Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Out of hours care in Germany - High utilization by adult patients with minor ailments?

BACKGROUND: Family practitioners (FPs) who work in Out-Of-Hours Care (OOHC) - especially in rural areas - complain about high workload related to low urgency and potentially unnecessary patient presentations with minor ailments. The aim of this study was to describe Reasons for Encounter (RFEs) in primary OOHC taken into account the doctor's perspective in the context of high workload without knowing patients' motives for visiting an OOHC-centre. METHODS: Within this descriptive study, OOHC data from 2012 were evaluated from a German statutory health insurance company in the federal state of Baden-Wuerttemberg. 1.53 Million of the 10.5 Million inhabitants of Baden-Wuerttemberg were covered. The frequency of the ICD-10 diagnoses was determined at the three- and four-digit-level. The rate of hospitalizations was used to estimate the severity of the evaluated cases. RESULTS: Taken as a whole, 163,711 reasons for encounter with 1,174 ICD-10 single diagnoses were documented, of these 62.2% were on weekends. Less than 5.0% of the examined patients were hospitalized. Low back pain-dorsalgia (M54) was the most common diagnosis in OOHC, with 10,843 cases. Injuries were found twelve times in the list of the 30 most frequent diagnoses. The most frequent infectious disease was acute upper respiratory infection of multiple and unspecified sites (J06). By analysing the ICD codes to four-digits and looking at the rate of hospitalizations, it can be assumed that many RFEs were of less urgency in terms of the prompt need for medical treatment. CONCLUSION: While it is acknowledged that it can be difficult to make an exact diagnosis in an OOHC setting, after analysing the ICD-10 diagnoses, the majority of reasons for encounter in OOHC were determined to be of low urgency, meaning that patients could have waited until regular consultation hours. In the OOHC setting, it is important to understand RFEs from both the patient perspective and the family practitioner perspective. Additionally, results like these can be used in staff education especially improving triage methods and medical recommendations and in developing specific guidelines for OOHC in Germany. Analysis of routine data, such as in this study, contributes to this understanding and contributes to resolving problems of coding.

[Assessment of ability to drive in patients with MCI and dementia]. / Beurteilung der Fahrtauglichkeit bei Patienten mit MCI und demenziellen Syndromen.

People with mild cognitive impairment and dementia are a frequent and continuously increasing patient group in practically all fields of medicine. The associated challenges involve nearly all areas of life in addition to the direct medical treatment. Assessment of the ability to drive in patients with cognitive deficits is becoming increasingly more important. What are the options available to physicians in order to make a valid assessment? Which legal aspects must be taken into consideration? Which rights and obligations arise from the framework conditions? These questions nowadays give rise to great uncertainty for many medical personnel; however, the increasing importance of these problems necessitates a clear procedure, which allows difficult decisions to be made with utmost sovereignty and legal certainty and to be able to give patients and relatives a plausible explanation. Because age is a substantial risk factor for the development of cognitive disorders, the question of the ability to drive is affected not only by neuropsychiatric diseases, such as mild cognitive disorders or dementia but also the frequently occurring somatic comorbidities. Estimation of the ability to drive is therefore a complex approach, which should be standardized in order to appreciate all relevant aspects. It would be desirable to have a practice-oriented algorithm, the formulation of which is the aim of this article. Additionally, we would like to make a contribution to road safety and make medical personnel fully aware of this topic.

[Care of patients with cancer pain in general practices in Germany]. / Versorgung von Patienten mit Tumorschmerzen in hausärztlichen Praxen in Deutschland.

