Genetic linkage in bipolar disorder

Bipolar disorder is an etiologically complex syndrome that is clearly heritable. Multiple genes, working singly or in concert, are likely to cause susceptibility to bipolar disorder. Bipolar disorder genetics has progressed rapidly in the last few decades. However, specific causal genetic mutations for bipolar disorder have not been identified. Both candidate gene studies and complete genome screens have been conducted. They have provided compelling evidence for several potential bipolar disorder susceptibility loci in several regions of the genome. The strongest evidence suggests that bipolar disorder susceptibility loci may lie in one or more genomic regions on chromosomes 18, 4, and 21. Other regions of interest, including those on chromosomes 5 and 8, are also under investigation. New approaches, such as the use of genetically isolated populations and the use of endophenotypes for bipolar disorder, hold promise for continued advancement in the search to identify specific bipolar disorder genes.     

Mood stability versus mood instability in bipolar disorder: a possible role for emotional mental imagery

A cognitive model of bipolar disorder suggests that mental imagery acts as an emotional amplifier of mood and may be heightened in bipolar disorder. First, we tested whether patients with bipolar disorder would score higher on mental imagery measures than a matched healthy control group. Second, we examined differences in imagery between patients divided into groups according to their level of mood stability. Mood ratings over approximately 6-months, made using a mobile phone messaging system, were used to divide patients into stable or unstable groups. Clinician decisions of mood stability were corroborated with statistical analysis. Results showed (I) compared to healthy controls, patients with bipolar disorder had significantly higher scores for general mental imagery use, more vivid imagery of future events, higher levels of intrusive prospective imagery, and more extreme imagery-based interpretation bias; (II) compared to patients with stable mood, patients with unstable mood had higher levels of intrusive prospective imagery, and this correlated highly with their current levels of anxiety and depression. The findings were consistent with predictions. Further investigation of imagery in bipolar disorder appears warranted as it may highlight processes that contribute to mood instability with relevance for cognitive behaviour therapy.     

Identity in bipolar disorder: Self-worth and achievement

This article considers self and self-concept in bipolar disorder. Bipolar disorder, defined on the basis of manic symptoms, is a highly debilitating psychopathology. It is heavily grounded in biology but symptom course is still very responsive to psychological and social forces in the lives of persons who have the disorder. This review assumes an overall view of the self that is typical of personality psychology: self as traits, self as goals and aspirations, and ongoing efforts to attain those goals. In this review, we will discuss two different facets of self and identity in bipolar disorder. First, we review a body of goal pursuit literature suggesting that persons with bipolar disorder endorse heightened ambitions for attaining goals and recognition from others. Second, we will review multiple findings which suggest that among persons with bipolar disorder, self-worth depends on measurable success in an extreme way. We will consider how the intersection of these two themes may lead to unique identity challenges for people with bipolar disorder, drawing from self-report, behavioral, and neuroscience findings to critically examine this viewpoint.     

Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. Previous studies have demonstrated that CGG KI mice have spatiotemporal information processing deficits and impaired visuomotor function that worsen with increasing CGG repeat length. Since skilled forelimb reaching requires integration of information from the visual and motor systems, skilled reaching performance could identify potential visuomotor dysfunction in CGG KI mice. To characterize motor deficits associated with the fragile X premutation, 6 month old female CGG KI mice heterozygous for trinucleotide repeats ranging from 70-200 CGG in length were tested for their ability to learn a skilled forelimb reaching task. The results demonstrate that female CGG KI mice show deficits for learning a skilled forelimb reaching task compared to wildtype littermates, and that these deficits worsen with increasing CGG repeat lengths.     

