Enantiomeric antidepressant drugs should be considered on individual merit

Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug-drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression.

Using the costs of drug therapy to screen patients for a community pharmacy-based medication review program

Objectives: To measure the positive predictive value (PPV) of the cost of drug therapy (threshold = 2000 Swiss francs [CHF], US$1440, <euro>1360) as a screening criterion for identifying patients who may benefit from medication review (MR). To describe identified drug-related problems (DRPs) and expense problems (EPs), and to estimate potential savings if all recommendations were accepted. Setting Five voluntary Swiss community pharmacies. Methods: Of 12,680 patients, 592 (4.7%) had drug therapy costs exceeding 2000 CHF over a six-month period from July 1 to December 31, 2002. This threshold limit was set to identify high-risk patients for DRPs and EPs. Three pharmacists consecutively conducted a medication review based on the pharmaceutical charts of 125 sampled patients who met the inclusion criterion. Main outcome measure: The PPV of a threshold of 2000 CHF for identifying patients who might benefit from a MR: true positives were patients with at least one DRP, while false positives were patients with no DRP. Results: The selection based on this criterion had a PPV of 86% for detecting patients with at least one DRP and 95% if EPs were also considered. There was a mean of 2.64 (SD = 2.20) DRPs per patient and a mean of 2.14 (SD = 1.39) EPs per patient. Of these patients, 90% were over 65 years old or were treated with at least five chronic medications, two common criteria for identifying patients at risk of DRPs. The main types of DRPs were drug-drug interactions, compliance problems and duplicate drugs. Mean daily drug cost per patient was CHF 14.87 (US$10.70, <euro>10.10). A potential savings of CHF 1.67 (US$1.20, <euro>1.14) per day (11%) was estimated if all recommendations to solve DRPs and EPs suggested herein were implemented. Conclusion: Further studies should investigate whether the potential benefit of medication reviews in preventing DRPs and containing costs in this patient group can be confirmed in a real practice environment. [Authors]

Adhésion thérapeutique du patient chronique: des concepts a la prise en charge ambulatoire [Medication adherence in chronic patients: from its concepts to its management in primary care].

Medication nonadherence is common and its determinants are diverse. Adherence is influenced by many parameters, such as patient's self-efficacy, knowledge of health risk, outcome expectations, benefits of change, and barriers and facilitators. The sociocognitive theory helps professionals to structure their approach and to support patients in managing their treatment. Professionals need skills and time, and benefit from coordination in care, in particular between physicians and pharmacists. This article presents the key elements of a medication adherence program as well as tools and some useful questions.

Assessing medication adherence: options to consider.

Background Adherence to chronic therapy is a key determinant of patient health outcomes in chronic disease. However, only about 50 % of patients adhere to chronic therapy. One of the challenges in promoting adherence is having an accurate understanding of adherence rates and the factors that contribute to non-adherence. There are many measures available to assess patient medication adherence. Aim of the review This review aims to present the commonly used indirect methods available for measuring medication adherence in routine healthcare and research studies. Method A literature review on medication adherence measures in patient populations with chronic conditions taking chronic medications was conducted through Medline (2003-2013). A complementary manual search of references cited in the retrieved studies was performed in order to identify any additional studies. Results Of the 238 initial Medline search results, 57 full texts were retrieved. Forty-seven articles were included as a result of the manual search. Adherence measures identified were: self-report (reported in 50 publications), electronic measures (33), pharmacy refills and claims data (26) and pill counts (25). Patient self-report, electronic measures, pharmacy refill and claims data were the most commonly used measures of adherence in research, routine practice, epidemiological and intervention studies. These methods, and their strengths and limitations have been described in this paper. Conclusion A multitude of indirect measures of adherence exist in the literature, however, there is no "gold" standard for measuring adherence to medications. Triangulation of methods increases the validity and reliability of the adherence data collected. To strengthen the adherence data collected and allow for comparison of data, future research and practice interventions should use an internationally accepted, operational standardized definition of medication adherence and clearly describe the medication adherence methods used.

Tools in pharmacovigilance in psychiatry: therapeutic drug monitoring, pharmacogenetic tests and drug-drug interactions databases

SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.

Aptitude à la conduite, pathologies psychiatriques et psychotropes chez la personne âgée [Driving ability, mental illness and psychotropic medication in the elderly].

Fitness to drive in elderly drivers is most commonly discussed with a focus on cognitive impairment. Therefore, this article is focussing on mental illness and the use of psychotropic drugs in elderly drivers, which can both interfere with fitness to drive. Based on a detailed literature review and on clinical judgement, we propose signposts and "red flags" to judge the individual risks. Health professionals dealing with elderly patients should in particular be aware of the dangers related to cumulative risks and need to inform the patients appropriately. For medico-legal reasons the information provided to patients must be written down in the medical record. Individual counselling is important as fitness to drive is a complex topic.

Psychopharmacology in supportive care of cancer: a review for the clinician. III. Antidepressants

This review covers pharmacokinetics, adverse effects and drug interactions of antidepressants and the indications for them, with the aim of assisting the clinician working in palliative and supportive care in the prescription of such drugs. Practical considerations and decision trees to be used prior to the prescription of an antidepressant are also part of this review. Special emphasis is put on the management of depression, which is frequent in patients with advanced cancer and often remains underdetected and undertreated, or is treated at a stage when there is little time for medication to have an effect.

