BIPOLAR DISORDER – FROM ENDOPHENOTYPES TO TREATMENT

Introduction: There are a lot of unresolved issues associated with the classification, diagnosis, clinical management and understanding of the underlying pathogenic mechanisms of bipolar affective disorder. Aim: To search for discrete endophenotypes in BAD. Subjects and methods: We studied various bipolar I and II and recurrent depression patient samples and healthy controls using descriptive data, self and clinician-rated scales for neurological and psychopathological symptoms, neurocognitive instruments, and inventories for temperamental and characterological features. We also looked into the efficacy, tolerability and cost/benefit ratio of sodium valproate in the treatment of acute mania. Results: BAD patients display deficits in the domains of memory, selective attention, working memory and psychomotor speed. Sensory, motor and complex neurological soft signs can be considered part and parcel of the symptomatology of BAD. The evidence linking hyperthymic temperament to the bipolar spectrum is not supported, while cyclothymia seems to be a marker of vulnerability to affective psychopathology. In contrast to others, we found significantly lower self-transcendence in BAD patients compared to controls. Early age of onset, abrupt onset, lability of mood and energy with late-day brightening and activation, discriminate bipolar from unipolar depression. Sodium valproate (especially if started intravenously) is a highly efficacious, cost-effective treatment approach for acute mania. Conclusion: The discovery of BAD endophenotypes can enhance early diagnosis, prevent errors in treatment and help elucidate the genetic vulnerability for this grave disease

Lifetime Bipolar Disorder comorbidity and related clinical characteristics in patients with primary Obsessive Compulsive Disorder: a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS)

IntroductionBipolar disorder (BD) and obsessive compulsive disorder (OCD) are prevalent, comorbid, and disabling conditions, often characterized by early onset and chronic course. When comorbid, OCD and BD can determine a more pernicious course of illness, posing therapeutic challenges for clinicians. Available reports on prevalence and clinical characteristics of comorbidity between BD and OCD showed mixed results, likely depending on the primary diagnosis of analyzed samples.MethodsWe assessed prevalence and clinical characteristics of BD comorbidity in a large international sample of patients with primary OCD (n = 401), through the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) snapshot database, by comparing OCD subjects with vs without BD comorbidity.ResultsAmong primary OCD patients, 6.2% showed comorbidity with BD. OCD patients with vs without BD comorbidity more frequently had a previous hospitalization (p < 0.001) and current augmentation therapies (p < 0.001). They also showed greater severity of OCD (p < 0.001), as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).ConclusionThese findings from a large international sample indicate that approximately 1 out of 16 patients with primary OCD may additionally have BD comorbidity along with other specific clinical characteristics, including more frequent previous hospitalizations, more complex therapeutic regimens, and a greater severity of OCD. Prospective international studies are needed to confirm our findings.Peer reviewe

Relationship of suicide rates with climate and economic variables in Europe during 2000-2012

The derived models explained 62.4 % of the variability of male suicidal rates. Economic variables alone explained 26.9 % and climate variables 37.6 %. For females, the respective figures were 41.7, 11.5 and 28.1 %. Male suicides correlated with high unemployment rate in the frame of high growth rate and high inflation and low GDP per capita, while female suicides correlated negatively with inflation. Both male and female suicides correlated with low temperature. Data from 29 European countries covering the years 2000-2012 and concerning male and female standardized suicidal rates (according to WHO), economic variables (according World Bank) and climate variables were gathered. The statistical analysis included cluster and principal component analysis and categorical regression. It is well known that suicidal rates vary considerably among European countries and the reasons for this are unknown, although several theories have been proposed. The effect of economic variables has been extensively studied but not that of climate. The current study reports that the climatic effect (cold climate) is stronger than the economic one, but both are present. It seems that in Europe suicidality follows the climate/temperature cline which interestingly is not from south to north but from south to north-east. This raises concerns that climate change could lead to an increase in suicide rates. The current study is essentially the first successful attempt to explain the differences across countries in Europe; however, it is an observational analysis based on aggregate data and thus there is a lack of control for confounders. RESULTS METHODS BACKGROUND DISCUSSIO

