To assess whether relative severity of irritability symptoms versus elation symptoms in mania is stable and predicts subsequent illness course in youth with DSM-IV bipolar I or II disorder or operationally defined bipolar disorder not otherwise specified.
Investigators used the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children to assess the most severe lifetime manic episode in bipolar youth aged 7–17 years who were recruited from 2000 to 2006 as part of the Course and Outcomes of Bipolar Youth prospective cohort study (N = 361), conducted at university-affiliated mental health clinics. Subjects with at least 4 years of follow-up (N = 309) were categorized as irritable-only (n = 30), elated-only (n = 42), or both irritable and elated (n = 237) at baseline. Stability of this categorization over follow-up was the primary outcome. The course of mood symptoms and episodes, risk of suicide attempt, and functioning over follow-up were also compared between baseline groups.
Most subjects experienced both irritability and elation during follow-up, and agreement between baseline and follow-up group assignment did not exceed that expected by chance (κ = 0.03; 95% CI, −0.06 to 0.12). Elated-only subjects were most likely to report the absence of both irritability and elation symptoms at every follow-up assessment (35.7%, versus 26.7% of irritable-only subjects and 16.9% of those with both irritability and elation; P = .01). Baseline groups experienced mania or hypomania for a similar proportion of the follow-up period, but irritable-only subjects experienced depression for a greater proportion of the follow-up period than did subjects who were both irritable and elated (53.9% versus 39.7%, respectively; P = .01). The groups did not otherwise differ by course of mood episode duration, polarity, bipolar diagnostic type, suicide attempt risk, or functional impairment.
Most bipolar youth eventually experienced both irritability and elation irrespective of history. Irritable-only youth were at similar risk for mania but at greater risk for depression compared with elated-only youth and youth who had both irritability and elation symptoms.
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder, but, to our knowledge, no studies examined the course of anxiety disorders in youth and adults with bipolar disorder.
As part of the Course and Outcome of Bipolar Youth study, 413 youth, ages 7 to 17 years who met criteria for Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) bipolar I disorder (n = 244), bipolar II disorder (n = 28), and operationally defined bipolar disorder not otherwise specified (n = 141) were recruited primarily from outpatient clinics. Subjects were followed on average for 5 years using the Longitudinal Interval Follow-Up Evaluation. We examined factors associated with the persistence (> 50% of the follow-up time) and onset of new anxiety disorders in youth with bipolar disorder.
Of the 170 youth who had anxiety at intake, 80.6% had an anxiety disorder at any time during the follow-up. Most of the anxiety disorders during the follow-up were of the same type as those present at intake. About 50% of the youth had persistent anxiety, particularly generalized anxiety disorder (GAD). Persistence was associated with multiple anxiety disorders, less follow-up time in euthymia, less conduct disorder, and less treatment with antimanic and antidepressant medications (all P values ≤ .05). Twenty-five percent of the sample who did not have an anxiety disorder at intake developed new anxiety disorders during follow-up, most commonly GAD. The onset of new anxiety disorders was significantly associated with being female, lower socioeconomic status, presence of attention-deficit/hyperactivity disorder and substance use disorder, and more follow-up time with manic or hypomanic symptoms (all P values ≤ .05)
Anxiety disorders in youth with bipolar disorder tend to persist, and new-onset anxiety disorders developed in a substantial proportion of the sample. Early identification of factors associated with the persistence and onset of new anxiety disorders may enable the development of strategies for treatment and prevention.
Individuals with early onset of bipolar disorder are at high risk for suicide. Yet, no study to date has examined factors associated with prospective risk for suicide attempts among youth with bipolar disorder.
To examine past, intake, and follow-up predictors of prospectively observed suicide attempts among youth with bipolar disorder.
We interviewed subjects, on average, every 9 months over a mean of 5 years using the Longitudinal Interval Follow-up Evaluation.
Outpatient and inpatient units at 3 university centers.
A total of 413 youths (mean [SD] age, 12.6 [3.3] years) who received a diagnosis of bipolar I disorder (n=244), bipolar II disorder (n=28), or bipolar disorder not otherwise specified (n=141).
