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Objective: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as “Europe”) have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs).Methods: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors.Results: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe.Conclusions: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study.

Background Depending on the classification system used, 5–40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. Methods Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. Results Mean age of participants was 40 ± 12 years (range 18–81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic Conclusion Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.

Objective Bipolar disorder has a wide range of clinical manifestations which may progress over time. The aim of this study was to test the applicability of a clinical staging model for bipolar disorder and to gain insight into the nature of the variables influencing progression through consecutive stages. Methods Using retrospectively reported longitudinal life chart data of 99 subjects from the Stanley Foundation Bipolar Network Naturalistic Follow-up Study, the occurrence, duration and timely sequence of stages 2-4 were determined per month. A multi-state model was used to calculate progression rates and identify determinants of illness progression. Stages 0, 1 and several other variables were added to the multi-state model to determine their influence on the progression rates. Results Five years after onset of BD (stage 2), 72% reached stage 3 (recurrent episodes) and 21% had reached stage 4 (continuous episodes), of whom 8% recovered back to stage 3. The progression from stage 2 to 3 was increased by a biphasic onset for both the depression-mania and the mania-depression course and by male sex. Conclusions Staging is a useful model to determine illness progression in longitudinal life chart data. Variables influencing transition rates were successfully identified.

Background The Stanley Foundation Bipolar Treatment Outcome Network (SFBN) recruited more than 900 outpatients from 1995 to 2002 from 4 sites in the United States (US) and 3 in the Netherlands and Germany (abbreviated as Europe). When funding was discontinued, the international group of investigators continued to work together as the Bipolar Collaborative Network (BCN), publishing so far 87 peer-reviewed manuscripts. On the 25th year anniversary of its founding, publication of a brief summary of some of the major findings appeared appropriate. Important insights into the course and treatment of adult outpatients with bipolar disorder were revealed and some methodological issues and lessons learned will be discussed. Results The illness is recurrent and pernicious and difficult to bring to a long-term remission. Virtually all aspects of the illness were more prevalent in the US compared to Europe. This included vastly more patients with early onset illness and those with more psychosocial adversity in childhood; more genetic vulnerability; more anxiety and substance abuse comorbidity; more episodes and rapid cycling; and more treatment non-responsiveness. Conclusions The findings provide a road map for a new round of much needed clinical treatment research studies. They also emphasize the need for the formation of a new network focusing on child and youth onset of mood disorders with a goal to achieve early precision diagnostics for intervention and prevention in attempting to make the course of bipolar illness more benign.

Visual processing abnormalities in schizophrenia (SZ) are poorly understood, yet predict functional outcomes in the disorder. Bipolar disorder (BD) may involve similar visual processing deficits. Converging evidence suggests that visual processing may be relatively normal at early stages of visual processing such as early visual cortex (EVC), but that processing abnormalities may become more pronounced by mid-level visual areas such as lateral occipital cortex (LO). However, little is known about the connectivity of the visual system in SZ and BD. If the flow of information to, from, or within the visual system is disrupted by reduced connectivity, this could help to explain perceptual deficits. In the present study, we performed a targeted analysis of the structural and functional connectivity of the visual system using graph-theoretic metrics in a sample of 48 SZ, 46 BD, and 47 control participants. Specifically, we calculated parallel measures of local efficiency for EVC and LO from both diffusion weighted imaging data (structural) and resting-state (functional) imaging data. We found no structural connectivity differences between the groups. However, there was a significant group difference in functional connectivity and a significant group-by-region interaction driven by reduced LO connectivity in SZ relative to HC, whereas BD was approximately intermediate to the other 2 groups. We replicated this pattern of results using a different brain atlas. These findings support and extend theoretical models of perceptual dysfunction in SZ, providing a framework for further investigation of visual deficits linked to functional outcomes in SZ and related disorders.

Introduction There is a high incidence of Axis II personality disorders (PDs) in patients with bipolar illness, but their influence on the prospectively measured course of bipolar disorder has been less well explicated.Methods 392 outpatients with bipolar disorder gave informed consent, completed the PDQ4 99 item personality disorder rating, and where clinically rated during at least one year of prospective naturalistic treatment. They were classified as Well on admission (N = 64) or Responders (N = 146) or Non-responders (N = 182) to treatment for at least six months.Results Patients who were positive for PDs were very infrequently represented in the category of Well on admission. In addition, patients with borderline, depressive, and schizoid PDs were significantly more likely to be Non-responders compared to Responders upon prospective naturalistic treatment in the network.Conclusions Patients with bipolar disorder and comorbid PDs were in general less likely to be Well from treatment in the community at network entry or to be a Responder to prospective treatment in the network. Therapeutic approaches to patients with PDs deserve specific study in an attempt to achieve a better long-term course of bipolar disorder.

IntroductionInstead of the typical assessment of risk of illness in the offspring based on a parent with bipolar disorder, we explored the potential multigenerational conveyance across several disorders of the vulnerability to illness in the offspring of a patient with bipolar disorder.MethodsA total of 968 outpatients (average age 41 years) with bipolar illness gave informed consent and filled out a detailed questionnaire about a family history in their parents, grandparents, and offspring of: depression; bipolar disorder; alcohol abuse; substance abuse; suicide attempt; or other illness. Of those with children, 346 were from the USA and 132 were from Europe. Amount and type of illness in progenitors in two and three previous generations were related to offspring illness.ResultsThe type of illness seen in both prior generations was associated with the same type of illness in the offspring of a bipolar patient, including depression, bipolar disorder, alcohol and substance abuse and other illness, but not suicide attempts. There was an impact of multiple generations, such that depression in grandparents and/or great-grandparents increased the risk of depression in the offspring from 12.6% to 41.4%.ConclusionsA family history of illness burden in prior generations was previously related to an earlier age of onset of bipolar illness in our adult patients with bipolar disorder and is now also found to be related to the incidence of multiple psychiatric illnesses in their offspring. Genetic and epigenetic mechanisms deserve consideration for this multigenerational conveyance of illness vulnerability, and clinical and public health attempts to prevent or slow this transmission are indicated.