Staging of Schizophrenia with the Use of PANSS: An International Multi-Center Study

Introduction: A specific clinically relevant staging model for schizophrenia has not yet been developed. The aim of the current study was to evaluate the factor structure of the PANSS and develop such a staging method.Methods: Twenty-nine centers from 25 countries contributed 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Analysis of covariance, Exploratory Factor Analysis, Discriminant Function Analysis, and inspection of resultant plots were performed.Results: Exploratory Factor Analysis returned 5 factors explaining 59% of the variance (positive, negative, excitement/hostility, depression/anxiety, and neurocognition). The staging model included 4 main stages with substages that were predominantly characterized by a single domain of symptoms (stage 1: positive; stages 2a and 2b: excitement/hostility; stage 3a and 3b: depression/anxiety; stage 4a and 4b: neurocognition). There were no differences between sexes. The Discriminant Function Analysis developed an algorithm that correctly classified >85% of patients.Discussion: This study elaborates a 5-factor solution and a clinical staging method for patients with schizophrenia. It is the largest study to address these issues among patients who are more likely to remain affiliated with mental health services for prolonged periods of time.<br /

An Investigation of Some Clinical and Psychological Aspects of Bipolar Affective Disorder // Проучвания върху някои клинични и психологични аспекти на биполярното афективно разстройство