A comparison of depressed patients with and without borderline personality disorder: implications for interpreting studies of the validity of the bipolar spectrum

The nosological status of borderline personality disorder as it relates to the bipolar disorder spectrum has been controversial. Studies have supported, in part, the validity of the bipolar spectrum by demonstrating that these patients, compared to patients with nonbipolar depression, are characterized by earlier age of onset of depression, recurrent depressive episodes, comorbid anxiety and substance use disorders and increased suicidality. However, all of these factors have likewise been found to distinguish depressed patients with and without borderline personality disorder. A family history of bipolar disorder is one of the few disorder specific validators. In the present study from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we compared the demographic and clinical characteristics of depressed patients with and without borderline personality disorder. We hypothesized that many of the factors used to validate the bipolar spectrum will also distinguish depressed patients with and without borderline personality disorder except, however, a family history of bipolar disorder. Two thousand nine hundred psychiatric outpatients at Rhode Island Hospital were evaluated with the Structured Clinical Interview for DSM-IV (SCID) and Structured Interview for DSM-IV Personality Disorders (SIDP-IV). Family history information regarding first-degree relatives was obtained from the patient using the Family History Research Diagnostic Criteria. One hundred and one patients with borderline personality disorder plus major depressive disorder were compared to 947 patients with major depressive disorder alone on the prevalence of bipolar disorder validators. Compared to depressed patients without borderline personality disorder, depressed patients with borderline personality disorder had a younger age of onset, more depressive episodes, a greater likelihood of experiencing atypical symptoms and had a higher prevalence of comorbid anxiety disorders, substance use disorders, and number of previous suicide attempts. The depressed patients with borderline personality disorder did not significantly differ from the patients without borderline personality disorder on morbid risk for bipolar disorder in first degree relatives. In addition, patients with a diagnosis of bipolar disorder had a significantly higher morbid risk of bipolar disorder in first degree relatives than the borderline personality disorder group. The findings indicate that many factors used to validate the bipolar spectrum are not disorder specific. These results raise questions about studies of the validity of the broad bipolar spectrum that do not assess borderline personality disorder. Our results do not support inclusion of borderline personality disorder as part of the bipolar spectrum.     

Elevated ambitions for fame among persons diagnosed with bipolar I disorder

A growing body of evidence suggests that people with bipolar disorder are highly goal-oriented. Compared to other persons, they expend more effort to attain rewards and view goal pursuit as more important to their self-worth. Persons at risk for mania and those diagnosed with bipolar spectrum disorders have been shown to endorse highly ambitious life goals, such as becoming a multimillionaire or achieving fame. This study is the first examination of whether such elevated goals characterize persons diagnosed with bipolar I disorder. We also examined whether elevated ambitions predicted symptom change over time. Ninety-two persons with bipolar I disorder and 81 age- and sex-matched controls completed the Willingly Approached Set of Statistically Unlikely Pursuits, a measure of extremely high life ambitions. A subset of the bipolar participants completed a 3-month follow-up interview. Participants with bipolar disorder endorsed higher ambitions for popular fame than did controls; moreover, heightened ambitions for popular fame and financial success predicted increases in manic symptoms in those with bipolar disorder over the next three months. Discussion focuses on goal regulation in bipolar disorder.     

Examining the Validity of Cyclothymic Disorder in a Youth Sample: Replication and Extension

DSM-IV-TR defines four subtypes of bipolar disorder (BP): bipolar I, bipolar II, cyclothymic disorder and bipolar not otherwise specified (NOS). However, cyclothymic disorder in children is rarely researched, or often subsumed in an “NOS” category. The present study tests the replicability of findings from an earlier study, and expands on the criterion validity of cyclothymic disorder in youth. Using the Robins and Guze (1970) framework we examined the validity of cyclothymic disorder as a subtype of BP. Using a youth (ages 5–17) outpatient clinical sample (N?=?894), participants with cyclothymic disorder (n?=?53) were compared to participants with other BP spectrum disorders (n?=?399) and to participants with non-bipolar disorders (n?=?442). Analyses tested differences in youth with cyclothymic disorder and bipolar disorder not otherwise specified who do, and those who do not, have a parent with BP. Compared to youth with non-bipolar disorders, youth with cyclothymic disorder had higher irritability (p?<?0.001), more comorbidity (p?<?0.001), greater sleep disturbance (p?<?0.005), and were more likely to have a family history of BP (p?<?0.001). Cyclothymic disorder was associated with a younger age of onset compared to depression (p?<?0.001) and bipolar II (p?=?0.05). Parental BP status was not significantly associated with any variables. Results support that cyclothymic disorder belongs on the bipolar spectrum. Epidemiological studies indicate that cyclothymic disorder is not uncommon and involves significant impairment. Failing to differentiate between cyclothymic disorder and bipolar NOS limits our knowledge about a significant proportion of cases of bipolarity.     

