder (PTSD) in a sample of the Albanian Kosovar population more than 2 years after the end of the conflict and to assess the effect of exposure to war-related events. A total of 340 households were randomly selected among 12,900 families returned from a country of asylum (Switzerland). All adults in each household were invited to participate (N = 996). The following instruments were used: the Albanian translations of the PTSD section of the Mini International Neuropsychiatric Interview and of the Medical Outcomes Study 36-Item Short Form, and a list of traumatic events adapted from the Harvard Trauma Questionnaire. The overall prevalence of PTSD was 23.5%. A strong cumulative effect of trauma was observed, with odds ratios for PTSD rising steeply with the number of events to which people were exposed. After taking into account traumatic events, multivariable analysis indicated that female gender, older age, and having left Kosovo during the conflict were significantly associated with higher frequency of PTSD, whereas significant heterogeneity among municipalities was observed. Stratified analysis for people who stayed and left the province during the war suggested that different patterns of trauma may be relevant in the two subsamples, with forced separation and isolation strongly associated with PTSD in people who stayed in Kosovo. PTSD diagnosis was also significantly associated with lower scores on all dimensions of the Medical Outcomes Study 36-Item Short Form and lower economic status. The results suggest that responding to medium-term and long-term mental health consequences of conflict is a necessary task for the global rehabilitation of health care systems in a war devastated country.