This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Background Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged >= 21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] >= 25 points), and reduced independence (UHDRS independence score <= 90%). Patients were randomly assigned (1: 1: 1: 1: 1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67.5, 90, or 112.5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials. gov (NCT02006472). Findings Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67.5 mg (n=82), 90 mg (n=81), or 112.5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67.5 mg group, 81 in the 90 mg group, and 81 in the 112.5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n= 4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112.5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies.

ZusammenfassungDie neu überarbeiteten Leitlinien Chorea/Morbus Huntington geben auf S2k Niveau einen Überblick über den Stand der Forschung zum Erkrankungsverlauf sowie zu neuen Ansätzen der symptomatischen und verlaufsmodifizierenden Therapie bei der Huntington-Krankheit. Im Gegensatz zu vielen anderen Leitlinien bevorzugen die Autoren aus den deutschsprachigen Ländern als Erstlinienbehandlung der Chorea Tiaprid. Aufgrund von Nebenwirkungen, welche unter Tetrabenazin auftreten können – wie etwa Depression oder Akathisie, ist es gängige Praxis, Tetrabenazin erst in zweiter Linie einzusetzen. Die Leitlinien nehmen Stellung zu rechtlichen Fragen der Präimplantationsdiagnostik (PID) und der pränatalen Diagnostik (PD) in Deutschland, Österreich und der Schweiz sowie zu den Unterschieden zwischen dem prädiktiven und dem differenzialdiagnostischen Einsatz der molekulargenetischen Diagnostik. In den Leitlinien wird darüber hinaus sehr ausführlich zu den möglichen Differenzialdiagnosen bei einer Chorea ungeklärter Ätiologie Stellung genommen.

Objective: The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method:The literature was searched using the electronic database of Pubmed.To identify the highest quality papers, we selected publications in psychiatric journals ranked in the top 25% by the ISI citation index 2010, i.e. the top 32 journals out of 126 listed, all with an impact factor of 3.6 or higher.The published original studies were then discussed and rated for the quality of their design, measures, and statistical methods.Results: 1% if the studies find a positive relationship between R/S and better mental health, 18.6% find mixed (positive and negative) results, and 4.7% reported a negative association.All studies on dementia, suicide and stress-related disorders found a positive association, as well as 79% and 67% of the papers on depression and substance abuse, respectively. Conclusion:There is growing evidence today that R/S is correlated with better mental health in the areas of depression, substance abuse, and suicide; insufficient evidence in neurosis and dementia; poor evidence in bipolar disorder and schizophrenia, and no evidence in many other mental disorders.

Objective: Religiosity and/or spirituality (R/S) has a deep impact on human psyche. This review describes the evidence on R/S on mental health. 72.1% if the studies find a positive relationship between R/S and better mental health, 18.6% find mixed (positive and negative) results, and 4.7% reported a negative association. All studies on dementia, suicide and stress-related disorders found a positive association, as well as 79% and 67% of the papers on depression and substance abuse, respectively. There is growing evidence today that R/S is correlated with better mental health in the areas of depression, substance abuse, and suicide; insufficient evidence in neurosis and dementia; poor evidence in bipolar disorder and schizophrenia, and no evidence in many other mental disorders.

Zwei Metaanalysen über Religiosität und psychische Gesundheit decken die Jahre 1978 bis 2010 ab. In diesen Jahren haben mehr als 70 % der Studien ergeben, dass Religiosität ein protektiver Faktor für die psychische Gesundheit ist. Aufgeschlüsselt auf die ICD-10-Diagnosegruppen kann man mit hohen Evidenzgrad festhalten, dass bei drei psychiatrischen Diagnosegruppen (Depression, Suchterkrankungen und Suizidalität) eine statistisch signifikante Korrelation zwischen Religiosität und besserer psychischer Gesundheit besteht. Zudem besteht es eine gewisse wissenschaftliche Evidenz, bei neurotischen Störungen und organischen psychischen Störungen, dass eine statistisch signifikante Korrelation zwischen Religiosität und besserer psychischer Gesundheit besteht. Ungenügende Evidenz findet sich bei der bipolaren Störung und beim schizophrenen Formenkreis aufgrund der niedrigen Qualität der wenigen vorliegenden Studien und den widersprüchlichen Ergebnissen. Abschließend gibt es keine Evidenz über den Zusammenhang von Religiosität und Essstörungen, Sexualstörungen, Phobien, Zwangserkrankungen, Persönlichkeitsstörungen, somatoforme Störungen und dissoziative Störungen.

