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Objective To compare white matter integrity (WMI) in bipolar disorder (BD) relative to healthy volunteers (HVs) and major depressive disorder (MDD). To determine the relationship of bipolar-specific differences in WMI to cerebral perfusion, body mass index (BMI), and blood pressure as indices of cardiovascular function. Methods Thirty-two participants with BD, 44 with MDD, and 41 HV were recruited. All BD and MDD participants were in a major depressive episode, and all but 12 BD participants were medication-free. 64-direction diffusion tensor imaging (DTI) and arterial spin labeling (ASL) sequences were obtained. Tract-based spatial statistics (TBSS) on four DTI indices were employed to distinguish patterns of DTI in BD relative to HV and MDD groups. BMI, blood pressure, and medical histories were also obtained for the BD participants. Results A cluster of lower axial diffusivity (AD) was found in BD participants in comparison to the HVs in the left posterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and internal capsule. Mean AD in the significant cluster was not associated with cerebral blood flow (CBF) in the region as measured by ASL, and was not associated with BMI or blood pressure. A cluster of lower AD was also found in the BD group when compared to MDD that had spatial overlap with the HV comparison. Conclusions The results indicate a deficit of AD in BD when compared to MDD and HV groups. No association between AD values and either cerebral perfusion, BMI, or blood pressure was found in BD.

Objectives To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored. Methods Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion. Results Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=−0.65 to 12.31). The number needed to treat for response (SSI

OBJECTIVES: Offspring of depressed parents are at increased risk for psychiatric disorders. Although bipolar disorder (BD) and major depressive disorder (MDD) are both found in the same families, it is not clear whether transmission to offspring of BD or MDD tends to occur from parents with the same mood disorder subtype. Our primary hypothesis was that the offspring of parents with BD would be at increased risk for BD and other comorbid disorders common to BD, such as anxiety and substance use, relative to the offspring of parents with MDD. The offspring of parents with BD versus those with MDD were also hypothesized to be at greater risk for externalizing disorders (i.e., conduct disorder, attention-deficit hyperactivity disorder, or antisocial personality disorder). METHODS: Parents (n = 320) with mood disorders and their offspring (n = 679) were studied. Adult offspring were administered the Structured Clinical Interview for DSM-IV Axis I Disorders to establish the presence of psychopathology. Offspring aged 10-18 years were assessed using the School Aged Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, and parents of children under the age of ten completed the Child Behavioral Checklist. Data were examined using Cox proportional hazard regression. RESULTS: There was no difference in hazard of mood disorders in the offspring of parents with BD as compared to the offspring of parents with MDD. However, a number of other parent and offspring characteristics increased the risk of mood, anxiety, externalizing, and substance use disorders in the offspring, including self-reported childhood abuse in the parent or offspring, offspring impulsive aggression, and the age at onset of parental mood disorder. CONCLUSIONS: Mood disorders are highly familial, a finding that appears independent of whether the parent's condition is unipolar or bipolar, suggesting considerable overlap in the heritability of MDD and BD. Although parental characteristics had a limited influence on the risk of offspring psychopathology, reported childhood adversity, be it in the parent or child, is a harbinger of negative outcomes. These risk factors extend previous findings, and are consistent with diathesis-stress conceptualizations. Language: en

Among subjects with bipolar disorder (BD), depression is much more prevalent (1, 2) and has stronger effects on mortality and psychosocial impairment than mania or hypomania (3, 4). Recently, the clinical, biological, and treatment characteristics of major depressive episodes (MDE) in BD as compared to major depressive disorder (MDD) have been a focus of attention for researchers and clinicians (5–21). However, specific clinical or biological markers for bipolar depression are still lacking. In current diagnostic systems, the same diagnostic criteria apply to MDE occurring during MDD or during the course of BD (22). In comparisons of MDD and depressed BD patients, atypical features, such as hypersomnia or leaden paralysis (5, 6, 9, 20), psychotic symptoms (13, 16, 17, 19), psychomotor retardation (5, 13, 16), shorter depressive episodes (13, 14), higher number of depressive recurrences (9, 18–20), family history of mood disorders (9, 14), comorbidity with substance abuse (8, 17), and earlier age at onset (7, 9, 18) are reported more frequently in BD; whereas, somatic disturbances (5, 6, 18), anxiety (7, 13), sleep loss (5, 6, 9, 11, 13, 14, 18), and appetite loss (5, 6, 14, 17) are reported more frequently in MDD. However, findings in one sample have seldom been replicated in another, resulting in conflicting results across studies. Most studies report on samples of bipolar I disorder (BD-I) patients or on heterogeneous samples comprising of mostly BD-I patients (5, 6, 13, 14, 16–18); only a few have addressed differences between bipolar II disorder (BD-II) and MDD (9–11, 23); and even fewer have compared BD-I and BD-II with MDD (19, 20). Those studies used clinical samples, which preclude extrapolation of their results to the general population, and did not account for the impact of severity of depression on the clinical presentation and treatment patterns. Current categorical classifications do not rely on specific clinical correlates to discriminate between different mood disorders. In fact, DSM-IV differences between MDD, BD-II, and BD-I are based on lifetime presence of increasing number and duration of manic symptoms (22). This, together with the absence of genetic or other biomarkers supporting boundaries between conditions (21, 24, 25), suggests that dimensional approaches may contribute to describe mood disorders more accurately. We used data from a large national representative survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (26), to address some of the gaps in previous research. Specifically, among individuals with a lifetime history of MDE, we compared those with lifetime BD-I, BD-II, and MDD on sociodemographic and clinical characteristics, symptoms of MDE, and lifetime treatment patterns, and explored whether the different mood diagnoses arrayed along a dimension. Our aim was to expand the knowledge regarding the differential features of MDE occurring in BD-I, BD-II, and MDD, which could aid in the clinical decision-making and the characterization of mood disorders in DSM-V.