[EN] Today’s diagnosis of bipolar affective disorder (BAD) relies almost entirely upon cross-sectional phenomenology and the distinction between BAD I, BAD II and unipolar depression (UPD) is practically based on lifetime existence of increasing number and persistence of manic symptoms. Yet, findings from various contemporary studies support a dimensional concept of an affective disorders spectrum viewed as a unitary phenomenon which can be most comprehensively envisaged from a longitudinal perspective. Focusing on endophenotypes instead on phenotypes (clinical entities) would improve identification of objective markers which exceed the scope of clinical observation. Nature, after all, does not operate with symptoms: evolution forms the normal dimensions of functioning and if their underlying mechanisms are disturbed the deviations are graded, transnosographic, i.e. spectral! This investigation comprises 25 studies by the author alone or in teams led by him during the period 1996 – 2015 plus an additional attempt for a critical analytic review. The studies are spread over 10 areas of research. A total of 1543 individuals were studied (892 by their files only). 750 patients had BAD, 294 had UPD, 20 were in their first major depressive episode (MDE), 375 had OCD, 40 were first–degree relatives of the bipolar probands, and 64 were controls without DSM-IV-TR axis I disorders. We checked consistently a number of relevant aspects of BAD for their possible endophenotypic value and in the course of our research managed to delineate some relevant endophenotypic markers. Our findings confirm a delay of several years till the proper diagnosis of BAD. Results demonstrate that the application of the instrument HCL-32 for primary screening exposes thrice as much patients with “hidden” bipolarity than the routine use of DSM-IV-TR criteria. More than a quarter of our depressed bipolar patients do not respond to adequate antidepressant treatment. Such findings mark pressing need of a complex diagnostic algorhythm for BAD. Current formal diagnostic criteria remain too restrictive notwithstanding the significant progress in DSM-5. Optimization requires detection of wide array of “bipolar stigmata” throughout the course of the disorder. The following distinguishers are significantly more frequent in BAD than in UPD: bipolar spectrum disorders in the family; sudden onset of the first lifetime MDE; onset before the age of 25 (average of 4.7 years earlier than UPD); much higher mean yearly frequency of depressive episodes; common residual symptoms persisting during the inter-episode intervals; marked lability of mood and energy during MDEs (and often also during remissions) with general activation and brightening of mood in late afternoon/evening; markedly disturbed concentration; hypersomnia. Persistent manic symptoms can be detected during MDE in both bipolar and unipolar patients. These results support strongly the notion that affective disorders form a broad dimensional continuum. The most conspicuous inter-group differences are not in severity/duration of depressed mood but in energy/activation. We are convinced that “core” and “additional” symptoms/diagnostic criteria of BAD need a careful reordering and that focusing on behaviour and not on mood is crucial for early detection of BAD. The long-term research of our team resulted in the construction of two diagnostic/predictive models of presence or conversion to BAD during current first/consecutive MDE. These models possess excellent sensitivity (83.7% and 90.7%, resp.), specificity (83.9% and 87.1%, resp.), and also display a very high practical predictive value (87.8% positive and 78.8% negative for a first MDE, and 90.7% positive and 87.1% negative for a consecutive MDE). The model for a first MDE comprises onset before age 25, evening brightening, high level of somatic anxiety (opposite value), markedly disturbed concentration, and presence of manic symptoms. Frequency of previous MDEs substitutes for manic symptoms in the model for a consecutive MDE. Our results demonstrate that high-level trait anxiety may be an important prerequisite for the development of an affective disorder. State anxiety associated with an affective episode is much higher in BAD than in UPD. Somatic anxiety is significantly more frequent in UPD than in BAD. 35 – 50% of the studied patients with UPD and BAD (without inter-group differences) suffer from lifetime comorbid anxiety disorders. The instrument BISS is a convenient and sensitive tool for detecting comorbid anxiety disorders as well as somatic presentations of anxiety. The comorbidity rate of other mental and medical disorders in BAD depends heavily on the used diagnostic algorhythm. Application of a dimensional approach describing an “affective spectrum” allows inclusion of the widespread individual symptoms from the “opposite pole” as well as a more comprehensive grasp on psychiatric and somatic comorbidity. We found a high rate of early-onset OCD, hypothyroidism, and hypertension which all exert pathoplastic influences upon onset, symptom profile and course of BAD. Our results support the very high suicide risk found in BAD. Additionally, all patients with previous suicide attempts display a