New anticonvulsant medication uses in bipolar disorder

Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.     

Cognitive Insight in Inpatients with Psychotic, Bipolar, and Major Depressive Disorders

The Beck Cognitive Insight Scale (BCIS; Beck, Baruch, Balter, Steer, & Warman, 2004) was administered to 42 (28%) inpatients with psychotic disorders, 52 (35%) with a bipolar disorder, and 56 (37%) with a major depressive disorder (MDD). The hypotheses were (a) that the mean level of cognitive insight in a psychotic or a bipolar disorder is lower than that in a MDD, (b) that the mean levels of cognitive insight in psychotic and bipolar disorders were comparable, and (c) that the mean BCIS index score for a bipolar disorder in which the most recent episode had been mania is lower than the mean BCIS index score for a bipolar disorder in which the most recent episode had been mixed or depressed. All three hypotheses were supported. The results were discussed as supporting cognitive insight as a psychological construct that varies predictably according to the nature of a psychiatric disorder.     

Brain network dysfunction in bipolar disorder

Bipolar disorder is a common psychiatric condition with significant associated morbidity and mortality. Despite its significance, the neurophysiology and neuropathology of this illness is incompletely understood. Recent advances in neuroimaging techniques have helped to begin clarifying these areas. Specifically, bipolar disorder appears to arise from abnormalities within discrete brain networks (eg, the anterior limbic network). The expression of the symptoms of bipolar disorder does not appear to result from single, localized brain lesions, but rather are emergent properties of dysfunction of these brain networks. As neuroimaging techniques continue to improve, the underlying neural basis of bipolar disorder will be clarified.     

Assessing the specificity of autobiographical memory in individuals at a trait-based vulnerability to bipolar disorder using a sentence completion task

Overgeneral autobiographical memory recall has been associated with the diagnosis of bipolar disorder, but the role of overgenerality in the vulnerability to bipolar disorder remains under-researched. While a previous study suggested that high-risk individuals for bipolar disorder recall emotionally negative memories in specific detail, this is in contrast to memory recall patterns noted in bipolar samples. The Autobiographical Memory Test (AMT) used in previous non-clinical studies has also been criticised for not being sensitive to overgenerality due to its repetition of specificity instructions and practice trials. The traditional AMT format may allow some individuals to override their trait-based tendencies to be overgeneral. The current study used a sentence completion task to assess memory specificity in groups of students at a low and high trait-based vulnerability for bipolar disorder. In contrast to previous research, high-risk individuals recalled fewer specific positive memories and greater numbers of overgeneral negative memories than low-risk individuals. These results support the notion that the vulnerability for bipolar disorder might be associated with similar recall biases as demonstrated in bipolar samples, and that the AMT might not be sufficiently sensitive to detect overgenerality in non-clinical groups. The implications of these findings and directions for future research are discussed.     

