Mood and disruptive behavior disorders and symptoms in the offspring of patients with bipolar I disorder

The study aimed to ascertain the prevalence of mood and disruptive behavior disorders and symptoms in 35 children of 29 adult outpatients with a DSM-IV diagnosis of bipolar I disorder, compared with 33 children of 29 healthy adults, matched with patients on age, socioeconomic status and education. The offspring of bipolar patients had a 9.48 fold higher risk of receiving a psychiatric diagnosis. While only two children of patients with bipolar disorder were diagnosed with a mood disorder, 30.9% displayed mild depressed mood, compared with 8.8% of the controls, a statistically significant difference. The bipolar offspring also scored significantly higher on the hyperactivity and conduct problems subscales as well as the ADHD index of the Conners’ Teacher Rating Scale. The disruptive behavior and mood symptoms observed in early life in the offspring of bipolar patients may indicate the need for early psychosocial intervention.     

ADHD and autism: differential diagnosis or overlapping traits? A selective review

According to DSM-IV TR and ICD-10, a diagnosis of autism or Asperger Syndrome precludes a diagnosis of attention-deficit/hyperactivity disorder (ADHD). However, despite the different conceptualization, population-based twin studies reported symptom overlap, and a recent epidemiologically based study reported a high rate of ADHD in autism and autism spectrum disorders (ASD). In the planned revision of the DSM-IV TR, dsm5 (www.dsm5.org), the diagnoses of autistic disorder and ADHD will not be mutually exclusive any longer. This provides the basis of more differentiated studies on overlap and distinction between both disorders. This review presents data on comorbidity rates and symptom overlap and discusses common and disorder-specific risk factors, including recent proteomic studies. Neuropsychological findings in the areas of attention, reward processing, and social cognition are then compared between both disorders, as these cognitive abilities show overlapping as well as specific impairment for one of both disorders. In addition, selective brain imaging findings are reported. Therapeutic options are summarized, and new approaches are discussed. The review concludes with a prospectus on open questions for research and clinical practice.     

Diagnosis of bipolar disorders: focus on bipolar disorder I and bipolar disorder II

Bipolar disorders are currently divided into 4 entities: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not otherwise specified, as described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). These subtypes of bipolar disorders cover a spectrum of severities, frequencies, and durations of manic and depressive symptoms. The differential diagnosis among these and with regard to other disorders with similar symptom features remains the foundation for treatment of bipolar disorders. It is clear that much diversity exists within these major subtypes, such that designations like "rapid cycling" and "bipolar III" are being put forward and probed for clinical relevance. Some of the concerns and advantages of including these less-established manifestations of bipolar disorders in our diagnostic thinking are discussed here, and the utility and drawbacks of our current diagnostic protocols are considered.     

Are atypical depression,borderline personality disorder and bipolar II disorder overlapping manifestations of a common cyclothymic diathesis?

The constructs of atypical depression, bipolar II disorder and borderline personality disorder (BPD) overlap. We explored the relationships between these constructs and their temperamental underpinnings. We examined 107 consecutive patients who met DSM-IV criteria for major depressive episode with atypical features. Those who also met the DSM-IV criteria for BPD (BPD+), compared with those who did not (BPD-), had a significantly higher lifetime comorbidity for body dysmorphic disorder, bulimia nervosa, narcissistic, dependent and avoidant personality disorders, and cyclothymia. BPD+ also scored higher on the Atypical Depression Diagnostic Scale items of mood reactivity, interpersonal sensitivity, functional impairment, avoidance of relationships, other rejection avoidance, and on the Hopkins Symptoms Check List obsessive-compulsive, interpersonal sensitivity, anxiety, anger-hostility, paranoid ideation and psychoticism factors. Logistic regression revealed that cyclothymic temperament accounted for much of the relationship between atypical depression and BPD, predicting 6 of 9 of the defining DSM-IV attributes of the latter. Trait mood lability (among BPD patients) and interpersonal sensitivity (among atypical depressive patients) appear to be related as part of an underlying cyclothymic temperamental matrix.     