Comorbid anxiety predicts a more severe course of illness in bipolar disorder (1-4) and is associated with poorer response to lithium and anticonvulsants (5). However, studies in bipolar disorder disagree about the relationship of comorbid anxiety to suicidal behavior: some found an association between comorbid anxiety symptoms or disorders and suicide attempts (6-13) and others did not (5, 14). Several studies in mood disorders in general (15, 16) have failed to find an association between anxiety symptoms or disorders with suicidality or have found a protective effect, after adjusting for other psychiatric disorders (17-22). Studies of comorbid panic and mood disorders have found an independent contribution to suicidality (23-25); however, none of these studies examined bipolar disorder specifically. In a systematic review of suicidal behaviors in bipolar disorder, Hawton et al. (26) found comorbid anxiety disorder was associated with attempted suicide, but not suicide. Sareen et al. (27) found that lifetime anxiety disorder comorbidity with mood disorders was associated with higher risk for suicide attempts than mood disorder alone, but did not assess Axis II disorders, nor examine bipolar disorder separately. None of these studies controlled for the potential confounding effect of other known risk factors for suicidal behavior that may involve heightened anxiety, such as Cluster B personality disorder (28-30). We have reported that in a sample of patients with unipolar major depressive episode the relationship of posttraumatic stress disorder (PTSD) and suicidal behavior may be explained by the presence of comorbid Cluster B personality disorder (31). Whether a similar pattern exists for comorbid bipolar and anxiety disorders has not been addressed. While two studies reported that comorbid Cluster B personality disorder increased the risk for suicidal behavior in bipolar disorder (8, 32), they did not evaluate comorbid anxiety disorder. No published study in bipolar disorder, to our knowledge, has examined the relative importance of comorbid anxiety and Cluster B personality disorders with respect to risk for suicidal behavior. In this study, we examine suicidal behavior (past attempts and suicidal ideation) in bipolar disorder patients for correlations with anxiety disorders, and also investigate the role of Cluster B personality disorder. Because anxiety disorders are highly comorbid with other anxiety disorders and tend to cluster together (9, 33), we examined the presence of any lifetime anxiety disorder. However, given the high comorbidity between bipolar and panic disorders (2, 7) and reports of more severe suicidal ideation among bipolar patients with panic disorder (23-25), we also specifically examined the effect of comorbid panic disorder. We tested the hypothesis that among bipolar patients, the presence of comorbid anxiety disorder correlates with suicidal behavior and ideation, but that this relationship is due to the effects of Cluster B personality disorders.

Objective: This study determined the clinical predictors of suicidal behavior during a 2-year follow-up of patients with bipolar disorder presenting with a major depressive episode (MDE). Method: Sixty four patients with DSM-III-R bipolar disorder were assessed at presentation for treatment of an MDE. Correlates of past suicidal behavior were determined by comparing patients with and without a history of suicide attempts using a t-test, Wilcoxon test or chi-squared test of independence on individual explanatory variables. Putative predictors of attempts during the follow-up period were tested separately using Cox proportional hazards regression analysis. Results: Twelve of 64 patients had at least one suicide attempt in the follow-up period, five of them attempted in the first 2 months and seven around or shortly after the 1-year follow-up visit. All attempters had a history of past suicide attempts. Most predictors of future suicidal behavior were correlates of past suicidal behavior. Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period. Conclusion: In this data set of bipolar patients we noted an intriguing picture of two clusters of suicide attempts. Hostility was the strongest risk factor. These findings may have implications in both the identification of at-risk patients and the timing of clinical interventions including aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptomatology.