Objectives A high incidence of Axis II personality disorders is described in patients with bipolar disorder; however, their relationship to mood state remains uncertain. Methods A total of 966 outpatients with bipolar disorder gave informed consent and filled out the Personality Disorder Questionnaire, 4th edition (PDQ4) and a questionnaire on demographics and course of illness prior to Bipolar Treatment Outcome Network entry at average age 41 years. Patients were rated at each visit for depression on the Inventory of Depressive Symptoms-Clinician version (IDS-C) and for mania on the Young Mania Rating Scale (YMRS). In a subgroup, the PDQ4 was retaken during periods of depression and euthymia. Results Patients met criteria for most personality disorders at a much higher rate when they took the PDQ4 while depressed compared to while euthymic, and scores were significantly related to the severity of depression (IDS) and of mania (YMRS) assessed within 2 weeks of taking the PDQ. Even when euthymic, more than quarter to half of the patients met criteria for a cluster A, B or C personality disorder. Conclusions A wide range of personality disorders occur in bipolar patients, but are highly dependent on filling out the form while depressed compared to while euthymic. How this relates to having a personality disorder assessed using a structured clinical interview remains to be tested. However, higher PDQ4 scores are related to an earlier age of onset of bipolar disorder and other factors portending a more difficult course of bipolar disorder, and the optimal treatment of these patients remains to be illuminated.

Background: Although bipolar disorder (BD) and borderline personality disorder (BPD) share clinical characteristics and frequently co-occur, their interrelationship is controversial. Especially, the differentiation of rapid cycling BD and BPD can be troublesome. This study investigates the relationship between borderline personality features (BPF) and prospective illness course in patients with BD, and explores the effects of current mood state on self-reported BPF profiles.Methods: The study included 375 patients who participated in the former Stanley Foundation Bipolar Network. All patients met DSM-IV criteria for bipolar-I disorder (n = 294), bipolar-II disorder (n = 72) or bipolar disorder NOS (n = 9). BPF were assessed with the self-rated Personality Diagnostic Questionnaire. Illness course was based on 1-year clinician rated prospective daily mood ratings with the life chart methodology. Regression analyses were used to estimate the relationships among these variables.Results: Although correlations were weak, results showed that having more BPF at baseline is associated with a higher episode frequency during subsequent 1-year follow-up. Of the nine BPF, affective instability, impulsivity, and self-mutilation/suicidality showed a relationship to full-duration as well as brief episode frequency. In contrast all other BPF were not related to episode frequency.Conclusions: Having more BPF was associated with an unfavorable illness course of BD. Affective instability, impulsivity, and self-mutilation/suicidality are associated with both rapid cycling BD and BPD. Still, many core features of BPD show no relationship to rapid cycling BD and can help in the differential diagnosis.

The authors compared medication-induced mood switch risk (primary outcome), as well as treatment response and side effects (secondary outcomes) with three acute-phase treatments for bipolar II depression.In a 16-week, double-blind, multisite comparison study, 142 participants with bipolar II depression were randomly assigned to receive lithium monotherapy (N=49), sertraline monotherapy (N=45), or combination treatment with lithium and sertraline (N=48). At each visit, mood was assessed using standardized rating scales. Rates of switch were compared, as were rates of treatment response and the presence and severity of treatment-emergent side effects.Twenty participants (14%) experienced a switch during the study period (hypomania, N=17; severe hypomania, N=3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N=89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response.Lithium monotherapy, sertraline monotherapy, and lithium/sertraline combination therapy were associated with similar switch and treatment response rates in participants with bipolar II depression. The dropout rate was higher in the lithium/sertraline combination treatment group, without any treatment acceleration advantage.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SZ) show substantial overlap. It has been suggested that a subgroup of patients might contribute to these overlapping features. This study employed a cross-diagnostic cluster analysis to identify subgroups of individuals with shared cognitive phenotypes. METHOD: 143 participants (68 BD patients, 39 SZ patients and 36 healthy controls) completed a battery of EEG and performance assessments on perception, nonsocial cognition and social cognition. A K-means cluster analysis was conducted with all participants across diagnostic groups. Clinical symptoms, functional capacity, and functional outcome were assessed in patients. RESULTS: A two-cluster solution across 3 groups was the most stable. One cluster including 44 BD patients, 31 controls and 5 SZ patients showed better cognition (High cluster) than the other cluster with 24 BD patients, 35 SZ patients and 5 controls (Low cluster). BD patients in the High cluster performed better than BD patients in the Low cluster across cognitive domains. Within each cluster, participants with different clinical diagnoses showed different profiles across cognitive domains. LIMITATIONS: All patients are in the chronic phase and out of mood episode at the time of assessment and most of the assessment were behavioral measures. CONCLUSIONS: This study identified two clusters with shared cognitive phenotype profiles that were not proxies for clinical diagnoses. The finding of better social cognitive performance of BD patients than SZ patients in the Lowe cluster suggest that relatively preserved social cognition may be important to identify disease process distinct to each disorder.