Rethinking psychosis: the disadvantages of a dichotomous classification now outweigh the advantages

Emil Kraepelin would clearly recognize his 19th century dichotomy within current operational classifications of psychosis. However, he might be surprised at its survival, given the extent to which it has been undermined by the weight of currently available empirical evidence. The failure of this evidence to influence diagnostic practice reflects not only the comfortable simplicity of the dichotomous approach, but also the fact that this approach has for many years continued to receive support from some areas of research, particularly genetic epidemiology. This, however, is changing and findings from genetic epidemiology are being reappraised. More importantly, the potential of molecular genetics to indicate biological systems involved in psychopathology has been recognized, and with it the potential to develop diagnostic classifications that have greater biological validity. Crucially, this will facilitate diagnostic schemes with much greater clinical utility, allowing clinicians to select treatments based on underlying pathogenesis. Recent molecular genetic findings have demonstrated very clearly the inadequacies of the dichotomous view, and highlighted the importance of better classifying cases with both psychotic and affective symptoms. In this article we discuss these issues and suggest ways forward, both immediately and for DSM-V and ICD-11. If psychiatry is to translate the opportunities offered by new research methodologies, we must move to a classificatory approach that is worthy of the 21st century.     

Transdiagnostic dimensions of psychosis in the Bipolar‐Schizophrenia Network on Intermediate Phenotypes (B‐SNIP)

The validity of the classification of non‐affective and affective psychoses as distinct entities has been disputed, but, despite calls for alternative approaches to defining psychosis syndromes, there is a dearth of empirical efforts to identify transdiagnostic phenotypes of psychosis. We aimed to investigate the validity and utility of general and specific symptom dimensions of psychosis cutting across schizophrenia, schizoaffective disorder and bipolar I disorder with psychosis. Multidimensional item‐response modeling was conducted on symptom ratings of the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Montgomery‐Åsberg Depression Rating Scale in the multicentre Bipolar‐Schizophrenia Network on Intermediate Phenotypes (B‐SNIP) consortium, which included 933 patients with a diagnosis of schizophrenia (N=397), schizoaffective disorder (N=224), or bipolar I disorder with psychosis (N=312). A bifactor model with one general symptom dimension, two distinct dimensions of non‐affective and affective psychosis, and five specific symptom dimensions of positive, negative, disorganized, manic and depressive symptoms provided the best model fit. There was further evidence on the utility of symptom dimensions for predicting B‐SNIP psychosis biotypes with greater accuracy than categorical DSM diagnoses. General, positive, negative and disorganized symptom dimension scores were higher in African American vs. Caucasian patients. Symptom dimensions accurately classified patients into categorical DSM diagnoses. This study provides evidence on the validity and utility of transdiagnostic symptom dimensions of psychosis that transcend traditional diagnostic boundaries of psychotic disorders. Findings further show promising avenues for research at the interface of dimensional psychopathological phenotypes and basic neurobiological dimensions of psychopathology.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

Late-life Onset Bipolar Disorder Presenting as a Case of Pseudo-Dementia: A Case Discussion and Review of Literature

Depression and comorbid cognitive impairment in the elderly can be difficult to distinguish from dementia. Adding to the complex differential is that depression may be part of a bipolar illness rather than a unipolar mood disorder. A diligent workup and close monitoring of patients can inform appropriate treatment and can make the difference between recovery and persistence of symptoms. The present case will illustrate how a comprehensive workup utilizing extensive data gathering, laboratory workup, use of neuropsychological testing, neuroimaging, and timely treatment can lead to successful clinical outcomes that can be sustained for many years.     

Delays before Diagnosis and Initiation of Treatment in Patients Presenting to Mental Health Services with Bipolar Disorder