Main Outcome Measures
Suicide attempt over prospective follow-up and past, intake, and follow-up predictors of suicide attempts.
Of the 413 youths with bipolar disorder, 76 (18%) made at least 1 suicide attempt within 5 years of study intake; of these, 31 (8% of the entire sample and 41% of attempters) made multiple attempts. Girls had higher rates of attempts than did boys, but rates were similar for bipolar subtypes. The most potent past and intake predictors of prospectively examined suicide attempts included severity of depressive episode at study intake and family history of depression. Follow-up data were aggregated over 8-week intervals; greater number of weeks spent with threshold depression, substance use disorder, and mixed mood symptoms and greater number of weeks spent receiving outpatient psychosocial services in the preceding 8-week period predicted greater likelihood of a suicide attempt.
Early-onset bipolar disorder is associated with high rates of suicide attempts. Factors such as intake depressive severity and family history of depression should be considered in the assessment of suicide risk among youth with bipolar disorder. Persistent depression, mixed presentations, and active substance use disorder signal imminent risk for suicidal behavior in this population.
To compare the dimensional psychopathology in offspring of parents with bipolar disorder (BP) with offspring of community control parents as assessed by the Child Behavior Checklist (CBCL).
Offspring of parents with BP, who were healthy or had no non-BP disorders (n = 319) and bipolar spectrum disorders (n = 35), and offspring of community controls (n = 235) ages 6–18 years old were compared using the CBCL, the CBCL-Dysregulation Profile (CBCL-DP), and a sum of the CBCL items associated with mood lability. The results were adjusted for multiple comparisons and any significant between-group demographic and clinical differences in both biological parents and offspring.
With few exceptions, several CBCL (e.g., Total, Internalizing, and Aggression Problems), CBCL-DP, and mood lability scores in non-BP offspring of parents with BP were significantly higher than in offspring of control parents. In addition, both groups of offspring showed significantly lower scores in most scales when compared with offspring of parents with BP who already developed BP. Similar results were obtained when analyzing the rates of subjects with CBCL T-scores that were two standard deviations or higher above the mean.
Even before developing BP, offspring of parents with BP had more severe and higher rates of dimensional psychopathology than offspring of control parents. Prospective follow-up studies in non-BP offspring of parents with BP are warranted to evaluate whether these dimensional profiles are prodromal manifestations of mood or other disorders and can predict those who are at higher risk to develop BP.
bipolar disorder; bipolar offspring; psychopathology; Child Behavior Checklist; dysregulation profile; mood lability
To determine the rate of diagnostic conversion from an operationalized diagnosis of Bipolar Disorder Not Otherwise Specified (BP-NOS) to Bipolar I or Bipolar II Disorders (BP-I/II) in youth over prospective follow-up and to identify factors associated with conversion.
Subjects were 140 children and adolescents recruited from clinical referrals or advertisement who met operationalized criteria for BP-NOS at intake and participated in at least one follow-up evaluation (91% of initial cohort). Diagnoses were assessed at follow-up interviews using the Longitudinal Interval Follow-Up Evaluation. The mean duration of follow-up was 5 years and the mean interval between assessments was 8.2 months.
Diagnostic conversion to BP-I/II occurred in 63 subjects (45%): 32 (23%) to BP-I (9 of whom had initially converted to BP-II) and 31 to only BP-II (22%). Median time from intake to conversion was 58 weeks. First or second-degree family history of mania or hypomania was the strongest baseline predictor of diagnostic conversion (p=.006). Over follow-up, conversion was associated with greater intensity of hypomanic symptoms and with greater exposure to specialized, intensive outpatient psychosocial treatments. There was no association between conversion and exposure to treatment with particular medication classes.
Children and adolescents referred with mood symptoms that meet operationalized criteria for BP-NOS, particularly those with a family history of BP, frequently progress to BP-I or BP-II disorders. Efforts to identify these youth and effectively intervene may have the potential to curtail the progression of mood disorders in this high-risk population.
Mood Disorders - Bipolar; Child Psychiatry; Adolescents; Diagnosis; Classification
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.
Offspring of parents with bipolar disorder are at increased risk for a range of psychopathology, including bipolar disorder. It is not clear if they also have impairments in their psychosocial functioning.
