Benjamin I. Goldstein

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009

The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first-line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first-line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second-line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not-recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long-acting injection, and adjunctive ziprasidone continue to be first-line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third-line options.

Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature.

OBJECTIVE To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder. DATA SOURCES MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications. STUDY SELECTION Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. DATA EXTRACTION Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated. DATA SYNTHESIS Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2-selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings. CONCLUSION Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.

Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study

OBJECTIVE The authors sought to assess the longitudinal course of youths with bipolar spectrum disorders over a 4-year period. METHOD At total of 413 youths (ages 7-17 years) with bipolar I disorder (N=244), bipolar II disorder (N=28), and bipolar disorder not otherwise specified (N=141) were enrolled in the study. Symptoms were ascertained retrospectively on average every 9.4 months for 4 years using the Longitudinal Interval Follow-Up Evaluation. Rates and time to recovery and recurrence and week-by-week symptomatic status were analyzed. RESULTS Approximately 2.5 years after onset of their index episode, 81.5% of the participants had fully recovered, but 1.5 years later 62.5% had a syndromal recurrence, particularly depression. One-third of the participants had one syndromal recurrence, and 30% had two or more. The polarity of the index episode predicted that of subsequent episodes. Participants were symptomatic during 60% of the follow-up period, particularly with subsyndromal symptoms of depression and mixed polarity, with numerous changes in mood polarity. Manic symptomatology, especially syndromal, was less frequent, and bipolar II was mainly manifested by depressive symptoms. Overall, 40% of the participants had syndromal or subsyndromal symptoms during 75% of the follow-up period, and 16% of the participants experienced psychotic symptoms during 17% the follow-up period. Twenty-five percent of youths with bipolar II converted to bipolar I, and 38% of those with bipolar disorder not otherwise specified converted to bipolar I or II. Early onset, diagnosis of bipolar disorder not otherwise specified, long illness duration, low socioeconomic status, and family history of mood disorders were associated with poorer outcomes. CONCLUSIONS Bipolar spectrum disorders in youths are characterized by episodic illness with subsyndromal and, less frequently, syndromal episodes with mainly depressive and mixed symptoms and rapid mood changes.

Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States

OBJECTIVE Despite ample evidence of excess cardiovascular mortality in bipolar disorder (BD), few studies have demonstrated increased prevalence of cardiovascular disease (CVD) and/or hypertension (HTN) in BD. We therefore examined this topic in a representative epidemiologic sample. METHOD The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions was used to determine whether prevalence of physician-diagnosed CVD and HTN is elevated among subjects with lifetime bipolar I disorder (BD-I), and whether CVD and HTN are prevalent at earlier ages among subjects with BD-I. RESULTS The age-, race-, and sex-adjusted prevalence of CVD was significantly greater among subjects with BD-I versus controls [odds ratio (OR) = 4.95, 95% confidence interval (CI): 4.27-5.75] and versus subjects with major depressive disorder [(MDD); OR =1.80, 95% CI: 1.52-2.14], as was the prevalence of HTN (OR = 2.38, 95% CI: 2.16-2.62 versus controls, OR = 1.44, 95% CI: 1.30-1.61 versus MDD; p < 0.0001 for all). Controlling additionally for marital status, education, income, obesity, smoking, anxiety disorders, and substance use disorders did not substantially alter these findings. The mean age of BD-I subjects with CVD and HTN was 14 and 13 years younger, respectively, than controls with CVD and HTN. CONCLUSIONS Adults with BD-I are at increased risk of CVD and HTN, prevalent over a decade earlier than non-BD adults. Strategies are needed to prevent excessive and premature cardiovascular burden in BD-I.

Biomarkers in bipolar disorder: A positional paper from the International Society for Bipolar Disorders Biomarkers Task Force

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

Psychosocial Functioning Among Bipolar Youth

BACKGROUND Evidence indicates that children and adolescents with bipolar disorder (BP) experience significant functional impairment. However, little is known about the association between psychosocial functioning and episodes of illness, demographic, and clinical variables in this population. METHODS Subjects included 446 patients aged 7 to 17 diagnosed with DSM-IV bipolar disorder via the K-SADS for the Course and Outcome of Bipolar Youth (COBY) study. The Psychosocial Functioning Schedule of the Adolescent Longitudinal Interval Follow-Up Assessment (A-LIFE) was administered at study intake. RESULTS Mild to moderate levels of psychosocial impairment were evident in work (includes academics), interpersonal, and overall domains of functioning among BP youth. Multivariate analyses indicated that the strongest predictors of psychosocial impairment were adolescence (regardless of age of onset), current mood episode, current affective symptom severity, current psychotic symptoms, and current comorbid conduct disorder. Bipolar youth in-episode were significantly more impaired than those in partial remission/recovery in every functional domain examined and were less satisfied with their functioning. Yet, BP youth in partial remission/recovery reported significant psychosocial impairment. LIMITATIONS Limitations include the reliance on patient and parent retrospective report of psychosocial functioning. Additionally, we did not account for the impact of psychosocial and pharmacological interventions on functioning. CONCLUSIONS Findings suggest pediatric BP is associated with significant impairment in psychosocial functioning during and between episodes, with greater impairment during mood episodes than during partial remission/recovery. Additionally, functional impairment in BP appears to increase during adolescence regardless of age of onset. Clinicians should carefully assess and address psychosocial impairment during and between mood episodes, with particular attention to the functioning of BP adolescents.

Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease A Scientific Statement From the American Heart Association

In the 2011 “Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents,” several medical conditions among youth were identified that predispose to accelerated atherosclerosis and early cardiovascular disease (CVD), and risk stratification and management strategies for youth with these conditions were elaborated. Major depressive disorder (MDD) and bipolar disorder (BD) among youth satisfy the criteria set for, and therefore merit inclusion among, Expert Panel tier II moderate-risk conditions. The combined prevalence of MDD and BD among adolescents in the United States is ≈10%, at least 10 times greater than the prevalence of the existing moderate-risk conditions combined. The high prevalence of MDD and BD underscores the importance of positioning these diseases alongside other pediatric diseases previously identified as moderate risk for CVD. The overall objective of this statement is to increase awareness and recognition of MDD and BD among youth as moderate-risk conditions for early CVD. To achieve this objective, the primary specific aims of this statement are to (1) summarize evidence that MDD and BD are tier II moderate-risk conditions associated with accelerated atherosclerosis and early CVD and (2) position MDD and BD as tier II moderate-risk conditions that require the application of risk stratification and management strategies in accordance with Expert Panel recommendations. In this scientific statement, there is an integration of the various factors that putatively underlie the association of MDD and BD with CVD, including pathophysiological mechanisms, traditional CVD risk factors, behavioral and environmental factors, and psychiatric medications.

Substance Use Disorders among Adolescents with Bipolar Spectrum Disorders

OBJECTIVE We set out to examine the prevalence and correlates of substance use disorders (SUD) in a large sample of adolescents with bipolar disorder (BP). METHODS Subjects were 249 adolescents ages 12 to 17 years old who fulfilled DSM-IV criteria for bipolar I disorder [(BPI), n = 154], or bipolar II disorder [(BPII), n = 25], or operationalized criteria for BP not otherwise specified [(BP NOS), n = 70], via the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS). As part of the multi-site Course and Outcome of Bipolar Youth study, demographic, clinical, and family history variables were measured via intake clinical interview with the subject and a parent/guardian. RESULTS The lifetime prevalence of SUD among adolescents with BP was 16% (40/249). Results from univariate analyses indicated that subjects with, as compared to without, SUD were significantly less likely to be living with both biological parents, and that there was significantly greater lifetime prevalence of physical abuse, sexual abuse, suicide attempts, conduct disorder, and posttraumatic stress disorder among subjects with SUD. Subjects with SUD reported significantly greater 12-month prevalence of trouble with police, and females with SUD reported significantly greater 12-month prevalence of pregnancy and abortion. Significant predictors of SUD in a logistic regression model included living with both biological parents (lower prevalence), conduct disorder and suicide attempts (increased prevalence). In logistic regression analyses controlling for demographic differences and conduct disorder, SUD remained significantly associated with trouble with police, whereas the association of SUD with pregnancy and abortion was reduced to a statistical trend. The prevalence of SUD was not significantly different among child- versus adolescent-onset BP subjects. CONCLUSIONS SUD among adolescents with BP is associated with profound hazards including suicide attempts, trouble with police, and teenage pregnancy and abortion.

Schedule for Affective Disorders and Schizophrenia for School- Age Children (K-SADS-PL) for the Assessment of Preschool Children- A Preliminary Psychometric Study

OBJECTIVE To assess the psychometrics of the schedule for affective disorders and schizophrenia for school-age children present and lifetime version (K-SADS-PL) in diagnosing DSM-IV psychiatric disorders and subsyndromal symptomatology in preschool children. METHOD Parents were interviewed about their children using the K-SADS-PL, and they completed the early childhood inventory-4 (ECI-4) and child behavior checklist for ages 1(1/2)-5 years (CBCL). Discriminant, divergent, and convergent validity of the K-SADS-PL were evaluated in 204 offspring ages 2-5 years old of parents from an ongoing study. Inter-rater reliability as well as predictive validity of intake diagnoses at second assessment approximately two years after intake were evaluated. Fourteen children were also assessed by the preschool age psychiatric assessment (PAPA). RESULTS Children who were diagnosed with oppositional defiant disorder, attention deficit hyperactivity disorder, anxiety, mood, or elimination disorders had significantly higher scores on the ECI-4 than children without these disorders. Significant correlations were found for all convergent CBCL scales. Divergent validity was acceptable for emotional disorders. Inter-rater kappa coefficients for all diagnoses were good. Above noted results were similar for children with at least one positive K-SADS-PL key screen symptom. A significantly higher percentage of children with an intake diagnosis had a diagnosis approximately two years after intake compared to those without an intake disorder. Overall, there was consistency between the PAPA and the K-SADS-PL. CONCLUSIONS Pending further testing, the K-SADS-PL may prove useful for the assessment of psychopathology in preschoolers.

Preliminary Findings Regarding Proinflammatory Markers and Brain-Derived Neurotrophic Factor Among Adolescents with Bipolar Spectrum Disorders

Mood symptoms in adult bipolar disorder are associated with increased proinflammatory markers and decreased brain-derived neurotrophic factor (BDNF). We examined serum interleukin-6, high-sensitivity C-reactive protein (hsCRP), and BDNF among 30 bipolar disorder adolescents. Hypomanic/manic symptoms were positively associated with hsCRP. BDNF levels were negatively associated with interleukin-6. Forty percent had cardiovascular high-risk hsCRP levels. Larger longitudinal studies are warranted.