BACKGROUND: In line with the increased life expectancy of people in Germany, the probability of falling ill with a malignant disease is continuously increasing. About 480,000 people in Germany contract cancer every year. One of the most important symptoms of a malignant disease is pain. Between 40 and 100% of patients with advanced cancer suffer from pain. The aim of this investigation is to show how German general practitioners care for these patients using analgetics. MATERIALS AND METHODS: The data were extracted from the CONTENT database (CONTinuous morbidity registration Epidemiologic NeTwork) of the Department of General Practice and Health Services Research at the University Hospital in Heidelberg. This database has data from more than 200,000 patients and more than 3 million physician/patient contacts. The prescriptions were classified using the ATC code. RESULTS: Patients experiencing pain from cancer received all kinds of analgetic drugs. The data comprises 9752 prescriptions for 1362 patients. There were 4975 (51.1 %) prescriptions for Class 1 analgesics, 929 (9.5 %) for Class 2 analgetics and 1918 (19.7 %) prescriptions for Class 3 analgetics. Coanalgetics were prescribed 1930 (19.7 %) times. 1,167 patients (85.7 %) were treated in the correct manner according to the guidelines of the World Health Organisation and 195 (14.3 %) were not. CONCLUSIONS: Most GPs in Germany follow the principles of WHO structured pain therapy. However, further improvement of the results may be achieved through intensive training of colleagues.

Driving performance and psychomotor function in depressed patients treated with agomelatine or venlafaxine.

OBJECTIVE: We conducted a randomized case-control study in depressive inpatients to assess the effects of agomelatine and venlafaxine on psychomotor functions related to driving skills and on driving performance in an on-road driving test. METHOD: 40 depressed inpatients treated with agomelatine (n = 20) or venlafaxine (n = 20) were tested before pharmacological treatment (t0), and on days 14 (t1) and 28 (t2). 20 healthy subjects were examined in the same time schedule to control for retest effects in psychomotor measures. Additionally, participants were rated in a standardized on-road driving test on day 28 by a licensed driving instructor, who was blind with respect to treatment, diagnosis and test results. RESULTS: After 4 weeks of treatment (t2) with agomelatine or venlafaxine, patients showed a significant reduction in depressive symptoms, and a distinct improvement in psychomotor functions. Controlling for retest effects in psychomotor measures, data indicate, that both patient groups significantly improved in tests measuring reactivity and stress-tolerance. Furthermore, prior discharge to outpatient treatment (day 28), 72.5% of patients were labeled abundantly fit to drive in the on-road driving test by a licensed driving instructor. However, patients did not reach the performance level of healthy controls in functional domains tested. Significant differences between treatment groups were not observed. CONCLUSION: Our results indicate that depressed inpatients treated with agomelatine or venlafaxine show a better test performance on tasks related to driving skills than do untreated depressives and could predominantly be rated as fit to drive on an actual driving test prior discharge to outpatient treatment.

[Characteristics of Health-Care Provision for Patients in Out-of-Hours Care and Regular Care]. / Charakteristika primärärztlicher Versorgung von Patienten außerhalb regulärer Sprechstundenzeiten im Vergleich zur Routineversorgung.

BACKGROUND: Little is known of the primary care characteristics in out of hours care centres (OOHC) as compared to regular care in Germany. Obviously the provision of patients in OOHC exhibits special characteristics concerning supply requirements, occupation and physician services, that require a first approximation. METHODS: The data retrieval is managed within the CONTENT (CONTinous morbidity registration Epidemiologic NeTwork) research network. The used software allows for classifying reasons for encounter (RFE), health-problems (diagnoses) and processes of care (prescriptions, referrals, hospitalisations) with the International Classification of Primary Care (ICPC). Furthermore the software allows for pseudonymised data export. One OOHC Centre in South Hessen is part of the network. Therefore, this allows the comparison of this OOHC centre with the regular care of the included 5 physicians in 4 practices of the same region. RESULTS: A 3-year period (01 April 2010-31 March 2013) with 192,827 patient contacts of 13,394 patients (58.1% female) in regular care and 14,354 patient contacts with 9,208 patients (64.1% female) in OOHC was described. Medium age of the patients of the regular provision was 59.6 vs. 45.7 years in the OOHC centre based on the contacts (p<0.0001). The most frequent RFE in the OOHC centre were fever and pain predominantly caused by acute infections, injuries or acute pain of the musculoskeletal system. In regular care there could be documented predominantly chronic health issues and vaccinations. The prevalent prescriptions in OOHC were therefore antibiotics and analgesics in regular care blood pressure medication and antidiabetic drugs. The rate of referrals was obviously lower than in regular care (7.1 vs. 22.7; p<0.0001), whereas the rate of hospitalisations was obviously higher in OOHC than in regular care (5.6 vs. 1.1; p<0.0001). CONCLUSION: With the help of the data, requirements, occupation, resulting diagnoses and care processes in regular and out of hours care can be compared and described in detail. We could document major differences between the provision in OOHC and regular care. The results encourage initiating further studies to ensure the supply of primary care in OOHC.