We compared the psychosocial functioning of three groups of children enrolled in the Pittsburgh Bipolar Offspring Study (BIOS): offspring of probands with bipolar disorder (n=388), offspring of probands with other types of psychopathology (n=132), and offspring of healthy probands (n=118). Psychosocial functioning was assessed at study intake using the schedule of the Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE), the Child Behaviour Check list (CBCL) and the Children's Global Assessment Scale (CGAS).
Offspring of probands with bipolar disorder exhibited impairments in various aspects of psychosocial functioning. On all measures, they had worse functioning in comparison with offspring of healthy probands. Offspring of probands with bipolar disorder generally exhibited more impairment than offspring of probands with non bipolar psychopathology. After adjusting for proband parent functioning and the child's Axis I psychopathology, functioning of offspring of probands with bipolar disorder was similar to that of offspring of healthy probands.
Data are cross-sectional and therefore do not allow for causal conclusions about the association between parental psychopathology, child psychopathology and offspring psychosocial functioning.
Offspring of parents with bipolar disorder exhibit impairments in psychosocial functioning which appear largely attributable to proband parent functional impairment and the child's own psychopathology. As such, interventions to improve parental functioning, as well as early interventions to treat the child's psychopathology may help reduce the risk for long-term functional impairment in offspring.
Bipolar disorder; offspring; social functioning
Clinical gene transfer holds promise for the treatment of many inherited and acquired disorders. A key consideration for all clinical gene transfer applications is the tight control of transgene expression. We have examined the safety and biodistribution of a serotype 2, recombinant adeno-associated viral (AAV2) vector that encodes a rapamycin-responsive chimeric transcription factor, which regulates the expression of a therapeutic transgene (human erythropoietin [hEpo]). The vector, AAV2-TF2.3w-hEpo (2.5 × 107–2.5 × 1010 particles), was administered once to a single submandibular gland of male and female mice and mediated hEpo expression in vivo following a rapamycin injection but not in its absence. Control (saline treated) and vector-treated animals maintained their weight, and consumed food and water, similarly. Vector delivery led to no significant toxicological effects as judged by hematology, clinical chemistry, and gross and microscopic pathology evaluations. On day 3 after vector delivery, vector copies were not only abundant in the targeted right submandibular gland but also detected in multiple other tissues. Vector was cleared from the targeted gland much more rapidly in female mice than in male mice. Overall, our results are consistent with the notion that administration of the AAV2-TF2.3w-hEpo vector to salivary glands posed no significant risk in mice.
AAV2 vector; safety; salivary gland; rapamycin; regulated gene expression
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.
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.
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.
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.
bipolar disorder; cardiovascular; cardiovascular disease; epidemiologic; hypertension
The Random Forests (RF) algorithm has become a commonly used machine learning algorithm for genetic association studies. It is well suited for genetic applications since it is both computationally efficient and models genetic causal mechanisms well. With its growing ubiquity, there has been inconsistent and less than optimal use of RF in the literature. The purpose of this review is to breakdown the theoretical and statistical basis of RF so that practitioners are able to apply it in their work. An emphasis is placed on showing how the various components contribute to bias and variance, as well as discussing variable importance measures. Applications specific to genetic studies are highlighted. To provide context, RF is compared to other commonly used machine learning algorithms.
machine learning; SNP; genome wide association studies
The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor required for HLA class II MHC-restricted antigen presentation. MHC genes, including the HLA class II DRB1*03:01 allele, are strongly associated with systemic lupus erythematosus (SLE). Recently the rs4774 CIITA missense variant (+1632G/C) was reported to be associated with susceptibility to multiple sclerosis. In the current study, we investigated CIITA, DRB1*03:01 and risk of SLE using a multi-stage analysis. In stage 1, 9 CIITA variants were tested in 658 cases and 1,363 controls (N = 2,021). In stage 2, rs4774 was tested in 684 cases and 2,938 controls (N = 3,622). We also performed a meta-analysis of the pooled 1,342 cases and 4,301 controls (N = 5,643). In stage 1, rs4774*C was associated with SLE (odds ratio [OR] = 1.24, 95% confidence interval [95% CI] = 1.07–1.44, P = 4.2 × 10−3). Similar results were observed in stage 2 (OR = 1.16, 95% CI = 1.02–1.33, P = 8.5×10−3) and the meta-analysis of the combined dataset (OR = 1.20, 95% CI = 1.09–1.33, Pmeta = 2.5×10−4). In all three analyses, the strongest evidence for association between rs4774*C and SLE was present in individuals who carried at least one copy of DRB1*03:01 (Pmeta= 1.9×10−3). Results support a role for CIITA in SLE, which appears to be stronger in the presence of DRB1*03:01.