high-level trait anxiety measured by the STAI. Our comparative studies do not support either the inclusion of hyperthymic temperament in BAD or the existence of a tight association of the depressive temperament to UPD. There is no correlation between age and type of temperament or, in other words, the dimensions of temperament are manifest already early in life and remain stable during development. Hyperthymic temperament is significantly more scarce in BAD in comparison to healthy controls and UPD and is in fact the most uncommon temperament type among the bipolar patients studied; Dominant hyperthymic temperament is associated with a lower risk of mental (especially, affective) disorders and also with a lower suicide risk. Depressive temperament is less conspicuous in the group with first MDE and more prominent among UPD patients which can be either a result of the overlap between diagnostic criteria for either conditions or accentuation of some temperamental characteristics under the influence of the disorder. Anxious temperament is much more common in UPD which once again reminds one of the well-established (even at the genetic level) associations between neuroticism and depression. Dominant cyclothymic temperament is significantly more frequent in BAD (especially, in BAD I) and is practically absent in the UPD samples studied. It stands out as an important factor for the development of alcoholism and is also associated with high suicide risk. We are thus convinced that cyclothymia is an expression of a biologically determined primary dysregulation of energy and emotional stability, so it is not a “temperament” but rather a component of the psychopathological bipolar spectrum. Its absence may even predict the absence of future (hypo) manic episodes. Bipolar patients display significantly higher impulsivity during an episode of either pole in comparison to healthy controls. Impulsivity level does not correlate with severity of depressive or manic symptoms. Thus, high impulsivity is obviously a trait characteristic of bipolar patients as a group and not just an epiphenomenon of the episode. There is also a trend to higher composite and motor impulsivity in manic/mixed episodes and to higher impulsivity of attention in depressive episodes of BAD in comparison to controls. There are measurable marked deficits in information-processing speed, sustained and selective attention, memory, and working memory. These are widespread in mania, more restricted in euthymia, and can also be registered in close relatives of bipolar probands (predominantly in inhibitory processes: selective attention/control on interference). Obviously, BAD is associated with characteristic deficits in certain cognitive domains which are broader and deeper in mania and diminish in remission to full recovery in some and to milder disturbances in other domains. Disturbed inhibitory control, wavering attention, and deficient working memory can explain at least partially the disorder in recall without any impairment in encoding processes as well as the diminished information-processing speed. Deficits grow more severe with each consecutive morbid episode. Compared to controls, BAD patients display a significantly greater total number of soft neurological signs (SNS) as well as significantly more SNS from each separate subgroup. Mean number of SNS does not distinguish either bipolars from healthy controls, or patients in mania from bipolar patients in depressive episode. Refining SNS profile and the profile of cognitive deficits together with registration of peculiarities in temperament and impulsivity components could delineate a more or less accurate “topical” diagnosis of brain alterations in BAD and of their potential transformations at each stage along the long-term course of the disease. In fact, for us this was the ultimate reason to plan, start and steadily follow for already two decades the whole complex research programme. The most serious limitations of this complex investigation of BAD are as follow: relatively small patient and control samples, predominant application of observational, cross-sectional and retrospective designs, deficient standardization and varying quality of the separate studies altogether. BAD is a severe lifelong phenotypically variable disorder which is manifested through a “multicolour” spectrum of disturbances and which has an additional “overgrowth” of various psychiatric and somatic comorbid conditions but is by its nature a unitary disease. The in-depth multifocal investigation of the various aspects of BAD can facilitate the construction of comprehensive algorhythms for recognition and intervention while defining endophenotype profiles can advance awareness of its true nature to a much higher level.