Objectives: The goal of this retrospective study was to examine factors differentiating persons with bipolar disorder who did or did not have comorbid lifetime substance use disorders (SUD) at an index assessment. We also explored the chronology of onset of mood and SUD. Methods: We studied 146 subjects with DSM-defined bipolar disorder. Subgroups with and without lifetime SUD were compared on demographic and clinical measures. Results: Substance abuse disorders in this bipolar sample were associated with male sex, impulsive-aggressive traits, comorbid conduct and Cluster B personality disorders, number of suicide attempts and earlier age at onset of a first mood episode. In a multivariable logistic regression analysis, male sex and aggression and possibly earlier age at mood disorder onset were associated with SUD. In those with or without SUD, the first mood episode tended to be depressive and to precede the onset of SUD. Conclusions: In persons with bipolar disorder, an earlier age of onset and aggressive traits appear to be factors associated with later development of comorbid SUD.

Objectives: Among mood disorders, bipolar disorder (BPD) is often noted to involve the highest rates of suicide attempts and possibly of completion. This study sought to determine whether suicide attempters with BPD exhibit suicide attempts with higher lethality than attempters with major depressive disorder (MDD) and to explore differences in clinical features associated with suicidal acts. Methods: Mood disordered suicide attempters were interviewed about Axis I and II diagnoses, lifetime history of suicide attempts, suicidal intent, suicidal ideation, the medical lethality of their most severe suicide attempt, severity of depression, hopelessness, lifetime aggression, and impulsivity. Results: The maximum lethality of suicidal acts tended to be higher among BPD attempters compared with those with MDD. However, there were no differences in the number of suicide attempts, intent to die or suicidal ideation. Suicide attempters with BPD reported higher levels of aggression and impulsivity but less hopelessness compared with MDD attempters. These differences could not be explained by Cluster B personality disorder comorbidity. Of note, within the BPD group, but not the MDD group, males reported suicidal acts with higher lethality. Multivariate analyses suggested that risk for more lethal suicide attempts is associated with BPD and male sex and that bipolar males appear to be especially vulnerable to these behaviors. Conclusions: Males with BPD make more lethal suicide attempts than females with BPD, an effect not observed among the MDD sample. Our findings suggest that higher rates of suicidal behavior in BPD may be due to a specific effect of BPD on males, leading to more dangerous suicidal behaviors. This effect, together with the larger proportion of males in the BPD group compared with the MDD group may lead to higher rates of reported attempted and completed suicide.

Objectives: Bipolar disorders are associated with high rates of suicide attempts (SAs) and completions. Several factors have been reported to be associated with suicide in persons with bipolar disorder, but most studies to date have been retrospective and have not utilized multivariate statistics to account for the redundant prediction among variables submitted for analysis. Methods: This study examined the association between baseline clinical and demographic variables and subsequent SAs and completions through 2 years of follow-up of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder using a pattern-mixture model. Results: Of the sample with complete data (n = 1,556), 57 patients (3.66%) experienced an SA or completion (CS). Several variables predicted suicidality (SA + CS) in this data set when considered alone, but after controlling for redundant prediction from other baseline characteristics, only history of suicide [odds ratio (OR) = 4.52, p

Objectives Whether risk of suicide attempts (SAs) differs between patients with bipolar disorder (BD) and patients with major depressive disorder (MDD) is unclear. We investigated whether cumulative risk differences are due to dissimilarities in time spent in high-risk states, incidence per unit time in high-risk states, or both. Methods Incidence rates for SAs during various illness phases, based on prospective life charts, were compared between patients from the Jorvi Bipolar Study (n = 176; 18 months) and the Vantaa Depression Study (n = 249; five years). Risk factors and their interactions with diagnosis were investigated with Cox proportional hazards models. Results By 18 months, 19.9% of patients with BD versus 9.5% of patients with MDD had attempted suicide. However, patients with BD spent 4.6% of the time in mixed episodes, and more time in major depressive episodes (MDEs) (35% versus 21%, respectively) and in subthreshold depression (39% versus 31%, respectively) than those with MDD. Compared with full remission, the combined incidence rates of SAs were 5-, 25-, and 65-fold in subthreshold depression, MDEs, and BD mixed states, respectively. Between cohorts, incidence of attempts was not different during comparable symptom states. In Cox models, hazard was elevated during MDEs and subthreshold depression, and among patients with preceding SAs, female patients, those with poor social support, and those aged

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Objectives: Distinguishing clinical characteristics of bipolar patients who have made a suicide attempt may help to identify at-risk individuals. We sought to identify such factors and to consider them within a stress-diathesis model of suicidal behavior. Methods: Patients with bipolar disorder (N = 96) were compared with respect to the presence or absence at baseline evaluation of a history of suicide attempt. We used multiple logistic regression analysis to assess the unique associations of independent variables to history of a past suicide attempt. Results: The regression analysis showed that a history of suicide attempt in bipolar disorder was associated with greater recent suicidal ideation, more psychiatric hospitalizations, lifetime aggressive traits and an earlier age at onset of a first mood episode. Conclusions: Aggressive traits and early treatment of mood disorders, especially major depressive episodes, are potential targets for suicide prevention in bipolar disorder.