systemic lupus erythematosus; autoimmunity; major histocompatibility complex; HLA; CIITA; MHC2TA
Bipolar disorder (BP) in youth is an impairing psychiatric disorder associated with high rates of relapse and recurrence. High rates of psychiatric and medical co-morbidities account for additional illness burden in pediatric BP. The elevated risk of overweight and obesity in this population is of particular concern. One of the likely etiologies for weight gain in youth with BP is use of mood-stabilizing medications. Although these medications can be effective for mood stabilization, excessive weight gain is a common side effect. Obesity is associated with a host of medical problems and is also correlated with worse psychiatric outcomes in BP, rendering the prevention of weight gain in this population particularly clinically relevant. In this article, we describe the rationale and development of a brief motivational intervention for preventing weight gain among youth with BP initiating mood-stabilizing pharmacological treatment and then present a case example illustrating the principles of the intervention.
Previous studies of clinical samples of adults with bipolar disorder (BD) suggest that there is increased prevalence of obesity and that obesity is associated with greater BD severity. We therefore examined this topic in a representative epidemiologic sample.
The 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions was used to determine whether the prevalence of obesity is elevated among subjects with lifetime BD, and whether obesity is associated with greater severity of BD.
The age-, race-, and sex-adjusted prevalence of obesity was significantly greater among subjects with BD versus controls [odds ratio (OR) = 1.65, 95% confidence interval (CI): 1.45–1.89, p < 0.001]. Obesity among subjects with BD was significantly positively associated with greater age, female sex, comorbid anxiety and medical conditions, and depression-related treatment utilization, and significantly negatively associated with past-year substance use disorder (SUD). In multivariable analyses, obesity among adults with BD was positively associated with age, comorbid anxiety disorders, duration of depressive episodes, and history of hospitalization for depression, and negatively associated with past-year SUD.
The increased prevalence of obesity in BD and its association with illness severity, particularly in relation to depression, cannot be attributed to biases inherent in treatment-seeking samples. Future studies are needed to examine the direction of the observed associations and to develop preventive and treatment strategies seeking to mitigate the burden of obesity in BD.
bipolar disorder; epidemiologic; obesity
To examine rates and identify risk factors for suicidal ideation among offspring of parents with bipolar disorder.
Subjects included 388 offspring of parents with bipolar disorder and 250 offspring of matched community controls enrolled in the Pittsburgh Bipolar Offspring Study (BIOS).
Offspring of bipolar probands displayed greater rates of lifetime suicidal ideation than offspring of controls (33% versus 20%). Factors most strongly associated with lifetime suicidal ideation in offspring of bipolar parents included offspring mood disorder, hostility, recent sexual abuse, and family conflict.
Offspring of parents with bipolar disorder are at elevated risk for suicidal ideation as compared with offspring of controls. Suicide risk assessment in this population should attend to specific risk factors identified.