Background: Patients with bipolar disorder from the US have more early-onset illness and a greater familial loading for psychiatric problems than those from the Netherlands or Germany (abbreviated here as Europe). We hypothesized that these regional differences in illness burden would extend to the patients siblings.Methods: Outpatients with bipolar disorder gave consent for participation in a treatment outcome network and for filling out detailed questionnaires. This included a family history of unipolar depression, bipolar disorder, suicide attempt, alcohol abuse/dependence, drug abuse/dependence, and "other" illness elicited for the patients' grandparents, parents, spouses, offspring, and siblings. Problems in the siblings were examined as a function of parental and grandparental problems and the patients' adverse illness characteristics or poor prognosis factors (PPFs).Results: Each problem in the siblings was significantly (p Limitations: Family history was based on patient report.Conclusions: Increased familial loading for psychiatric problems extends through 4 generations of patients with bipolar disorder from the US compared to Europe, and appears to "breed true" into the siblings of the patients. In addition to early onset, a variety of PPFs are associated with the burden of psychiatric problems in the patients' siblings and offspring. Greater attention to the multigenerational prevalence of illness in patients from the US is indicated.

Functional magnetic resonance imaging (fMRI) adaptation (also known as fMRI repetition suppression) has been widely used to characterize stimulus selectivity in vivo, a fundamental feature of neuronal processing in the brain. We investigated whether SZ patients and BD patients show aberrant fMRI adaptation for object perception. About 52 SZ patients, 55 BD patients, and 53 community controls completed an object discrimination task with three conditions: the same object presented twice, two exemplars from the same category, and two exemplars from different categories. We also administered two functional localizer tasks. A region of interest analysis was employed to evaluate a priori hypotheses about the lateral occipital complex (LOC) and early visual cortex (EVC). An exploratory whole brain analysis was also conducted. In the LOC and EVC, controls showed the expected reduced fMRI responses to repeated presentation of the same objects compared with different objects (i.e., fMRI adaptation for objects, p

OBJECTIVE: Given that a cohort effect is rarely mentioned as one of the possible contributors to the increased incidence of childhood-onset bipolar disorder in the United States, we reexamined evidence for the phenomenon within our outpatient Bipolar Collaborative Network.METHODS: 968 outpatients (mean age, 41 years) with DSM bipolar disorder from 1995 to 2002 from 4 sites in the United States and 3 in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic, illness, and family history information on a patient questionnaire. Family history of bipolar disorder, depression, suicide attempt, alcohol abuse, substance abuse, and "other" illness was collected for each parent and the 4 grandparents. Age at onset and family history of illness burden were then assessed as a function of the age of the patient at network entry.RESULTS: Data for patients aged 35 years or older (n = 613) were included in the first analysis. Compared to older patients, those who were younger when they entered the network had an earlier age at onset of their bipolar disorder (r = 0.33, P < .001). Similarly, the youngest patients at entry (representing the most recent cohorts) had parents and grandparents with more psychiatric illness than patients born in earlier cohorts (n = 968).CONCLUSIONS: These preliminary data, taken with the substantial literature, suggest a cohort effect for earlier age at onset of bipolar disorder and greater burden of psychiatric disorders in 2 generations of direct progenitors of our patients. The resulting likely increase in severity of bipolar illness in future generations based on this earlier age at onset and increased familial loading, particularly in the United States, deserves focused clinical and public health attention and attempts at amelioration.

Objective: To report use and treatment success rates of medications for bipolar disorder as a function of patients' clinical characteristics.Method: Outpatients with bipolar illness diagnosed by SCID were rated by research assistants on the NIMH-LCM and those who had an good response for at least 6 months (much or very much improved on the CGI-BP) were considered responders (treatment "success"). Clinical characteristics associated with treatment response in the literature were examined for how often a drug was in a successful regimen when a given characteristic was either present or absent.Results: Lithium was less successful in those with histories of rapid cycling, substance abuse, or (surprisingly) a positive parental history of mood disorders. Valproate was less successful in those with >= 20 prior episodes. Lamotrigine (LTG) was less successful in those with a parental history of mood disorders or in BP-I compared to BP-II disorder. Antidepressants (ADs) had low success rates, especially in those with a history of anxiety disorders. Benzodiazepines had low success rates in those with child abuse, substance use, or >= 20 episodes. Atypical antipsychotics were less successful in the presence of rapid cycling, >= 20 prior episodes, or a greater number of poor prognosis factors.Conclusion: Success rates reflect medications used in combination with an average of two other drugs during naturalistic treatment and thus should be considered exploratory. However, the low long-term success rates of drugs (even when used in combination with others) that occurred in the presence of many very common clinical characteristics of bipolar illness speak to the need for the development of alternative treatment strategies. (C) 2016 Elsevier Inc. All rights reserved.

Background Evidence is emerging that early onset bipolar disorder and the duration of the delay to first treatment are both risk factors for poor treatment outcome. We report on the incidence and implications of these two risk factors in patients from the United States (US) versus Europe. Methods Age of onset and age at first treatment for depression or mania was assessed in 967 outpatients with bipolar disorder who gave informed consent for participation and filling out a detailed questionnaire. Age at onset and treatment delay were compared in the 675 patients from the US and 292 from the Netherlands and Germany (abbreviated as Europe). Both were then graphed and analyzed. Results Age of onset of bipolar disorder was earlier in the US than in Europeans by an average of 6–7 years with similar results in those with first onsets of depression or of mania. Delay to first treatment was strongly inversely related to age of onset and was twice as long in the US than in Europe, and especially different for mania in adolescents. The longer delay to treatment in the US was not solely due to earlier age of onset. Conclusions Treatment delay is a remedial risk factor and could be shortened with better recognition of the higher incidence of early onset bipolar disorder in the US, which also associated with more genetic and environmental vulnerability factors compared to Europe. New treatment and research initiatives are needed to address these liabilities so that children with bipolar achieve more positive long-term outcomes.