[BG] Диагностиката на биполярното афективно разстройство (БАР) поставя редица все още нерешени проблеми. Клиницистът се лута между неразпознаване и свръхдиагностициране, защото дефинирането на разстройството лежи почти изцяло върху „напречна“, моментна феноменология и различаването на БАР I, БАР II и униполярната депресия (УПД) се основава по същество върху пожизненото наличие на нарастващ брой и устойчивост на манийни симптоми. Множество разнообразни съвременни проучвания подкрепят димензионалното гледище за спектър на разстройствата на настроението като единен феномен, осмислян най-пълноценно в надлъжен план. Фокусирането върху ендофенотипове, а не върху фенотипове (клинични диагнози), би подобрило способността за идентифициране на обективни маркери, надхвърлящи възможностите на феноменологичното наблюдение. Природата не „работи“ със симптоми: еволюцията оформя нормалните димензии на функциониране и при разстройване на подлежащите им механизми отклоненията са степенни, транснозографски, т.е. спектрални! Представени са 25 собствени проучвания (проведени самостоятелно и в ръководен от автора екип през периода 1996 – 2015 г.) и един допълнителен опит за критичен аналитичен обзор. Обхванати са 10 области на изследване. Изследвани са общо 1543 индивида (892 - само по документи). 750 пациента са с верифицирано БАР; 294 – с УПД; 20 – с пръв ГДЕ; 375 – с ОКР; 40 са първостепенни родственици на биполярни пробанди; 64 са контроли без психиатрична диагноза по ос I на DSM-IV-TR. Заложени са валидни и значими индекси за последователна проверка на евентуалната ендофенотипна стойност на редица характеристики на БАР и в хода на работата са очертани някои важни ендофенотипни маркери на болестта. Потвърждава се дългогодишното отлагане на правилната диагноза БАР. Над ? от изследваните пациенти не се повлияват от адекватно по доза и продължителност лечение с антидепресант(и) по време на депресивен епизод. Тези находки подчертават императивната необходимост от комплексен диагностичен алгоритъм. Оказва се, че използването на HCL-32 при първично скриниране осветява три пъти повече пациенти със „скрита“ биполярност, отколкото рутинното диагностициране по DSM-IV-TR. Официализираните диагностични критерии за БАР все още осигуряват твърде рестриктивна диагноза въпреки значимия скорошен прогрес в DSM-5. Оптимизацията изисква улавяне на пъстра палитра „биполярни стигми“ по време на всички етапи на болестта. Регистрираме следните статистически значими разграничители с УПД: внезапна изява на първия ГДЕ в живота; ср. 4,7 г. по-ранна при БАР, респ. значимо по-честа изява преди 25 г.; значимо по-чести предходни депресивни епизоди; много чести остатъчни симптоми, персистиращи през интерепизодните интервали; изразена лабилност на настроението и енергията по време на депресивните епизоди, а често – и между тях с обща активация и разведряване привечер; подчертано нарушена концентрация; хиперсомния. Констатираме значима честота на разстройства от биполярния спектър във фамилиите. Оказва се, че не само много от биполярните пациенти имат персистиращи манийни симптоми в рамките на ГДЕ, но и че такива симптоми се откриват при пациенти с „УПД“. Изброените находки дават сериозни аргументи за концепцията, че афективните разстройства стоят в общ димензионален континуум. Най-подчертаните отлики между двете групи депресивни пациенти са не в тежестта/продължителността на спада в настроението, а на ниво енергия/активност. Убедено твърдим, че „сърцевинните“ и „добавъчните“ симптоми, респ. диагностичните критерии за БАР се нуждаят от внимателно пренареждане, като фокусирането върху поведението, а не върху настроението, е решаващо при ранната диагноза на БАР. Дългогодишните проучвания на нашия екип позволиха изграждане и успешно изпробване в практиката на два прогностично-диагностични модела за наличие на/преминаване към БАР при пръв/следващ голям депресивен епизод с отлична чувствителност (съотв. 83,7% и 90,7%) и специфичност (съотв. 83,9% и 87,1%). Моделите са с много висока практическа прогностична стойност (87,8% позитивна и 78,8% негативна за първи епизод; съотв. 90,7% позитивна и 87,1% за пореден депресивен епизод) при AUC съотв. 90,5% и 94,4% и са лесни за ползване чрез компютризирана програма за скринингова оценка на вероятността за принадлежност на индексен ГДЕ към БАР. Компоненти на моделите са: 1) при пръв ГДЕ: изява до 25-годишна възраст; разведряване привечер; високо ниво на соматична тревожност; подчертано нарушена концентрация; наличие на манийни симптоми по време на депресивния епизод; 2) при пореден ГДЕ: начало на болестта до 25-годишна възраст; разведряване привечер; високо ниво на соматична тревожност; подчертано нарушена концентрация по време на депресивния епизод; честота на депресивните епизоди в хода на болестта. Високото ниво на трайна, „личностова“ тревожност може да е важна предпоставка за развитие на афективно разстройство. Свързаната с епизода тревожност е по-изразена при БАР, а соматичната тревожност е значимо по-честа при УПД. При 35 – 50% в отделните извадки изследвани пациенти с УПД и БАР се регистрират категориално определяни тревожни разстройства, без честотата им да се различава статистически значимо между двете афективни субпопулации. Инструментът BISS е достатъчно удобен и чувствителен за улавяне както на коморбидни тревожни разстройства, така и на соматични прояви на тревожност. В изследваните извадки се открива много често и рано изявено наличие на ОКР, хипотиреоидизъм, хипертония и те оказват патопластично влияние върху изявата, симптоматиката и хода на БАР. Регистрираната честота на психиатричен и на соматичен коморбидитет зависи подчертано от използвания диагностичен алгоритъм за БАР. Възприемането на димензионален подход, описващ „афективен спектър“, позволява и вграждане на широко разпространените единични симптоми от „противоположния полюс“ по време на разгърнат афективен епизод, и по-пълноценно обхващане на психиатричния и соматичния коморбидитет при БАР. Потвърждава се наличието на много висок суицидалитет при БАР. При всички пациенти с предходни суицидни опити е налице по-висока личностова тревожност, измерена чрез описа STAI. Нашите сравнителни проучвания не подкрепят нито предложението за включване на хипертимния темперамент, респ. на депресивни епизоди при хипертимен темперамент в биполярния спектър, нито разпространеното схващане за сигурна връзка между депресивния темперамент и УПД. Липсва корелация между възраст и темперамент, т.