Background BN82451B is a small, orally active molecule with good CNS penetration. Preclinical studies in tgHD R6/2 mice suggested improved motor function and prolonged survival. In addition antidyskinetic activity was observed in other models. The proposed mechanisms of action (MOA) are (1) antiexcytotoxic due to a sodium channel blocking potential, (2) antioxidant, (3) anti-inflammatory due to a cyclooxygenase (COX) inhibitory potential and (4) mitochondrial protective. Aims The primary objective of this phase 2a study (NCT02231580) is to investigate the safety and tolerability of BN82451B bid versus placebo for 28 days in male HD subjects. Secondary objectives include assessment of pharmacokinetics and of pharmacodynamics via the effects on quantitative motor (Q-Motor) measures. UHDRS subscales are implemented as exploratory measures. Methods Subjects: We intend to recruit 30 male HD subjects. 24 receive BN82451B and 6 placebo. The study is conducted in an inpatient setting at a single phase I unit in Germany. Design A sequential design was chosen to enable dose escalation starting with 40 mg bid with a potential maximum dose of 80 mg bid. Three subsequent cohorts of 10 patients each are randomised with different starting doses. Subjects in group one are treated with 40 mg bid for 14 days and may be increased to 60 mg bid the subsequent 14 days. In group 2, subjects may first receive 60 mg bid with possible increase to 80 mg bid. Group 3 subjects may receive 80 mg bid for 28 days. Dose increases in the consecutive groups are subject to approval by a Data Review Committee (DRC). The decision to increase the dose in individual patient will be based on the investigator’s judgement. Results Results of the study are expected for Q4/2016. Conclusions Recruitment in this trial is difficult as in-patient periods of nearly one month are logistically challenging. Safety data will be available soon and pharmacodynamics readouts such as Q-motor measures may help to guide decisions on the further path of development of BN82451B.

Since 1978, two systematic evidence-based reviews of the available data on religiosity and mental health in the field of psychiatry have been done. More than 70 % found a relationship between level of religious/spiritual involvement and less mental disorder (positive), some found mixed results (positive and negative), and only about 5 % reported more mental disorder (negative), as was originally suggested by Sigmund Freud. There is good evidence that religious involvement is correlated with better mental health in the areas of depression, substance abuse, and suicide; some evidence in stress-related disorders and dementia; insufficient evidence in bipolar disorder and schizophrenia, and no data in many other mental disorders.

Die Erfassung der verschiedenen Dimensionen der gesundheitsbezogenen Lebensqualität stellt ein wichtiges Instrument in Therapiestudien und bei der Behandlung von Huntington-Patienten dar. Beim Morbus Huntington (MH) zielen sämtliche Behandlungsansätze mangels kausaler Therapie auf eine Linderung der Symptome und Verbesserung der Lebensqualität ab. Ziel der vorliegenden Studie war, den Einfluss krankheitsspezifischer Merkmale beim MH auf die gesundheitsbezogene Lebensqualität von Patienten zu untersuchen.

The assessment of health-related quality of life (hrQoL) is an important tool in therapy studies and in the treatment of patients with Huntington's disease (HD). In the absence of causal interventions, HD therapy targets the alleviation of symptoms aiming to improve impaired hrQoL. The aim of this study was to determine the impact of disease characteristics on hrQoL in HD.A total of 80 genetically confirmed HD patients underwent an assessment using the Unified Huntington's Disease Rating Scale, the Beck Depression Inventory, the Hamilton Rating Scale and the SF-36, a scale for the assessment of physical and mental QoL.Multiple regression analysis revealed that health-related physical and mental QoL was considerably influenced by the functional capacity. The mental QoL also correlated with the degree of depressive symptoms, age and the number of CAG repeats. However, there was no statistical relation between QoL and motor and cognitive abilities.This study underlines the relationship between function capacity and depressive symptoms with mental and physical QoL. This is the first time that hrQoL has been investigated in a German speaking cohort. The results are in accordance with previous studies of hrQoL in HD.