The effect of assortative mating on offspring is often not considered. Here, we present data on illness in the spouse and the parents of patients with bipolar disorder as they affect illness in the offspring. A history of psychiatric illness (depression, bipolar disorder, suicide attempt, alcohol abuse, drug abuse, and “other” illness) was elicited for the parents, spouse, and the offspring of 968 patients with bipolar disorder (540 of whom had children) who gave informed consent for participation in a treatment outcome network. Assortative mating for a mood disorder in the spouse and parents in those from the United States (US) was compared to those from the Netherlands and Germany and related to illnesses in the offspring. There was more illness and assortative mating for a mood disorder in both the spouse and patient’s parents from the US compared to Europe. In the parents of the US patients, assortative mating for a mood disorder was associated with more depression, bipolar disorder, alcohol, and “other” illness in the offspring. Compared to the Europeans, there was more assortative mating for mood and other disorders in two generations of those from the US. This bilineal positivity for a parental mood disorder was related to more depression a second generation later in the patients’ offspring. In clinical assessment of risk of illness in the offspring, the history of psychiatric illness in the spouse and patient’s parents might provide additional information.

Objectives: Connectomics have allowed researchers to study integrative patterns of neural connectivity in humans. Yet, it is unclear how connectomics may elucidate structureefunction relationships in bipolar I disorder (BPI). Expanding on our previous structural connectome study, here we used an overlapping sample with additional psychometric and fMRI data to relate structural connectome properties to both fMRI signals and cognitive performance. Methods: 42 subjects completed a neuropsychological (NP) battery covering domains of processing speed, verbal memory, working memory, and cognitive flexibility. 32 subjects also had fMRI data performing a Go/NoGo task. Results: Bipolar participants had lower NP performance across all domains, but only working memory reached statistical significance. In BPI participants, processing speed was significantly associated with both white matter integrity (WMI) in the corpus callosum and interhemispheric network integration. Mediation models further revealed that the relationship between interhemispheric integration and processing speed was mediated by WMI, and processing speed mediated the relationship between WMI and working memory. Bipolar subjects had significantly decreased BA47 activation during NoGo vs. Go. Significant predictors of BA47 fMRI activations during the Go/NoGo task were its nodal path length (left hemisphere) and its nodal clustering coefficient (right hemisphere). Conclusions: This study suggests that structural connectome changes underlie abnormalities in fMRI activation and cognitive performance in euthymic BPI subjects. Results support that BA47 structural connectome changes may be a trait marker for BPI. Future studies are needed to determine if these “connectome signatures” may also confer a biological risk and/or serve as predictors of relapse.

ObjectivesPhysical or sexual abuse in childhood is known to have an adverse effect on the course of bipolar disorder, but the impact of verbal abuse has not been well elucidated.MethodsWe examined the occurrence and frequency (never to frequently) of each type of abuse in childhood in 634 US adult outpatients (average age 40years). Patients gave informed consent and provided information about their age of onset and course of illness prior to study entry.ResultsVerbal abuse alone occurred in 24% of the patients. Similar to a history of physical or sexual abuse, a history of verbal abuse was related to an earlier age of onset of bipolar disorder and other poor prognosis characteristics, including anxiety and substance abuse comorbidity, rapid cycling, and a deteriorating illness course as reflected in ratings of increasing frequency or severity of mania and depression.ConclusionsA lasting adverse impact of the experience of verbal abuse in childhood is suggested by its relationship to an earlier age of onset of bipolar disorder, other poor prognosis factors, and a deteriorating course of illness. Verbal abuse is a common confound in comparison groups defined by a lack of physical or sexual abuse. Ameliorating the impact of verbal abuse on the unfolding course of bipolar disorder appears to be an important target of therapeutics and worthy of attempts at primary and secondary prophylaxis. Family-based treatments that focus on psychoeducation, enhancing intra-family communication, and coping skills may be particularly helpful.

Objective:The study addressed whether a collaborative model for chronic care, described in part I (this issue), improves outcome for bipolar disorder.Methods:The intervention was designed to improve outcome by enhancing patient self-management skills with group psychoeducation; providing clinician decision support with simplified practice guidelines; and improving access to care, continuity of care, and information flow via nurse care coordinators. In an effectiveness design veterans with bipolar disorder at 11 Veterans Affairs hospitals were randomly assigned to three years of care in the intervention or continued usual care. Blinded clinical and functional measures were obtained every eight weeks. Intention-to-treat analysis (N=306) with mixed-effects models addressed the hypothesis that improvements would accrue over three years, consistent with social learning theory.Results:The intervention significantly reduced weeks in affective episode, primarily mania. Broad-based improvements were demonstrated i...

The authors assessed how family history loading affected the course of illness in patients from the United States. A total of 676 outpatients with bipolar disorder from the United States rated their illness and provided a parental and grandparental history of mood disorder, substance abuse, and other clinical conditions. A positive family history for each illness was associated with almost all of the seven poor prognosis factors established in the study (abuse in childhood, early onset, anxiety and substance abuse comorbidity, rapid cycling, multiple episodes, and worsening of severity or frequency of episodes). Family history for psychiatric difficulties in parents and grandparents was associated with a more complex and difficult course of bipolar illness.

Introduction Deficits in visual perception are well-established in schizophrenia and are linked to abnormal activity in the lateral occipital complex (LOC). Related deficits may exist in bipolar disorder. LOC contains neurons tuned to object features. It is unknown whether neural tuning in LOC or other visual areas is abnormal in patients, contributing to abnormal perception during visual tasks. This study used multivariate pattern analysis (MVPA) to investigate perceptual tuning for objects in schizophrenia and bipolar disorder. Methods Fifty schizophrenia participants, 51 bipolar disorder participants, and 47 matched healthy controls completed five functional magnetic resonance imaging (fMRI) runs of a perceptual task in which they viewed pictures of four different objects and an outdoor scene. We performed classification analyses designed to assess the distinctiveness of activity corresponding to perception of each stimulus in LOC (a functionally localized region of interest). We also performed similar classification analyses throughout the brain using a searchlight technique. We compared classification accuracy and patterns of classification errors across groups. Results Stimulus classification accuracy was significantly above chance in all groups in LOC and throughout visual cortex. Classification errors were mostly within-category confusions (e.g., misclassifying one chair as another chair). There were no group differences in classification accuracy or patterns of confusion. Conclusions The results show for the first time MVPA can be used successfully to classify individual perceptual stimuli in schizophrenia and bipolar disorder. However, the results do not provide evidence of abnormal neural tuning in schizophrenia and bipolar disorder., Highlights • Abnormal visual perception exists in schizophrenia and, likely, bipolar disorder • Neural processing abnormalities underlying those deficits are not well understood • We used multivariate analyses of fMRI data to assess patients' visual processing • We establish for the first time that such methods work well in these patient groups • The analyses did not show group differences in neural processing of visual stimuli