The hoarding dimension of OCD: psychological comorbidity and the five-factor personality model

Although hoarding has been associated with several psychological disorders, it is most frequently linked to obsessive-compulsive disorder (OCD). The present study assessed hoarding obsessions and compulsions in 204 individuals with OCD, and evaluated how hoarding was related to obsessive-compulsive symptom severity, psychological comorbidity, and personality as measured by the five-factor model. Results indicated that hoarding in OCD is a dimensional variable that is positively associated with dysphoria, total number of lifetime Axis I disorders, and lifetime histories of bipolar I, PTSD, and body dysmorphic disorder. Hoarding was negatively correlated with the NEO-Personality Inventory-Revised (NEO-PI-R) factor of Conscientiousness and positively associated with the NEO-PI-R factor of Neuroticism. When all personality and psychopathology variables were entered into a regression equation, dysphoria, bipolar II disorder, Conscientiousness, age, and Extraversion emerged as significant predictors of hoarding severity. Recommendations are made for clinicians and for future research.     

Stressful life events, bipolar disorder, and the "kindling model"

A common misconception is that bipolar disorder is an endogenous process. However, previous research suggests a role for life events in the onset of and recovery from bipolar episodes. Yet, there remains some question as to whether the relationship between life events and onset changes over the course of the disorder as a result of the number of episodes an individual has experienced. Using a rigorous interview measure of stressful life events, the current study tested the kindling model (R. M. Post, 1992), which theorizes that major life events play a diminishing role over the course of illness in bipolar patients. Analyses revealed that the number of episodes experienced does not appear to have a significant effect on bipolar 1 patients' reactivity to external stressors. In addition, the results suggest that a more complex relationship exists among age, stress, and onset of new episodes than can be adequately explained by the kindling model.     

Reactivity to a laboratory stressor among individuals with bipolar I disorder in full or partial remission

Strong links have been documented between life events and the course of bipolar disorder. Laboratory studies of stress provide an opportunity to understand the mechanisms involved in reactivity to stressors, but few such studies have been done in the bipolar field. In the current study, 28 people with bipolar I disorder in full or partial remission and 40 people with no history of a mood disorder were randomly assigned to 1 of 3 conditions involving different levels of failure feedback on a concept formation task. Confidence, affective reactions, and performance on a subsequent anagram task were assessed. Results provide tentative support for reactivity to the stressor among the bipolar group, although reactivity was limited to impaired anagram performance.     

Functional magnetic resonance imaging studies in bipolar disorder

Abnormalities in brain activation using functional magnetic resonance imaging (fMRI) during cognitive and emotional tasks have been identified in bipolar disorder patients, in frontal, subcortical and limbic regions. Several studies also indicate that mood state may be differentiated by lateralization of brain activation in fronto-limbic regions. The interpretation of fMRI studies in bipolar disorder is limited by the choice of regions of interest, medication effects, comorbidity, and task performance. These studies suggest that there is a complex alteration in regions important for neural networks underlying cognition and emotional processing in bipolar disorder. However, measuring changes in specific brain regions does not identify how these neural networks are affected. New analytical techniques of fMRI data are needed in order to resolve some of these issues and identify how changes in neural networks relate to cognitive and emotional processing in bipolar disorder.     

双相障碍及其社会-心理治疗的研究现状

双相障碍是以起伏性躁狂或抑郁为特征的慢性周期性精神疾病。近年来,社会-心理疗法作为药物治疗的辅助手段被引入到该类疾病的治疗过程中。本文基于近期关于双相障碍的病因学的研究,评述了各种不同形式的社会-心理疗法在双相障碍治疗中的应用及其疗效,指出今后的研究需要进行严格的临床设计,以保证不同研究间的可比性和可重复性;应尽可能延长追踪观察的时间,并进行大样本多变量研究,以保证研究结果的普遍性。     