[Reality of treatment in psychotherapy: Results of a survey of German psychiatric hospitals]. / Versorgungsrealität in der Psychotherapie : Ergebnisse der Befragung deutscher psychiatrischer Versorgungskliniken.

OBJECTIVES: Since the introduction of the qualification as specialist for psychiatry and psychotherapy, in addition to psychopharmacotherapy psychotherapy is an integral component of the treatment of mentally ill people. A survey was carried out to evaluate the reality of clinical routine use of psychotherapy in German psychiatric hospitals. METHODS: Between October 2011 and March 2012 German hospitals of psychiatry and psychotherapy were contacted by the head organization, the conference of national directors (Bundesdirektorenkonferenz), to participate in a survey regarding the application of psychotherapy in the real clinical world of daily treatment. With an anonymous questionnaire, data were requested as either a printed form or online version. RESULTS: Data from 25 psychiatric hospitals in the year 2010 could be analysed (average number of beds 300 of which 53 were for psychosomatic/psychotherapeutic patients) and a total of 87,000 inpatients were treated whereby 34 % were diagnosed as F1 addictive disorders and 24 % as F3 affective disorders. More than 80 % of the hospitals applied group therapies of relaxation, cognitive behavior therapy, social competence training and specific techniques, such as dialectic-behavior therapy. As individual treatment methods, patients with depressive disorders were treated with cognitive behavior therapy, interpersonal psychotherapy or psychodynamic therapy in more than 50 % of the cases. Relaxation techniques were offered in most cases by the nursing staff, behavior therapy by psychologists and physicians and psychodynamic therapy mainly by psychiatrists.

[Patient care in an out-of-hours care practice - a descriptive study of the CONTENT project]. / Die medizinische Versorgung in einer kassenärztlichen Bereitschaftsdienstzentrale - Eine deskriptive Studie aus dem CONTENT-Projekt.

BACKGROUND: Little published research is available about the content of out of hours care (OOHC) in Germany. CONTENT is a project of the University Hospital Heidelberg to build up a morbidity registry for ambulatory health care. One of the participating practices of the network is a rural OOHC centre. The study reports exemplarily on the work of this practice. METHODS: The design of the study is cross-sectional. One of the 2 available CONTENT practice-softwares was used for data retrieval. The softwares allow for classifying reasons for encounter (RFE), health problems (diagnoses) and processes of care with the International Classification of Primary Care (ICPC-2). Furthermore the softwares allow for pseudonymised data export. RESULTS: A 3-year period with 15 886 patient contacts of 9 542 patients (65.9% female) is described. Close to 8% of the population in the catchment area visited the practice at least once in a year. Medium age of the patients was 42 years (range 0-104). The groups of the 25-44-year-old and the 45-64-year-old patients formed together 43% of all contacts. The most frequent RFE were: fever (5.8%), sore throat (4.8%), cough (4.8%), earache (3.9%) and insect bites (3.6%). Frequencies of these RFEs differed considerably between the age groups. With the help of the data, resulting diagnoses and care processes can be described in detail. CONCLUSION: This study describes, for the first time in Germany, the work of an OOHC practice. Data capture to accomplish this was feasible within existing practice software and without much extra work. If more OOHC practices would participate in the CONTENT project a more representative picture of OOHC in Germany could be established.

[Driving ability with affective disorders and under psychotropic drugs]. / Fahrtauglichkeit bei affektiven Störungen und unter Psychopharmaka.