OBJECTIVE: The authors reviewed the published literature on the acute and long-term neurobehavioral effects on infants and children of either in utero exposure to maternal depression or in utero exposure to antidepressants. DATA SOURCES: The PubMed electronic database was searched to locate 292 English-language studies from the first available year to October 2013 using the keywords pregnancy, antidepressants, depression, perinatal, and neurobehavioral. STUDY SELECTION: The authors reviewed only prospective studies that assessed the impact of maternal depression during pregnancy or maternal antidepressant treatment during pregnancy on (1) clearly defined short-term behavioral outcomes in infants (perinatal outcome) or (2) longer-term behavioral outcomes in infants and children (neurodevelopmental outcome). DATA EXTRACTION: Studies were included if they were prospective and assessed the impact of maternal depression or maternal antidepressant treatment during pregnancy on clearly measurable, objective short-term and longer-term behavioral outcomes in infants and children. RESULTS: Untreated depression during pregnancy is associated with short-term neonatal effects, including increased distress after delivery, less than optimal orientation and motor activity, and disrupted sleep. Longer-term effects on neurobehavioral outcome have also been reported, including disruptive social behavior, depression, and changes in the period of sensitivity for language discrimination. Antidepressant exposure during pregnancy is associated with adverse short-term perinatal symptomatology, including effects on autonomic and motor activity, habituation, and sleep. Longer-term studies of neurobehavioral outcomes of in utero antidepressant exposure suggest potential effects on gross motor function and language development but not cognition. CONCLUSIONS: In utero exposure to either maternal depression or antidepressants carries risks to the developing fetus. Treatment decisions regarding whether and how to treat depression during pregnancy must be made on an individual basis, with careful consideration of the impact of these decisions on both mother and infant. Language: en

Medical comorbidities are common in patients with bipolar (BP) disorder but have not been previously examined for differences between United States and Europe. More than 900 outpatients with BP I and BP II disorder (mean age, 41 years) filled out a questionnaire including the occurrence of 30 listed medical conditions. The patients from the United States were from Los Angeles, Dallas, Cincinnati, and Bethesda, whereas those from Europe were from Utrecht, Freiberg, and Munich. Those from the United States had a significantly higher incidence of obesity and nine other medical comorbidities than those from Europe, who had only more cases of hyperthyroidism. The burden of medical comorbidities in patients with BP disorder from the United States seems higher than in patients from Europe. Given the adversities, morbidity, and early mortality associated with these conditions and their interaction with the morbidity and lethality of BP disorder itself, greater efforts at treatment and prevention of these medical comorbidities would seem indicated.

Considerable data suggest that compared to some European countries, in the U.S. there are more childhood onset bipolar disorders, more adverse courses of illness, and greater treatment resistance. Psychosocial variables related to these findings have not been adequately explored. Therefore we analyzed psychosocial stressors in three time domains: childhood; the year prior to illness Onset; and the Last Episode from questionnaires in 968 outpatients (mean age 41) with bipolar I or II disorder; 676 from four sites in the U.S. and 292 from three in the Netherlands and Germany (abbreviated here as Europe). Compared to the Europeans, those from the U.S. had significantly more stressors in childhood and prior to the last episode. Stressors prior to the last episode were related to: childhood stressors; an earlier age at illness onset; anxiety and substance abuse comorbidity; lower income; both parents having an affective illness; and feeling more stigma. These data suggest a greater prevalence of adverse life events in childhood and over the course of bipolar illness in the U.S. compared to the Netherlands and Germany. Clinical, therapeutic, and public health approaches to these illness-relevant stressors require further exploration. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Mechanistic understandings of forms of incidental emotion regulation have implications for basic and translational research in the affective sciences. In this study we applied Dynamic Causal Modeling (DCM) for fMRI to a common paradigm of labeling facial affect to elucidate prefrontal to subcortical influences. Four brain regions were used to model affect labeling, including right ventrolateral prefrontal cortex (vlPFC), amygdala and Broca's area. 64 models were compared, for each of 45 healthy subjects. Family level inference split the model space to a likely driving input and Bayesian Model Selection within the winning family of 32 models revealed a strong pattern of endogenous network connectivity. Modulatory effects of labeling were most prominently observed following Bayesian Model Averaging, with the dampening influence on amygdala originating from Broca's area but much more strongly from right vlPFC. These results solidify and extend previous correlation and regression-based estimations of negative corticolimbic coupling. © 2013 Elsevier Inc.

ObjectiveEarly-onset bipolar (BP) disorder and other poor prognosis characteristics are more prevalent in patients from the United States than from the Netherlands and Germany (abbreviated as Europe). We explored the impact of parental loading for affective illness on onset and other characteristics of BP disorder.MethodParental history for unipolar (UP) and bipolar (BP) depression and course of illness characteristics were obtained from self-report in adults (average age 42) with BP disorder. Illness characteristics were examined by chi(2) and multinomial logistic regression in relationship to the degree of parental loading: i) both parents negative; ii) one UP disorder; iii) one with BP disorder; and iv) both affected.ResultsAfter controlling for many poor prognosis factors, compared with those from Europe, patients from the United States had more iii) one parent with BP disorder and iv) both parents affected. An early age of onset of BP disorder was independently associated with this increased parental loading for affective disorder.ConclusionParental history of BP disorder and both parents with a mood disorder were more common in the United States than Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics. These findings deserve replication and exploration of the potential mechanisms involved and their therapeutic implications.