The "good enough" mood stabilizer: a review of the clinical evidence

A growing family of medications is used for mood stabilization in bipolar disorder. These medications fall into two broad categories according to likely mechanisms of action. Within the categories, specific drugs may vary in their efficacy for different phases of the disorder. The first category, including lithium, anticonvulsants, and some novel treatments, appears to have mechanisms related to intracellular second messengers. These medications have more pronounced antimanic than antidepressant effects, except for lamotrigine, which has antidepressant effects without precipitating mania. The second group of mood stabilizers is the atypical antipsychotics, which act through dopamine and other monoamines. Olanzapine and in all likelihood other drugs in the class possess marked, acute antimanic properties and possible antidepressant properties, but require further study before they can be used as routine options in long-term care. It is clear that the advent of multiple mood stabilizer candidates has not yet led to a single ideal therapy for bipolar disorder, but rather to options that can be flexibly tailored to the lifetime needs of individual patients, in sequences or combinations, and perhaps in conjunction with other classes of psychotropics.     

Mental imagery as an emotional amplifier: application to bipolar disorder

Cognitions in the form of mental images have a more powerful impact on emotion than their verbal counterparts. This review synthesizes the cognitive science of imagery and emotion with transdiagnostic clinical research, yielding novel predictions for the basis of emotional volatility in bipolar disorder. Anxiety is extremely common in patients with bipolar disorder and is associated with increased dysfunction and suicidality, yet it is poorly understood and rarely treated. Mental imagery is a neglected aspect of bipolar anxiety although in anxiety disorders such as posttraumatic stress disorder and social phobia focusing on imagery has been crucial for the development of cognitive behavior therapy (CBT).In this review we present a cognitive model of imagery and emotion applied to bipolar disorder. Within this model mental imagery amplifies emotion, drawing on Clark's cyclical panic model [(1986). A cognitive approach to panic. Behaviour Research and Therapy, 24, 461–470]. We (1) emphasise imagery's amplification of anxiety (cycle one); (2) suggest that imagery amplifies the defining (hypo-) mania of bipolar disorder (cycle two), whereby the overly positive misinterpretation of triggers leads to mood elevation (escalated by imagery), increasing associated beliefs, goals, and action likelihood (all strengthened by imagery).Imagery suggests a unifying explanation for key unexplained features of bipolar disorder: ubiquitous anxiety, mood instability and creativity. Introducing imagery has novel implications for bipolar treatment innovation - an area where CBT improvements are much-needed.     

Responsiveness to Threat and Incentive in Bipolar Disorder: Relations of the BIS/BAS Scales with Symptoms

Over the past 10 years, theorists have suggested that bipolar disorder symptoms result from increases and decreases in the activity of the Behavioral Activation or Facilitation System (BAS or BFS) and the Behavioral Inhibition System (BIS). These neurobehavioral systems are thought to determine the intensity of affective and behavioral responses to incentives and threats. This study examined cross-sectional and prospective associations of self-reported BIS and BAS with mania and depression in a sample of 59 individuals diagnosed with Bipolar I disorder. Depression was tied to BIS, pointing to the importance of sensitivity to threats in depression. However, links between BIS and depression appeared state-dependent. BAS subscales did not correlate with manic symptoms in a state-dependent manner; however, BAS (total scale and reward responsiveness subscale) predicted relative intensification of manic symptoms over time. Thus, evidence suggests that BAS sensitivity may constitute a vulnerability to mania among persons diagnosed with bipolar disorder. Discussion focuses on the integrative potential of the BIS/BAS constructs for linking psychosocial and biological research on bipolar disorder.     

Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia?

Does narcolepsy, a neurological disease, need to be considered when diagnosing major mental illness? Clinicians have reported cases of narcolepsy with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective disorder). The role of narcolepsy in psychiatric patients has remained obscure and problematic, and it may be more prevalent than commonly believed. Classical narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since 1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the understanding of narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine, with resultant suppression of sleep. They also project to basal forebrain areas and cortex. A literature review regarding the differential diagnosis of narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it is now possible to rule out classical narcolepsy in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy will likely require stimulants to fully recover. Many conventional antipsychotic drugs would worsen their symptoms and make them appear to become a "chronic psychotic," while in fact they can now be properly diagnosed and treated.