BackgroundBipolar disorder is a significant cause of morbidity and mortality. Although existing treatments are effective, there is often a substantial delay before diagnosis and treatment initiation. We sought to investigate factors associated with the delay before diagnosis of bipolar disorder and the onset of treatment in secondary mental healthcare.MethodRetrospective cohort study using anonymised electronic mental health record data from the South London and Maudsley NHS Foundation Trust (SLaM) Biomedical Research Centre (BRC) Case Register on 1364 adults diagnosed with bipolar disorder between 2007 and 2012. The following predictor variables were analysed in a multivariable Cox regression analysis: age, gender, ethnicity, compulsory admission to hospital under the UK Mental Health Act, marital status and other diagnoses prior to bipolar disorder. The outcomes were time to recorded diagnosis from first presentation to specialist mental health services (the diagnostic delay), and time to the start of appropriate therapy (treatment delay).ResultsThe median diagnostic delay was 62 days (interquartile range: 17–243) and median treatment delay was 31 days (4–122). Compulsory hospital admission was associated with a significant reduction in both diagnostic delay (hazard ratio 2.58, 95% CI 2.18–3.06) and treatment delay (4.40, 3.63–5.62). Prior diagnoses of other psychiatric disorders were associated with increased diagnostic delay, particularly alcohol (0.48, 0.33–0.41) and substance misuse disorders (0.44, 0.31–0.61). Prior diagnosis of schizophrenia and psychotic depression were associated with reduced treatment delay.ConclusionsSome individuals experience a significant delay in diagnosis and treatment of bipolar disorder after initiation of specialist mental healthcare, particularly those who have prior diagnoses of alcohol and substance misuse disorders. These findings highlight a need for further study on strategies to better identify underlying symptoms and offer appropriate treatment sooner in order to facilitate improved clinical outcomes, such as developing specialist early intervention services to identify and treat people with bipolar disorder.     

使用多因素易患性阈值模型评估双相情感障碍的遗传度缺失

为了评估双向情感障碍的遗传度缺失,文章通过查询美国国家人类基因组研究所(National Human Genome Research Institute,NHGRI)的gwascatalog目录,检索出所有已发现的双相情感障碍易感变异,使用多因素易患性阈值模型计算每个易感变异对双相情感障碍遗传度的解释度。将所有易感变异遗传度解释度求和得到双相情感障碍已知易感变异对遗传度的总解释度,使用此总解释度评估双相情感障碍的遗传度缺失。结果显示,已知双相情感障碍易感变异对双相情感障碍遗传度的合计解释度为38.34%,尚有61.66%的遗传度无法被已有易感变异解释,属于遗传度缺失。双相情感障碍38.34%的遗传度解释度较早前国外同类研究大幅度提高,表明随着新的双相情感障碍易感变异被不断发现,双相情感障碍遗传度缺失得到大幅度减小。但双相情感障碍遗传度缺失依然存在且数目较大的事实也表明双相情感障碍尚存在许多未知的分子遗传学机制有待进一步阐明。     

Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset

Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological alterations. This disorder is typically characterized by cyclical and recurrent episodes of mania and depression but is heterogeneous in its clinical presentation and outcome. Although the DSM-IV-TR criteria identify several features that are of phenomenological relevance, these are of less utility for defining homogeneous subgroups, for analyses of correlations with biomarkers or for directing focused medication strategies. We provide a comprehensive review of existing evidence regarding to age at onset in bipolar disorder. Eight admixture studies demonstrate three homogeneous subgroups of patients with bipolar disorder identified according to age at onset (early, intermediate and late age at onset), with two cutoff points, at 21 and 34 years. It is suggested that the early-onset subgroup has specific clinical features and outcomes different from those of the other subgroups. Early-onset subgroup may be considered a more suitable clinical phenotype for the identification of susceptibility genes with recent data demonstrating associations with genetic variants specifically in this subgroup. The use of age at onset as a specifier may also facilitate the identification of other biological markers for use in brain imaging, circadian, inflammatory and cognitive research. A key challenge is posed by the use of age at onset in treatment decision algorithms, although further research is required to increase the evidence-base. We discuss three potential benefits of specifying age at onset, namely: focused medication strategies, the targeted prevention of specific comorbid conditions and decreasing the duration of untreated illness. We argue that age at onset should be included as a specifier for bipolar disorders.     

Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features

Bipolar mixed states combine depressive and manic features, presenting diagnostic and treatment challenges and reflecting a severe form of the illness. DSM-IV criteria for a mixed state require combined depressive and manic syndromes, but a range of mixed states has been described clinically. A unified definition of mixed states would be valuable in understanding their diagnosis, mechanism and treatment implications. We investigated the manner in which depressive and manic features combine to produce a continuum of mixed states. In 88 subjects with bipolar disorder (DSM-IV), we evaluated symptoms and clinical characteristics, and compared depression-based, mania-based, and other published definitions of mixed states. We developed an index of the extent to which symptoms were mixed (Mixed State Index, MSI) and characterized its relationship to clinical state. Predominately manic and depressive mixed states using criteria from recent literature, as well as Kraepelinian mixed states, had similar symptoms and MSI scores. Anxiety correlated significantly with depression scores in manic subjects and with mania scores in depressed subjects. Discriminant function analysis associated mixed states with symptoms of hyperactivity and negative cognitions, but not subjective depressive or elevated mood. High MSI scores were associated with severe course of illness. For depressive or manic episodes, characteristics of mixed states emerged with two symptoms of the opposite polarity. This was a cross-sectional study. Mixed states appear to be a continuum. An index of the degree to which depressive and manic symptoms combine appears useful in identifying and characterizing mixed states. We propose a depressive or manic episode with three or more symptoms of the opposite polarity as a parsimonious definition of a mixed state.     