Impulsive risk taking contributes to deleterious outcomes among clinical populations. Indeed, pathological impulsivity and risk taking are common in patients with serious mental illness, and have severe clinical repercussions including novelty seeking, response disinhibition, aggression, and substance abuse. Thus, the current study seeks to examine self-reported impulsivity (Barratt Impulsivity Scale) and performance-based behavioral risk taking (Balloon Analogue Risk Task) in bipolar disorder and schizophrenia. Participants included 68 individuals with bipolar disorder, 38 with schizophrenia, and 36 healthy controls. Self-reported impulsivity was elevated in the bipolar group compared with schizophrenia patients and healthy controls, who did not differ from each other. On the risk-taking task, schizophrenia patients were significantly more risk averse than the bipolar patients and controls. Aside from the diagnostic group differences, there was a significant effect of antipsychotic (AP) medication within the bipolar group: bipolar patients taking AP medications were more risk averse than those not taking AP medications. This difference in risk taking because of AP medications was not explained by history of psychosis. Similarly, the differences in risk taking between schizophrenia and bipolar disorder were not fully explained by AP effects. Implications for clinical practice and future research are discussed. © 2014 American College of Neuropsychopharmacology.

In this article, we present path length associated community estimation (PLACE), a comprehensive framework for studying node-level community structure. Instead of the well-known Q modularity metric, PLACE utilizes a novel metric, ΨPL, which measures the difference between intercommunity versus intracommunity path lengths. We compared community structures in human healthy brain networks generated using these two metrics and argued that ΨPL may have theoretical advantages. PLACE consists of the following: (1) extracting community structure using top-down hierarchical binary trees, where a branch at each bifurcation denotes a collection of nodes that form a community at that level, (2) constructing and assessing mean group community structure, and (3) detecting node-level changes in community between groups. We applied PLACE and investigated the structural brain networks obtained from a sample of 25 euthymic bipolar I subjects versus 25 gender- and age-matched healthy controls. Results showed community structural differences in posterior default mode network regions, with the bipolar group exhibiting left-right decoupling. Hum Brain Mapp 35:2253–2264, 2014. © 2013 Wiley Periodicals, Inc.

Objective: A role for childhood adversity in the development of numerous medical conditions in adults has been described in the general population, but has not been examined in patients with bipolar disorder who have multiple medical comorbidities which contribute to their premature mortality. Methods: More than 900 outpatients (average age 41) with bipolar disorder completed questionnaires that included information about the occurrence of verbal, physical, or sexual abuse in childhood and whether their parents had a mood or substance abuse disorder, or a history of suicidality. These factors were combined to form a total childhood adversity score, which was then related to one or more of 30 medical conditions patients rated as present or absent. Results: The child adversity score was significantly related to the total number of medical comorbidities a patient had (po .001), as well as to 11 specific medical conditions that could be modeled in a logistic regression (po .03). These included: asthma, arthritis, allergies, chronic fatigue syndrome, chronic menstrual irregularities, fibromyalgia, head injury (without loss of consciousness), hypertension, hypotension, irritable bowel syndrome, and migraine headaches. Limitations: The contribution of parental diagnosis to childhood adversity is highly inferential. Conclusions: These data link childhood adversity to the later occurrence of multiple medical conditions in adult outpatients with bipolar disorder. Recognition of these relationships and early treatment intervention may help avert a more severe course of not only bipolar disorder but also of its prominent medical comorbidities and their combined adverse effects on patients’health, wellbeing, and longevity. & 2012 Elsevier B.V. All rights reserved.

Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted.

Bipolar disorder is a serious psychiatric illness thought to involve deficits in the neural substrates for emotion regulation because of its characteristic profile of lifetime depressed and manic mood episodes (1, 2). Neuroimaging research in healthy subjects has revealed a number of brain areas involved in emotional regulation, including subcortical (e.g., amygdala) and ventrolateral prefrontal cortical (vlPFC) regions (3, 4). Research in both humans and primates has additionally demonstrated strong anatomical projections between these areas, forming the substrate for which functional coupling (connectivity) is possible (5, 6). The amygdala, for example, is functionally responsive to emotional stimuli, while the vlPFC is instrumental in the regulation of that response. In healthy subjects, during down-regulation of emotion, the functional connectivity between these areas has been observed to increase (7, 8). The above-referenced functional magnetic resonance imaging (fMRI) studies of emotion regulation involve observation of brain activity while subjects perform a task. Recent studies that have evaluated subjects while not performing any cognitive tasks–e.g., resting state studies–have also revealed intrinsic activation patterns in the brain. Resting state fMRI provides complementary information to task-based fMRI in that both provide a platform for examining functional brain networks. Spatially distributed large-scale brain networks can be reliably derived and interrogated by either kind of fMRI experiment (9–11) and one could argue that both contribute different dimensions to a full characterization of brain activity. A variety of methods have been used to analyze such data (12) and have been applied to diverse clinical populations in the effort to delineate disease-related dysfunctions in connectivity (13). While there are a handful of studies that have investigated functional connectivity in bipolar disorder, few are resting state studies (Table 1). Of these, there is some overlap with the regions used as seeds, such as the medial prefrontal cortex (14, 15) or amygdala (16, 17) but the findings show differences in connectivity in lateralization (left or right hemisphere), sign (positive or negative coupling), and between-group differences (healthy subjects > bipolar disorder or bipolar disorder > healthy subjects). Three of these studies investigated bipolar mania and/or depression (14, 15, 17); however, one combined several mood states into its bipolar disorder sample (16) while another combined bipolar I and II disorder subjects (14). This latter issue is particularly problematic as there is evidence to suggest that patterns of activation and connectivity change with different mood state and subtype of bipolar disorder (17–19). For a clearer picture of the underlying pathophysiology of bipolar disorder, further research that investigates common regions in both hemispheres in single mood states and in single bipolar disorder subtypes is necessary. Table 1 A selection of functional magnetic resonance imaging (fMRI)connectivity studies in bipolar disorder The goal of the present resting state study was to elucidate differences in intrinsic functional connectivity that might contribute to mood lability in bipolar I disorder. We therefore took a focused approach to assessing connectivity in two bilateral brain regions strongly implicated in emotion regulation (four regions in total: right and left amygdalae and right and left vlPFC) in a group of euthymic bipolar I disorder subjects. We hypothesized that subjects with bipolar I disorder would demonstrate aberrant functional connectivity relative to healthy subjects between amygdalae and lateral vlPFC–regions that subserve emotion regulation. Furthermore, observed alterations of brain connectivity during the euthymic state may be considered a potential biomarker of trait aspects of the disease.