е. темпераментовите димензии се изявяват рано в живота и се съхраняват стабилни в хода на развитието. Хипертимният темперамент е значимо по-рядък при БАР, отколкото при здрави индивиди и при пациенти с УПД и всъщност е най-редкият темпераментов тип в тази група. Потвърждава се съобщаваният по-малък риск за изява на психични (и по-конкретно – афективни) заболявания и по-ниския суициден риск при по-изразен хипертимен темперамент. Депресивният темперамент е по-неизпъкващ сред групата с пръв ГДЕ и има по-изразено присъствие сред пациентите с УПД, като това може да е или резултат от припокриване между критериите за конкретния темпераментов тип и за конкретната афективна болест, или акцентуиране на темпераментови характеристики под въздействие на болестта. Тревожният темперамент е много по-чест при УПД и това отново насочва към отдавна установените (вече - и на генетично ниво) връзки между невротицизъм и депресия. Проучванията ни сочат, че доминиращият циклотимен темперамент е значимо по-чест при БАР (и особено – при БАР I), отколкото при УПД; представлява важен рисков фактор за развитие на алкохолизъм и е свързан с висок суициден риск. Циклотимният темперамент практически липсва в изследваните извадки с УПД и може би дори има статус на предиктор за липса на бъдещи (хипо)манийни епизоди. Поддържаме, че циклотимията - първична биологично обусловена дисрегулация на енергетичната и емоционалната стабилност - не е „темперамент“, а компонент от психопатологичния биполярен спектър. Независимо от полярността на актуалния болестен епизод, биполярните пациенти имат по-високо ниво на импулсивност от здрави контроли. То не корелира с общата тежест нито на депресивните, нито на манийните симптоми, т.е. представлява трайна характеристика, а не епифеномен на епизода. Очертава се и ясна тенденция към по-висока обща и моторна импулсивност при маниен/смесен афективен епизод и към по-висока импулсивност на вниманието при биполярни пациенти в депресивен епизод спрямо здрави контроли. Установените изразени измерими нарушения в скоростта на обработка на информация, устойчивостта и селективността на вниманието, паметта, работната памет са обширни и най-изразени при маниен епизод, съществуват в по-ограничена степен през еутимните периоди и се регистрират у близки родственици на биполярните пробанди (предимно в инхибиторни процеси: селективно внимание/контрол върху интерференцията). Характерният дефицит в определени области на когнитивните функции се разширява и задълбочава по време на маниен епизод, а при резолюцията му се възстановява до норма в някои и до по-меко нарушение - в други домени. Най-вероятно неустойчивото внимание, смутеният инхибиторен контрол и нарушението на работната памет биха могли да обяснят поне отчасти както увреждането на репродукцията при съхранени процеси на енкодиране, така и смутената психомоторна бързина. Дефицитите се задълбочават с всеки нов болестен епизод в хода на БАР. В сравнение с контроли при БАР се регистрират значимо повече меки неврологични признаци (МНП) - както общо, така и по отделни групи. Средният брой регистрирани МНП не зависи от полярността на актуалния епизод. Броят твърди неврологични признаци не разграничава нито биполярните пациенти от здравите контроли, нито пациентите в мания от пациентите в депресия. Прецизирането на конкретните МНП и конкретните когнитивни нарушения в съчетание с регистриране на особеностите в профилите на темперамента и в компонентите на импулсивността би дало възможност за повече или по-малко ясна „топична“ диагноза на мозъчните промени при БАР и за потенциалните им изменения във всеки етап от дългосрочния ход на болестта. Именно в това виждаме дълбокия смисъл на цялостната комплексна програма за изследване на БАР, която замислихме, стартирахме и неотклонно следваме вече две десетилетия. Най-сериозните недостатъци на представяното комплексно проучване на БАР според нас са следните: сравнително малки извадки пациенти и контроли; преобладаващо използване на обсервационни, напречни и ретроспективни дизайни; непълноценно стандартизиране и, общо взето, неравномерно качество на проведените изследвания. БАР е тежка, пожизнено протичаща, фенотипно многообразна, изявяваща се с „шарен“ спектър прояви и допълнително „обрастнала“ с разнообразен психиатричен и соматичен коморбидитет, но в същността си единна болест. Задълбоченото многопосочно проучване на различните й аспекти позволява създаването на относително пълноценна представа за разпознаването и за контролирането й, а изграждането на ендофенотипове позволява вникване в естеството й