奥氮平与碳酸锂分别联合丙戊酸钠治疗双相障碍躁狂发作的临床疗效比较

目的：比较奥氮平与碳酸锂分别联合丙戊酸钠治疗双相障碍躁狂发作的临床疗效,探讨提高双相障碍躁狂发作临床疗效的药物治疗方案。方法：选择双相障碍躁狂发作患者90例,随机均分为A组与B组,A组给予奥氮平联合丙戊酸钠治疗,B组给予碳酸锂联合丙戊酸钠治疗,比较两组患者治疗第2周、第4周、第6周躁狂量表（BRMS）评分、副反应量表（TESS）评分和治疗第6周的临床疗效。结果：两组患者在上述方面比较,差异均具有统计学意义（P〈O．05）,A组临床疗效好于B组。结论：药物治疗双相障碍躁狂发作时,应选择奥氮平联合丙戊酸钠治疗方案,可提高临床疗效,减少用药后副反应。     

Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders,bipolar disorder and major depressive disorder: a systematic review and meta‐analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = ?3.6, p = 0.0003, r² = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.     

An empirically derived approach to the classification and diagnosis of mood disorders

This article describes a system for diagnosing mood disorders that is empirically derived and designed for its clinical utility in everyday practice. A ran-dom national sample of psychiatrists and clinical psychologists described a randomly selected current patient with a measure designed for clinically ex-perienced informants, the Mood Disorder Diagnostic Questionnaire (MDDQ), and completed additional research forms. We applied factor analysis to the MDDQ to identify naturally occurring diagnostic groupings within the patient sample. The analysis yielded three clinically distinct mood disorder dimen-sions or spectra, consistent with the major mood disturbances included in the DSM and ICD over successive editions (major depression, dysthymia, and mania), along with a suicide risk index. Diagnostic criteria were determined strictly empirically. Initial data using diagnostic efficiency statistics sup-ported the accuracy of the dimensions in discriminating DSM-IV diagnoses; regression analyses supported the discriminant validity of the MDDQ scales; and correlational analysis demonstrated coherent patterns of association with family history of mood disorders and functional outcomes, supporting va-lidity. Perhaps most importantly, the MDDQ diagnostic scales demonstrated incremental validity in predicting adaptive functioning and psychiatric his-tory over and above DSM-IV diagnosis. The empirically derived syndromes can be used to diagnose mood syndromes dimensionally without complex di-agnostic algorithms or can be combined into diagnostic prototypes that eliminate the need for ever-expanding categories of mood disorders that are clini-cally unwieldy.     

Candidate biomarkers in psychiatric disorders: state of the field

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event-related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting-state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error-related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting-state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well-defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.     

Altered Myelination of the Hippocampal Formation in Subjects with Schizophrenia and Bipolar Disorder

Myelination of the frontal and temporal lobes occurs at a similar time period as symptom onset in schizophrenia. To assess this potential relationship, we compared myelination and oligodendrocyte numbers in the hippocampal formation of controls and matched subjects with schizophrenia and bipolar disorder. The levels and distribution of the myelin marker myelin basic protein (MBP) and the oligodendrocyte marker adenomatous polyposis coli (APC) were measured using immunocytochemistry. MBP immunoreactivity (IR) was increased in several hippocampal subregions of control females versus control males. Female subjects with schizophrenia and bipolar disorder exhibited decreased myelination in the hippocampal formation while male subjects with bipolar disorder showed increased MBP levels in the superior medullary lamina. In contrast, the number of APC immunoreactive cells did not differ in any disorder or region. Our results demonstrate an interaction between gender, mental illness, and myelination, and may be related to cognitive deficits seen in schizophrenia and bipolar disorder.