There are only few data available regarding the effects of depressive disorders on road safety due to methodological shortcomings. Patients with acute severe depression or manias are unqualified for driving but after clinical remission driving ability can be attested under psychiatric supervision in most cases. So far there are only few data available about a patient's fitness to drive under psychotropic medication. Regarding the effects of antidepressants on road safety depressed patients obviously benefit from treatment with newer antidepressants; however, at least some subgroups of patients do not reach the performance level of healthy subjects. Approximately 17 % of remission bipolar patients must be regarded as unable to drive and 27 % of patients with schizophrenia on discharge from hospital. Benzodiazepines are clearly associated with increased risk of road traffic accidents. Impaired driving ability of young attention deficit hyperactivity disorder (ADHS) patients is improved under treatment with methylphenidate. Counselling patients with respect to driving ability must be carried out individually taking into account factors of the illness, personality, attitudes and coping strategies as well as different psychopharmacological effects.

[Dementia and driving]. / Demenz und Autofahren.

For most people driving is essential for mobility to maintain independence and to take part in activities of daily living. Ageing per se does not impair driving but in cases of medical conditions, such as cognitive impairment and dementia, driving safety can be impaired. Thus clinicians are often called upon to counsel patients and to make recommendations on their fitness to drive. Dementia in the early stages of the illness does not necessarily preclude driving ability. Patients with mild dementia pose a risk with respect to traffic safety and an individual assessment with regular follow-up investigations should be made. Especially patients with frontotemporal dementia should cease driving early in the course of the disease. Screening tests that focus on visuospatial abilities, attention and executive functions can improve the prediction of driving ability in patients with dementia. In many cases an on-road driving test to evaluate the ability to compensate for functional impairments is essential. In order to preserve personal autonomy as long as possible patients should be individually counselled taking into account driving experience, insight into functional impairments, personality and the capability to compensate for functional disabilities.

[Principles of evaluating driving ability for neurological and psychiatric diseases]. / Grundlagen der Fahreignungsbeurteilung bei neurologischen und psychischen Erkrankungen.

If attending physicians and psychologists recognize restricted or a lack of driving ability they are obliged to inform their patients appropriately. In Germany the legal basis for assessing driving ability is the "Fahrerlaubnis-Verordnung" (FeV, driving licence act), supplemented by guidelines for evaluating driving ability. In each individual case it has to be clarified whether and to what extent permanent or paroxysmally occurring disorders affect driving ability and whether lack of insight ability or personality defects are a threat to driving safety. In addition, it has to be considered whether compensation opportunities exist that enable restricted driving ability. If an expert opinion is requested by the driving licence authority in Germany the medical expert must have a specific qualification and should not be the attending physician.

Prospective ECG-gated High-Pitch Photon-Counting CT Angiography: Evaluation of measurement accuracy for aortic annulus sizing in TAVR planning.

PURPOSE: In planning transcatheter aortic valve replacement (TAVR), retrospective cardiac spiral-CT is recommended to measure aortic annulus with subsequent CT-angiography (CTA) to evaluate access routes. Photon-counting detector (PCD)-CT enables to assess the aortic annulus in desired cardiac phases, using prospective ECG-gated high-pitch CTA. The aim of this study was to evaluate the measurement accuracy of aortic annulus using prospective ECG-gated high-pitch CTA against retrospective spiral-CT reference. METHOD: Thirty patients underwent cardiac spiral-CT and prospective ECG-gated (30% R-R on aortic valve level) high-pitch CTA. Using propensity score matching, another 30 patients were identified whose CTA was performed using high-pitch mode without ECG-synchronization. Two investigators measured annular diameter, perimeter, and area on cardiac spiral-CT and high-pitch CTA. RESULTS: The aortic valve was imaged in systole in 90 % of prospective ECG-gated CTA cases but only 50 % of non-ECG-gated CTA cases (p = 0.002). There was a strong correlation (r ≥ 0.94) without significant differences (p ≥ 0.09) between cardiac spiral-CT and prospective ECG-gated high-pitch CTA for all annulus measurements. In contrast, significant differences were found in annular short-axis diameter and area between cardiac spiral-CT and non-ECG-gated high-pitch CTA (p ≤ 0.03). Furthermore, prospective ECG-gated high-pitch CTA showed significantly reduced radiation exposure compared with cardiac spiral-CT (CTDI 4.52 vs. 24.10 mGy; p < 0.001). CONCLUSION: PCD-CT-based prospective ECG-gated high-pitch scans with targeted systolic acquisition at the level of the aortic valve can simultaneously visualize TAVR access routes and accurately measure systolic annulus size. This approach could aid in optimizing protocols to achieve lower radiation doses in the growing population of younger, low-risk TAVR patients.

Treatment of comorbid anxiety and depression with escitalopram: results of a post-marketing surveillance study.

INTRODUCTION: In this 16-week post-marketing surveillance (PMS) study, antidepressant effects and tolerability of escitalopram was examined in 2 911 patients with comorbid depression and anxiety. METHODS: Antidepressant effects were assessed using a modified version of the Montgomery-Åsberg depression rating scale (svMADRS), the Hamilton anxiety scale (HAMA) and the hospital anxiety depression scale (HADS-D) and the clinical global impression scale (CGI-S, CGI-I). RESULTS: Treatment was completed by 2 718 patients, whose severity of depression decreased from a mean svMADRS total score of 33.0 to 8.9. At the end of the study, the remission rate (svMADRS≤12) was 72.9% and the response rate (≥50% decrease in svMADRS score) was 83.1% (LOCF). Similarly, the severity of anxiety symptoms decreased from a mean HAMA total score of 28.8-8.8; the remission rate (HAMA<10) was 63.9% and the response rate (decrease≥50%) was 80.2%. The most frequent adverse events were nausea (1.6%), agitation (1.1%) and fatigue (0.7%). DISCUSSION: Antidepressant effects and good tolerability of escitalopram were confirmed in everyday practice in patients with comorbid depression and anxiety. The high response and remission rates were within the range reported in previous RTC's of escitalopram vs. comparators or vs. placebo.

Early improvement and serum concentrations of citalopram to predict antidepressant drug response of patients with major depression.

INTRODUCTION: Post hoc analyses of clinical trials have shown that early improvement around day 14 is highly predictive for later response. More-over, evidence has been given that sufficiently high concentrations of antidepressant drugs in blood are required to attain response. In this study, we determined cut-off levels for citalopram serum concentrations and clinical improvement during the early phase of treatment to predict later response and the predictive power of these measures either alone or in combination. METHODS: Inpatients with depressive disorder according to ICD-10 who received citalopram were included. Psychopathology was assessed by the 17-item Hamilton Depression (HAMD-17) rating scale, and serum concentrations of citalopram were measured in weekly intervals. RESULTS: The analysis included 55 inpatients. Receiver operating characteristics analysis revealed for citalopram a serum concentration of 53 ng/ml on day 7 and a clinical improvement of 24% on the HAMD-17 scale on day 14 as significant cut-off values to predict response after 5 weeks of treatment. Both measures taken together predicted response on week 5 with 73% sensitivity and 85% specificity with an odds ratio of 14.6. DISCUSSION: It is concluded that treatment with citalopram should be guided by symptom rating at baseline and on day 14 and serum concentration determination on day 7.

The antidepressant agomelatine in daily practice: results of the non-interventional study VIVALDI.

The non-interventional study VIVALDI was carried out to evaluate the treatment with agomelatine, an innovative antidepressant, in routine practice.665 psychiatrists treated 3 317 patients over 12 weeks with agomelatine and documented antidepressant effects via svMADRS, CGI scale and CircScreen questionnaire. Subgroups with severe depression (svMADRS ≥30) and elderly patients (≥65 years) were also analyzed.In the total population, svMADRS total score decreased from 30.6 at baseline to 12.8 at final visit, in severely depressed patients from 36.7 to 14.7, in elderly patients from 29.0 to 12.2. In total 65.8% of patients could be classified as responders (≥50% decrease in svMADRS total score) and 54.8% as remitters (svMADRS ≤12). Daytime sleepiness was ameliorated in 78.2% of patients. Adverse drug reactions were reported for 10.0%, 8.9% and 10.1% of patients in total population, severely ill and elderly patients, respectively.In this study, the antidepressant effects, improvement of circadian rhythm disorders and good tolerability of agomelatine were observed in unselected depressed patients, including multimorbid elderly and severely depressed patients under routine practice.