Background Bipolar disorder (BD) is a chronic mental illness characterized by severe disruptions in mood and cognition. Diffusion tensor imaging (DTI) studies suggest that white matter (WM) tract abnormalities may contribute to the clinical hallmarks of the disorder. Using DTI and whole brain voxel-based analysis, we mapped the profile of WM anomalies in BD. All patients in our sample were euthymic and lithium free when scanned. Methods Diffusion-weighted and T1-weighted structural brain images were acquired from 23 lithium-free euthymic subjects with bipolar I disorder and 19 age- and sex-matched healthy control subjects on a 1.5 T MRI scanner. Scans were processed to provide measures of fractional anisotropy (FA) and mean and radial diffusivity (MD and RD) at each WM voxel, and processed scans were nonlinearly aligned to a customized brain imaging template for statistical group comparisons. Results Relative to controls, the bipolar group showed widespread regions of lower FA, including the corpus callosum, cortical and thalamic association fibers. MD and RD were abnormally elevated in patients in many of these same regions. Conclusions Our findings agree with prior reports of WM abnormalities in the corpus callosum and further link a bipolar diagnosis with structural abnormalities of the tapetum, fornix and stria terminalis. Future studies assessing the diagnostic specificity and prognostic implications of these abnormalities would be of interest., Highlights • Using DTI and whole brain voxel-based analysis, we mapped WM anomalies in BD. • Relative to controls, the bipolar group showed widespread regions of lower FA. • MD and RD were abnormally elevated in patients in many of these same regions.

Background The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, downregulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion downregulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects. Methods Thirty BPI and 26 control subjects underwent functional magnetic resonance imaging scanning while performing an emotion processing task with passive viewing and emotion downregulation conditions. Contrasts were made for each group comparing the downregulation and passive viewing conditions, and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological interaction analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC). Results Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion downregulation tasks. Between-group analyses revealed similar activation of BPI and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus, and bilateral dorsal lateral prefrontal cortex during emotion downregulation in subjects with BPI. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared with subjects with BPI. Conclusions This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate, and subcortical structures, are present in BPI subjects, even while euthymic.

Background This represents the first graph theory-based brain network analysis study in bipolar disorder, a chronic and disabling psychiatric disorder characterized by severe mood swings. Many imaging studies have investigated white matter in bipolar disorder, with results suggesting abnormal white matter structural integrity, particularly in the fronto-limbic and callosal systems. However, many inconsistencies remain in the literature, and no study to date has conducted brain network analyses with a graph-theoretic approach. Methods We acquired 64-direction diffusion-weighted magnetic resonance imaging on 25 euthymic bipolar I disorder subjects and 24 gender- and age-equivalent healthy subjects. White matter integrity measures including fractional anisotropy and mean diffusivity were compared in the whole brain. Additionally, structural connectivity matrices based on whole-brain deterministic tractography were constructed, followed by the computation of both global and local brain network measures. We also designed novel metrics to further probe inter-hemispheric integration. Results Network analyses revealed that the bipolar brain networks exhibited significantly longer characteristic path length, lower clustering coefficient, and lower global efficiency relative to those of control subjects. Further analyses revealed impaired inter-hemispheric but relatively preserved intra-hemispheric integration. These findings were supported by whole-brain white matter analyses that revealed significantly lower integrity in the corpus callosum in bipolar subjects. There were also abnormalities in nodal network measures in structures within the limbic system, especially the left hippocampus, the left lateral orbitofrontal cortex, and the bilateral isthmus cingulate. Conclusions These results suggest abnormalities in structural network organization in bipolar disorder, particularly in inter-hemispheric integration and within the limbic system.

Background Postmortem and imaging studies provide converging evidence that the frontal lobe myelination trajectory is dysregulated in schizophrenia (SZ) and suggest that early in treatment, antipsychotic medications increase intracortical myelin (ICM). We used magnetic resonance imaging to examine whether the ICM trajectory in SZ is dysregulated and altered by antipsychotic treatment. Methods We examined 93 subjects with SZ (64 men and 29 women) taking second-generation oral antipsychotics with medication exposures of 0–333 months in conjunction with 80 healthy control subjects (52 men and 28 women). Frontal lobe ICM volume was estimated using a novel dual contrast magnetic resonance imaging method that combines two images that track different tissue components. Results When plotted against oral antipsychotic exposure duration, ICM of subjects with SZ was higher as a function of medication exposure during the first year of treatment but declined thereafter. In the age range examined, ICM of subjects with SZ was lower with increased age, while ICM of healthy control subjects was not. Conclusions In adults with SZ, the relationship between length of exposure to oral second-generation antipsychotics and ICM was positive during the first year of treatment but was negative after this initial period, consistent with suboptimal later adherence after initial adherence. This ICM trajectory resembles clinically observed antipsychotic response trajectory with high rates of remission in the first year followed by progressively lower response rates. The results support postmortem evidence that SZ pathophysiology involves ICM deficits and suggest that correcting these deficits may be an important mechanism of action for antipsychotics.

Background Performance during cognitive control functional magnetic resonance imaging (fMRI) tasks are associated with frontal lobe hypoactivation in patients with bipolar disorder, even while euthymic. We examine the structural underpinnings for this functional abnormality simultaneously with brain activation data. Methods In a sample of 90 adults (45 with interepisode bipolar I disorder and 45 healthy controls), we explored abnormal functional activation patterns in euthymic patients with bipolar disorder during a Go/NoGo fMRI task and their associations with regional deficits in cortical gray matter thickness. Cross-sectional differences in fMRI activation were used to form a priori hypotheses for region of interest cortical gray matter thickness analyses. Blood oxygen level–dependent fMRI to structural magnetic resonance imaging thickness correlations were conducted across the sample and within patients and controls separately. Results During response inhibition (NoGo − Go), patients with bipolar I disorder showed significant hypoactivation and reduced thickness in the inferior frontal cortex, superior frontal gyrus, and cingulate compared to controls. Cingulate hypoactivation corresponded with reduced regional thickness. A significant activation by disease state interaction was observed with thickness in left prefrontal areas. Conclusions Reduced cingulate fMRI activation is associated with reduced cortical thickness. In the left frontal lobe, a thinner cortex was associated with increased fMRI activation in patients but showed a reverse trend in controls. These findings suggest that reduced activation in the inferior frontal cortex and cingulate during a response inhibition task may have an underlying structural etiology, which may explain task-related functional hypoactivation that persists even when patients are euthymic.

OBJECTIVE: DSM-5 introduced the "with mixed features" specifier for major depressive episodes. The authors assessed the prevalence and phenomenology of mixed depression among bipolar disorder patients and qualitatively compared a range of diagnostic thresholds for mixed depression.METHOD: In a naturalistic study, 907 adult outpatients with bipolar disorder participating in the Stanley Foundation Bipolar Network were followed longitudinally across 14,310 visits from 1995 to 2002. The Inventory of Depressive Symptomatology-Clinician-Rated Version (IDS-C) and the Young Mania Rating Scale (YMRS) were administered at each visit.RESULTS: Mixed depression, defined as an IDS-C score ≥15 and a YMRS score >2 and CONCLUSIONS: Among outpatients with bipolar disorder, concurrent hypomanic symptoms observed during visits with depression were common, particularly in women. The DSM-5 diagnostic criteria for depression with mixed features may yield inadequate sensitivity to detect patients with mixed depression.

Background: Family history and adversity in childhood are two replicated risk factors for early onset bipolar disorder. However, their combined impact has not been adequately studied.Methods: Based on questionnaire data from 968 outpatients with bipolar disorder who gave informed consent, the relationship and interaction of: 1) parental and grandparental total burden of psychiatric illness; and 2) the degree of adversity the patient experienced in childhood on their age of onset of bipolar disorder was examined with multiple regression and illustrated with a heat map.Results: The familial loading and child adversity vulnerability factors were significantly related to age of onset of bipolar and their combined effect was even larger. A heat map showed that at the extremes (none of each factor vs high amounts of both) the average age of onset differed by almost 20 years (mean = 25.8 vs 5.9 years of age).Limitations: The data were not based on interviews of family members and came from unverified answers on a patient questionnaire.Conclusions: Family loading for psychiatric illness and adversity in childhood combine to have a very large influence on age of onset of bipolar disorder. These variables should be considered in assessment of risk for illness onset in different populations, the need for early intervention, and in the design of studies of primary and secondary prevention. (C) 2016 Elsevier Ltd. All rights reserved.

OBJECTIVE: This study aimed to determine the relative extent of impairment in social and nonsocial cognitive domains in patients with bipolar disorder compared with schizophrenia patients and healthy comparison subjects. METHODS: Sixty-eight clinically stable outpatients with bipolar disorder, 38 clinically stable outpatients with schizophrenia, and 36 healthy comparison subjects completed a range of social (facial affect perception, emotional regulation, empathic accuracy, mental state attribution, and self-referential memory) and nonsocial (speed of processing, attention/vigilance, working memory, verbal memory, visual memory, and reasoning/problem solving) cognitive tasks. RESULTS: For each social cognitive task, patients with bipolar disorder did not differ significantly from comparison subjects, and both groups performed better than schizophrenia patients. Within the bipolar group, clinical features and medication status were not related to social cognitive performance. Bipolar patients showed performance patterns across tasks (i.e., profiles) that were similar to those of comparison subjects on both social and nonsocial cognitive domains, whereas both groups differed from schizophrenia patients for both domains. Regarding relative impairment across the two cognitive domains, results revealed a significant group-by-domain interaction in which bipolar patients showed less impaired social than nonsocial cognition, while schizophrenia patients showed the opposite pattern. CONCLUSIONS: Bipolar patients showed less impairment on social relative to nonsocial cognitive performance, whereas schizophrenia patients showed more impairment on social relative to nonsocial cognitive performance. These results suggest that these two cognitive domains play different roles in bipolar disorder compared with in schizophrenia.

Lori L. Altshuler, MD, died on November 5, 2015, at her home in Manhattan Beach, California. It is easy to list Lori's many important contributions to psychiatry, but doing so describes only one facet of a wonderfully multidimensional and talented person. Yes, Lori held the Julia S. Gouw Endowed Chair in Mood Disorders at UCLA.