BACKGROUND:The majority of Huntington's disease (HD) mutation carriers experience some psychopathology during their lifetime, varying from irritability to psychosis, but prevalences of particular symptoms vary widely due to diverse study populations in different stages of HD and the use of different assessment methods.METHODS:The study population consisted of 1993 HD mutation carriers from 15 European countries, all participating in the observational REGISTRY study. The behavioural section of the Unified HD Rating Scale was used to examine the prevalence and correlates of five neuropsychiatric features: depression, irritability/aggression, obsessive/compulsive behaviours, apathy and psychosis.RESULTS:Twenty-seven per cent of the participants did not have any neuropsychiatric symptom in the last month. Moderate to severe apathy occurred in 28.1% of the participants, whereas moderate to severe depression was found in 12.7%. Irritable/aggressive symptoms were present in 13.9% of the participants, and 13.2% showed obsessive/compulsive behaviours. Moderate to severe psychotic symptoms were found in only 1.2%. Only 54.9% of all participants with moderate to severe depression used antidepressants, suggesting undertreatment of depression. Obsessive/compulsive behaviours and irritability/aggression were inversely correlated with the Total Functional Capacity score, but with apathy showing the strongest inverse association.CONCLUSIONS:A variety of neuropsychiatric symptoms are highly prevalent in different stages of HD in this European HD population, with apathy as the most frequent symptom. Depression, irritability/aggression and OCBs are prevalent in all stages of HD. Apathy was the key neuropsychiatric symptom occurring most often in advanced HD stages. Due to possible selection of relatively healthy participants, prevalences reported in this study might be an underestimation of prevalence in the entire HD population.

Depresif semptomlar ve dinî/manevî pratikler tüm dünyada yaygındır, fakat bunların kesişim noktası genel ruh sağlığı uzmanlarının nispeten çok az ilgisini çekmektedir. Bu makale son elli yıl süresince (1962’den 2011’e kadar) dinî /manevî bağlanma (involvement)* ile depresif semptomlar ya da bozukluklar arasındaki ilişkileri inceleyen nicel araştırmaları gözden geçirmekte ve bir sentez yapmaktadır. Şu anda en azından 444 araştırma nicel olarak bu ilişkileri incelemiştir. Bunların % 60’ından fazlası, daha fazla dindar / manevî yaşantısı olanlarda daha az depresyon ve depresyondan daha hızlı bir şekilde iyileşmenin var olduğunu ya da dinî/manevî bir müdahaleye karşılık olarak depresyon şiddetinde bir azalma olduğunu ortaya koymaktadır. Buna karşılık araştırmaların sadece % 6’sı daha fazla depresyonu ortaya koymaktadır. Metodolojik olarak en titiz olan 178 araştırmadan 119’u (% 67), din / maneviyat ile depresyon arasında ters ilişki olduğunu ortaya çıkarmıştır. Dinî inançlar ve pratikler, insanlara stresli yaşam koşulları ile daha iyi başa çıkmada yardım edebilir, (hayatlarına) umut ve anlam verebilir ve destek verici bir toplulukla depresyonlu kimseleri çepeçevre kuşatabilir. Bununla birlikte bazı topluluklarda veya bireylerde dinî inançlar suçluluk duygusunu arttırabilir ve insanlar, dinî geleneklerindeki yüksek standartlara göre yaşamakta başarısız olduklarında cesaretsizliğe yol açabilir. Dinî / manevî faktörlerin depresyonu önlemedeki rolünü anlama, çözümü kolaylaştırma ya da daha fazla depresyona neden olma yönünde klinisyenlerin, bunun başlı başına hastalar için bir engel ya da kaynak olup olmadığını tespit etmelerine yardımcı olacaktır

Religion/spirituality has been increasingly examined in medical research during the past two decades. Despite the increasing number of published studies, a systematic evidence-based review of the available data in the field of psychiatry has not been done during the last 20 years. The literature was searched using PubMed (1990-2010). We examined original research on religion, religiosity, spirituality, and related terms published in the top 25 % of psychiatry and neurology journals according to the ISI journals citation index 2010. Most studies focused on religion or religiosity and only 7 % involved interventions. Among the 43 publications that met these criteria, thirty-one (72.1 %) found a relationship between level of religious/spiritual involvement and less mental disorder (positive), eight (18.6 %) found mixed results (positive and negative), and two (4.7 %) reported more mental disorder (negative). All studies on dementia, suicide, and stress-related disorders found a positive association, as well as 79 and 67 % of the papers on depression and substance abuse, respectively. In contrast, findings from the few studies in schizophrenia were mixed, and in bipolar disorder, indicated no association or a negative one. There is good evidence that religious involvement is correlated with better mental health in the areas of depression, substance abuse, and suicide; some evidence in stress-related disorders and dementia; insufficient evidence in bipolar disorder and schizophrenia, and no data in many other mental disorders.