Objectives: Bipolar disorder is a severe illness that is associated with suicidal behavior. A biological predictor of highly lethal suicide attempts in patients with bipolar disorder would be valuable. We hypothesized that cerebrospinal fluid (CSF) monoamine metabolite levels are related to lethality of suicide attempts in bipolar patients and examined the relation between CSF 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and maximum lethality of suicide attempts at baseline and during a 2-year follow up. Methods: Twenty-seven bipolar depressed patients participated in the study. Demographic and clinical parameters were examined and recorded. Lumbar punctures were performed and CSF 5-HIAA, HVA, and MHPG were assayed by high-performance liquid chromatography with electrochemical detection. Following discharge, patients were evaluated after 3 months, 1 year, and 2 years. Each follow-up interview included an in-depth assessment of suicidal behavior during the intervening time period. Results: Six subjects made suicide attempts during the 2-year follow-up. Bipolar patients who attempted suicide during the follow-up period had higher aggression and hostility scale scores compared to bipolar subjects who did not make a suicide attempt during the follow-up period. CSF 5-HIAA, HVA, and MHPG levels were negatively correlated with the maximum lethality of suicide attempts during the 2-year follow-up period. Conclusions: Our finding is the first observation that CSF monoamine metabolite levels may be predictors of lethality of suicide attempts in patients with bipolar disorder. Further studies are necessary to answer the question whether CSF monoamine metabolite levels are clinically useful biochemical predictors of highly lethal suicide attempts or completed suicides.

To the Editor: We thank Dr. Weinstock and colleagues for noting our recent article on differences in depressive episodes in major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II) analyzing data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (1). In our study we documented the existence of a linear trend in the severity of major depressive episodes: highest for BD-I, followed by BD-II, and lastly by MDD. As Dr. Weinstock and colleagues point out, our conclusions converge with those of their studies (2, 3) and with those from other groups whose work also draws on NESARC data (4). It is reassuring that the conclusions of our studies converge despite addressing two complementary but rather different questions. Dr. Weinstock’s analyses focused on the differences in probability of DSM-IV depression symptom endorsement after adjusting for disorder severity across unipolar and bipolar depressive disorders (2, 3). By contrast, because we were interested in the nosological question of whether different mood disorders arrayed along a dimension, we decided to move beyond symptoms and examined the existence of linear trends in BD-I, BD-II, or MDD across a broad range of variables, including sociodemographic characteristics, clinical characteristics, and lifetime treatment patterns. Our results, which remained significant when stratifying the analyses by gender and by race/ethnicity, strongly supported the existence of a spectrum of severity. Our analyses were also complementary regarding sampling selection. Dr. Weinstock’s group included individuals based on endorsement of lifetime depressed mood and/or anhedonia regardless of whether they met DSM-IV criteria for MDD, BD-I, or BD-II. Consistent with the focus of our analyses, we used DSM-IV diagnoses as inclusion criteria, as we were interested in contributing data to the discussion of the DSM-5 mood disorders classification. Despite these differences in sampling selection, our conclusions pointed in the same direction. The adjustment for other covariates was also complementary in the analyses conducted by the two groups. To adjust for the severity of depressive symptomatology when comparing symptom differences between bipolar and unipolar depression, Dr. Weinstock’s group relied on item response theory methods. As our focus was broader, we were concerned about the effect of other potential confounders beyond severity of depression, including unmeasured confounders. Therefore, in addition to adjusting for number of symptoms of depression, we adjusted for the Short Form Health Survey–12, a global reliable and valid impairment measure in population surveys that takes into account the severity of depression as well as the impact of other disorders (5). Finally, our analyses were complementary in the statistical approach to multiple comparisons. Dr. Weinstock and colleagues used the Benjamini–Hochberg correction. They raise the concern that, because we did not apply a similar correction to our analyses, our analyses run the risk of inflating type I error. Because we conducted 290 comparisons at an α = 0.05, we could expect 290 × 0.05 = 14.5 to be significant simply by chance. We found that 192 were. A test of binomial proportions indicates that the probability of having at least 192 significant tests out of 290 is approximately 1 in 10000000. Therefore, our pattern of results is highly unlikely to be due to chance. We believe that, overall, the findings of these groups of studies consistently suggest the existence of a continuum of depressive clinical syndromes that would be better characterized by dimensional approaches. In this regard, severity is being considered for inclusion as a specifier in upcoming diagnostic classifications (6). We eagerly await studies with epidemiological, clinical or biological data that may contribute to clarify the structure of mood disorders.