Prevalence and factors associated with incidents related to medication in surgical patients

The aim of this study was to estimate the prevalence and factors associated with the occurrence of incidents related to medication, registered in the medical records of patients admitted to a Surgical Clinic, in 2010. This is a cross-sectional study, conducted at a university hospital, with a sample of 735 hospitalizations. Was performed the categorization of types of incidents, multivariate analysis of regression logistic and calculated the prevalence. The prevalence of drug-related incidents was estimated at 48.0% and were identified, as factors related to the occurrence of these incidents: length of hospitalization more than four days, prescribed three or more medications per day and realization of surgery intervention. It is expected to have contributed for the professionals and area managers can identify risky situations and rethink their actions.

Matters Relating to a Forced Move of, Use of a Chemical Agent on and Withdrawal of Medication for Inmate Craig Gardner, 1994

Case Number 91-151 Craig Gardner, an inmate in the Iowa prison system, was the subject of a force move by correctional officers while incarcerated at the Iowa State Penitentiary (ISP). This action involved the use of a chemical agent. This investigation began as a review of the use of a chemical agent in a forced cell move on June 30, 1991.

Frequency and Type of Side Effects of Immunomodulating Medication in the Swiss Inflammatory Bowel Disease Cohort

Background: Medical treatment of inflammatory bowel disease (IBD) is becoming more and more complex, as several classes of immuno-modulating drugs (IMD) are often used simultaneously. Thus, the probability of adverse effects is greatly increased. Most studies reporting on adverse effects focus on single therapy, and studies providing a global survey of side effects for multiple treatments are lacking. Aim: To assess the type and frequency of adverse events in IBD patients treated with single and multiple IMD therapy. Methods: Analysis of data from the Swiss IBD Cohort Study (SIBDCS) that collects data on a large sample of IBD patients from hospitals and private practices across Switzerland. The following IMD categories were analyzed: 5-ASA, azathioprine (Aza), 6-mercaptopurine (6-MP), methotrexate (MTX), anti-TNF (infliximab, adalimumab, certolizumab-pegol), cyclosporine, tacrolimus, and steroids. The following side effects were assessed: hepatitis, pancreatitis, leucopenia, thrombopenia, nephritis, allergic reaction, pneumonitis, infections (including tuberculosis), osteoporosis, abdominal pain/diarrhea (unrelated to IBD activity), cataract, diabetes, exanthema, hirsutism, lupus-like syndrome, myalgias, depression/psychosis, tumor development. Results: A total of 1,961 patients were analyzed (977 [50%] female, mean age 42.1 ± 14.4 years): 1,119 with Crohn's disease (CD), 800 with ulcerative colitis (UC), and 42 with indeterminate colitis (IC). Three-hundred eighteen (16.2%) patients were not treated with any of the above-mentioned medications, while 650 (33.2%), 569 (29%) and 424 (21.6%) patients had one-, two-, and three- or more- IMD therapy, respectively. Of the 1,643 patients treated with IMD, 535 (32.6%) patients reported at least one side effect. We found a significant correlation between the number of drugs used by a patient and the frequency of side effects (17.4% side effects for one drug, 29% for 2 drugs, and 60.6% for three or more drugs, p < 0.001). The frequency of side effects for the different IMD classes were as follows: 5-ASA (n = 980 treated patients) 10.8%, Aza/6-MP (n = 636) 51.9% (pancreatitis in 57 = 9%, hepatitis in 17 = 2.7% of treated patients), MTX (n = 146) 42.5% (hepatitis in 4 = 2.7% of treated patients), anti-TNF (n = 255) 23.1%, cyclosporine (n = 49) 10.2%, tacrolimus (n = 5) 20%, steroids (systemic or topical, n = 1,150) 9.6%. Conclusion: IBD treatment is associated with a significant number of side effects. A direct correlation between the number of IMD used simultaneously and the frequency of side effects was observed. The results of this study indicate that treating physicians should be vigilant for the occurrence of side effects in IBD patients under single and/or multiple drug therapy.

Exploring the implementation of a medication adherence programme by community pharmacists : a qualitative study

Background Medication adherence has been identified as an important factor for clinical success. Twenty-four Swiss community pharmacists participated in the implementation of an adherence support programme for patients with hypertension, diabetes mellitus and/or dyslipidemia. The programme combined tailored consultations with patients about medication taking (expected at an average of one intervention per month) and the delivery of each drug in an electronic monitoring system (MEMS6?). Objective To explore pharmacists' perceptions and experiences with implementation of the medication adherence programme and to clarify why only seven patients were enrolled in total. Setting Community pharmacies in French-speaking Switzerland. Method Individual in-depth interviews were audio-recorded, with 20 of the pharmacists who participated in the adherence programme. These were transcribed verbatim, coded and thematically analysed. Process quality was ensured by using an audit trail detailing the development of codes and themes; furthermore, each step in the coding and analysis was verified by a second, experienced qualitative researcher. Main outcome measure Community pharmacists' experiences and perceptions of the determining factors influencing the implementation of the adherence programme. Results Four major barriers were identified: (1) poor communication with patients resulting in insufficient promotion of the programme; (2) insufficient collaboration with physicians; (3) difficulty in integrating the programme into pharmacy organisation; and (4) insufficient pharmacist motivation. This was related to the remuneration perceived as insufficient and to the absence of clear strategic thinking about the pharmacist position in the health care system. One major facilitator of the programme's implementation was pre-existing collaboration with physicians. Conclusion A wide range of barriers was identified. The implementation of medication adherence programmes in Swiss community pharmacies would benefit from an extended training aimed at developing communication and change management skills. Individualised onsite support addressing relevant barriers would also be necessary throughout the implementation process.