Driving ability under sertindole.

INTRODUCTION: Fitness to drive is an important prerequisite for the functional autonomy and thus also relevant for patients with a psychiatric illness. The efficacy of sertindole in the treatment of positive and negative schizophrenia symptoms has been shown in various studies. However, hitherto there exist no data about patients' fitness to drive under sertindole. METHODS: A non-randomized clinical study with 30 schizophrenic inpatients receiving sertindole (n=10), risperidone (n=10) or quetiapine (n=10) was conducted. Patients were tested under steady-state plasma level conditions prior to discharge to outpatient treatment. Data were collected with the computerized Act and React Testsystem (ART90) and the Wiener Determinationsgerät (WDG) measuring psychomotor skills relevant for fitness to drive. RESULTS: The main findings of this study are (i) that about 26% of schizophrenic patients, -following psychopathologic stabilization and prior discharge to outpatient treatment show severe impairments with respect to driving skills. (ii) Statistically significant differences between atypical antipsychotics could neither be demonstrated on the level of the global driving ability score nor on individual functional domains essential for fitness to drive. CONCLUSION: With respect to driving skills no differences have been found between patients treated with sertindole, risperidone or quetia-pine. However, a great proportion of schizophrenic patients partly remitted must be considered as unfit to drive, even when stabilized on treatment with atypical antipsychotics.

The serotonin transporter promoter polymorphism (5-HTTLPR) affects the relation between antidepressant serum concentrations and effectiveness in major depression.

INTRODUCTION: Both the serotonin transporter promotor polymorphism (5-HTTLPR) and serum concentrations of SSRIs have been shown to affect response to SSRIs. Results, however, are inconsistent. The aim of this study was to investigate whether remission or response to SSRIs is influenced by an interaction of 5-HTTLPR and SSRI serum concentrations. METHODS: 49 patients with major depression and SSRI treatment were genotyped for the 5-HTTLPR locus including the rs25531. Drug serum concentrations and depression severity were measured weekly. RESULTS: Logistic regression analysis revealed a significant association between 5-HTTLPR, SSRI serum concentrations and response to treatment. A favourable treatment outcome correlated with SSRI serum concentration in 5-HTTLPR-L(A) allele carriers (r² = 34.3 %; p = 0.001), but not in S/L(G)-allele carriers (p = 0.31). DISCUSSION: In the group of L(A) allele carriers, those MDD patients with a high antidepressant serum concentrations responded better to treatment than patients with a low serum concentration. We conclude that the 5-HTTLPR might affect reponse to SRRI subject to serum concentrations. If replicated this might be a starting point for prospective clinical trials.

Evaluating depressive symptoms and their impact on outcome in schizophrenia applying the Calgary Depression Scale.

OBJECTIVE: To examine depressive symptoms, their course during treatment, and influence on outcome. METHOD: Weekly Calgary Depression Scale for Schizophrenia ratings were performed in 249 inpatients with schizophrenia. Early response was defined as a 20% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia from admission to week 2, response as a 50% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) from admission to discharge and remission according to the consensus criteria. RESULTS: Thirty six per cent of the patients were depressed at admission, with 23% of them still being depressed at discharge. Depressed patients scored significantly higher on the PANSS negative and general psychopathology subscore, featured more impairments in subjective well-being (P < 0.0001) and functioning (P < 0.0001). They suffered from more suicidality (P = 0.0021), and had greater insight into their illness (P = 0.0105). No significant differences were found regarding early response, response, and remission. CONCLUSION: Patients with depressive symptoms should be monitored closely, given the burden of negative symptoms, their impairments in well-being and functioning and the threat of suicidality.