BIPOLAR DISORDER – FROM ENDOPHENOTYPES TO TREATMENT

Introduction: There are a lot of unresolved issues associated with the classification, diagnosis, clinical management and understanding of the underlying pathogenic mechanisms of bipolar affective disorder. Aim: To search for discrete endophenotypes in BAD. Subjects and methods: We studied various bipolar I and II and recurrent depression patient samples and healthy controls using descriptive data, self and clinician-rated scales for neurological and psychopathological symptoms, neurocognitive instruments, and inventories for temperamental and characterological features. We also looked into the efficacy, tolerability and cost/benefit ratio of sodium valproate in the treatment of acute mania. Results: BAD patients display deficits in the domains of memory, selective attention, working memory and psychomotor speed. Sensory, motor and complex neurological soft signs can be considered part and parcel of the symptomatology of BAD. The evidence linking hyperthymic temperament to the bipolar spectrum is not supported, while cyclothymia seems to be a marker of vulnerability to affective psychopathology. In contrast to others, we found significantly lower self-transcendence in BAD patients compared to controls. Early age of onset, abrupt onset, lability of mood and energy with late-day brightening and activation, discriminate bipolar from unipolar depression. Sodium valproate (especially if started intravenously) is a highly efficacious, cost-effective treatment approach for acute mania. Conclusion: The discovery of BAD endophenotypes can enhance early diagnosis, prevent errors in treatment and help elucidate the genetic vulnerability for this grave disease

Cigarette smoking in patients with obsessive compulsive disorder: a report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS)

Obsessive compulsive disorder (OCD) showed a lower prevalence of cigarette smoking compared to other psychiatric disorders in previous and recent reports. We assessed the prevalence and clinical correlates of the phenomenon in an international sample of 504 OCD patients recruited through the International College of Obsessive Compulsive Spectrum Disorders (ICOCS) network. Cigarette smoking showed a cross-sectional prevalence of 24.4% in the sample, with significant differences across countries. Females were more represented among smoking patients (16% vs 7%; p <.001). Patients with comorbid Tourette's syndrome (p <.05) and tic disorder (p <.05) were also more represented among smoking subjects. Former smokers reported a higher number of suicide attempts (p <.05). We found a lower cross-sectional prevalence of smoking among OCD patients compared to findings from previous studies in patients with other psychiatric disorders but higher compared to previous and more recent OCD studies. Geographic differences were found and smoking was more common in females and comorbid Tourette's syndrome/tic disorde

The European First Episode Schizophrenia Trial (EUFEST): Rationale and design of the trial

Background: Most studies comparing second generation antipsychotics with classical neuroleptics have been conducted in more or less chronic schizophrenia patients. Such studies were usually conducted in highly selected samples, and were generally designed and financed by the manufacturer of the drug tested. These and other facts have stimulated discussions regarding the effectiveness of the new generation of antipsychotics. Aims: The aim of the European First Episode Schizophrenia Trial (EUFEST) is to compare treatment with amisulpride, quetiapine, olanzapine and ziprasidone to a low dose of haloperidol in an unselected sample of first episode schizophrenia patients with minimal prior exposure to antipsychotics. Methods: 500 patients between the ages of 18-40 meeting DSM-IV criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder are randomly allocated to one year of treatment with one of the drugs under study. The primary outcome measure is retention in treatment, defined as time to discontinuation of study drug. Loss of retention can be the result of insufficient clinical effect, or lack of tolerability or acceptance. Secondary measures include changes in different dimensions of psychopathology, side effects, compliance, social needs, quality of life, substance abuse and cognitive functions. Conclusions: At present, more than 400 patients have been recruited and randomized in the following countries: Austria, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, the Netherlands, Poland, Rumania, Spain, Sweden and Switzerland: The study should be finished by the end of 2006 and it is expected that results will yield relevant clinical information with regard to the effectiveness of the second generation antipsychotics. This effort represents the first independently designed trans-European schizophrenia treatment trial

Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial

BACKGROUND: Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS: We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS: The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION: This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement