Lower Switch Rate in Depressed Patients With Bipolar II Than Bipolar I Disorder Treated Adjunctively With Second-Generation Antidepressants.

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. Methods: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score ≥3 (mildly ill). Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.Reprinted from Am J Psychiatry 2006; 163:313-315, with permission from American Psychiatric Association Publishing. Copyright © 2006.

Are personality disorders in bipolar patients more frequent in the US than Europe?

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.

Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes.

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 < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria. 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.

25 Years of the International Bipolar Collaborative Network (BCN).

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.

Structural and Functional Connectivity of Visual Cortex in Schizophrenia and Bipolar Disorder: A Graph-Theoretic Analysis.

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.

Relationship of comorbid personality disorders to prospective outcome in bipolar disorder.

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.

Double jeopardy in the United States: Early onset bipolar disorder and treatment delay.

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.

More assortative mating in US compared to European parents and spouses of patients with bipolar disorder: implications for psychiatric illness in the offspring.

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.

Testing a clinical staging model for bipolar disorder using longitudinal life chart data.

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.

fMRI evidence of aberrant neural adaptation for objects in schizophrenia and bipolar disorder.

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 < .001). SZ patients showed an adaptation effect that was significantly smaller compared with controls. BD patients showed a lack of fMRI adaptation. The whole brain analyses showed enhanced fMRI responses to repeated presentation of the same objects only in BD patients in several brain regions including anterior cingulate cortex. This study was the first to employ fMRI adaptation for objects in SZ and BD. The current findings provide empirical evidence of aberrant fMRI adaptation in the visual cortex in SZ and BD, but in distinctly different ways.

Lower Switch Rate in Depressed Patients With Bipolar II Than Bipolar I Disorder Treated Adjunctively With Second-Generation Antidepressants.

(Reprinted with permission from Am J Psychiatry 2006; 163:313-315).

Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder.

INTRODUCTION: Instead 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. METHODS: A 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. RESULTS: The 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%. CONCLUSIONS: A 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.

Abnormal Trajectory of Intracortical Myelination in Schizophrenia Implicates White Matter in Disease Pathophysiology and the Therapeutic Mechanism of Action of Antipsychotics.

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.

Prevalence of axis II comorbidities in bipolar disorder: relationship to mood state.

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.

Assessing neural tuning for object perception in schizophrenia and bipolar disorder with multivariate pattern analysis of fMRI data.

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.

The relationship between self-reported borderline personality features and prospective illness course in bipolar disorder.

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.

Prospective Longitudinal Study of Predictors of Postpartum-Onset Depression in Women With a History of Major Depressive Disorder.

OBJECTIVE: Risk factors for postpartum depression in euthymic pregnant women with histories of major depressive disorder (MDD) were evaluated. METHODS: From April 2003 to March 2009, 343 pregnant women with a history of Structured Clinical Interview for DSM-IV (SCID)-diagnosed major depressive disorder were prospectively assessed from the third trimester into the postpartum period using the SCID mood module and 17-item Hamilton Depression Rating Scale (HDRS). Data from 300 subjects who completed at least 2 mood module assessments (1 within 60 days before and the other within 60 days after delivery) were analyzed for predictive associations between variables assessed in the third trimester and the development of a postpartum depression. RESULTS: The majority of women were euthymic in pregnancy by SCID criteria. Women with third trimester SCID-diagnosed depression (n = 45) versus euthymia (n = 255) had a significantly higher risk for having depression after delivery (24% vs 11%, P = .013). For pregnant euthymic women, third trimester total HDRS scores significantly predicted postpartum depression (P < .0001); specifically, scores on 3 HDRS items alone-work activities, early insomnia, and suicidality-significantly predicted postpartum depression. Antidepressant use in the third trimester in euthymic women did not confer protection against the onset of postpartum depression. CONCLUSIONS: Among women with a history of MDD who are euthymic in the third trimester, 3 HDRS items-work activities, early insomnia, and suicidality-may be useful as screening items for clinicians working with pregnant women with histories of MDD to identify a group at risk for developing postpartum depression. Additionally, in euthymic women with a history of MDD, antidepressant use in the third trimester may not reduce the risk of developing postpartum depression.

Switch Rates During Acute Treatment for Bipolar II Depression With Lithium, Sertraline, or the Two Combined: A Randomized Double-Blind Comparison.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

More childhood onset bipolar disorder in the United States than Canada or Europe: Implications for treatment and prevention.

Evidence of a high or increasing incidence of childhood onset bipolar disorder in the United States (US) has been viewed skeptically. Here we review evidence that childhood onsets of bipolar disorder are more common in the US than in Europe, treatment delays are longer, and illness course is more adverse and difficult. Epidemiological data and studies of offspring at high risk also support these findings. In our cohort of outpatients with bipolar disorder, two of the major vulnerability factors for early onset - genetics and environmental adversity in childhood - were also greater in the US than in Europe. An increased familial loading for multiple psychiatric disorders was apparent in 4 generations of the family members of the patients from the US, and that familial burden was linked to early onset bipolar disorder. Since both early onset and treatment delay are risk factors for a poor outcome in adulthood, new clinical, research, and public health initiatives are needed to begin to address and ameliorate this ongoing and potentially devastating clinical situation.

Illnesses in siblings of US patients with bipolar disorder relate to multigenerational family history and patients severity of illness.

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<0.001) more prevalent in those from the US than in those from Europe. In the US, problems in the parents and grandparents were almost uniformly associated with the same problems in the siblings, and sibling problems were related to the number of PPFs observed in the patients. 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.