bipolar disorder; offspring; suicidal ideation; high risk
The primary genetic risk factor in multiple sclerosis (MS) is the HLA-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has yet to be elucidated. Several lines of evidence support a role for neuroendocrine system involvement in autoimmunity which may, in part, be genetically determined. Here, we comprehensively investigated variation within eight candidate hypothalamic–pituitary–adrenal (HPA) axis genes and susceptibility to MS. A total of 326 SNPs were investigated in a discovery dataset of 1343 MS cases and 1379 healthy controls of European ancestry using a multi-analytical strategy. Random Forests, a supervised machine-learning algorithm, identified eight intronic SNPs within the corticotrophin-releasing hormone receptor 1 or CRHR1 locus on 17q21.31 as important predictors of MS. On the basis of univariate analyses, six CRHR1 variants were associated with decreased risk for disease following a conservative correction for multiple tests. Independent replication was observed for CRHR1 in a large meta-analysis comprising 2624 MS cases and 7220 healthy controls of European ancestry. Results from a combined meta-analysis of all 3967 MS cases and 8599 controls provide strong evidence for the involvement of CRHR1 in MS. The strongest association was observed for rs242936 (OR = 0.82, 95% CI = 0.74–0.90, P = 9.7 × 10−5). Replicated CRHR1 variants appear to exist on a single associated haplotype. Further investigation of mechanisms involved in HPA axis regulation and response to stress in MS pathogenesis is warranted.
Anxiety disorders are among the most common comorbid conditions in youth with bipolar disorder (BP). We aimed to examine the prevalence and correlates of comorbid anxiety disorders among youth with BP.
As part of the Course and Outcome of Bipolar Youth study (COBY), 446 youth ages 7 to 17, who met DSM-IV criteria for BP-I (n=260), BP-II (n=32) or operationalized criteria for BP not otherwise specified (BP-NOS; n=154) were included. Subjects were evaluated for current and lifetime Axis-I psychiatric disorders at intake using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children–Present and Lifetime version (K-SADS-PL), and standardized instruments to assess functioning and family history.
Forty-four percent (n=194) of the sample met DSM-IV criteria for at least one lifetime anxiety disorder, most commonly Separation Anxiety (24%) and Generalized Anxiety Disorders (16%). Nearly 20% met criteria for two or more anxiety disorders. Overall, anxiety disorders predated the onset of BP. BP-II subjects were more likely than BP-I or BP-NOS subjects to have a comorbid anxiety disorder. After adjusting for confounding factors, BP youth with anxiety were more likely to have BP-II, longer duration of mood symptoms, more severe ratings of depression, and family history of depression, hopelessness and somatic complaints during their worst lifetime depressive episode than those without anxiety.
Comorbid anxiety disorders are common in youth with BP, and most often predate BP onset. BP-II, a family history of depression, and more severe lifetime depressive episodes distinguish BP youth with comorbid anxiety disorders from those without. Careful consideration should be given to the assessment of comorbid anxiety in BP youth.
Youth; anxiety; bipolar disorder; prevalence; clinical correlates
The purpose of this study is to examine the prevalence and correlates of non-suicidal self-injury (NSSI) among children and adolescents diagnosed with bipolar disorder (BP).
Four hundred-thirty two youth with a diagnosis of BP and their parents, including 193 children and 239 adolescents, completed a diagnostic interview and instruments to assess youth clinical and illness history, youth comorbidity, parental mood disorder, and psychosocial functioning.
Approximately 22% of children and 22% of adolescents reported NSSI during the course of their most recent mood episode. In a multivariate model controlling for global impairment, among children, a BPI or BPII diagnosis (versus BPNOS), psychosis, separation anxiety disorder, and greater severity of depressive symptoms were found to be associated with NSSI. Among adolescents, a mixed episode, a suicide attempt, greater severity of depressive symptoms, and poor psychosocial functioning were found to be associated with NSSI. Neither the presence of a youth comorbid disruptive behavior disorder nor a parental mood disorder was associated with NSSI.
The primary limitations of this study include the use of a cross-sectional study design, lack of a control group, and limited generalizability of study results to non-clinical and ethnically diverse samples.
NSSI is not uncommon among youth with BP, particularly those who present with BPI or BPII, psychosis, a mixed episode, suicidal behavior, severe depressive symptoms, separation anxiety, and/or poor psychosocial functioning. However, the relative importance of these factors in relation to NSSI may vary with age. Treatments for BP that are developmentally sensitive, examine the function of NSSI for each youth, and teach adaptive skills to address emotional and social needs, may prove to be most successful.
Bipolar Disorder; Self-Injury; Suicide; Comorbidity; Psychosocial
Despite the known association between substance use disorders (SUD) and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD.
Youth with MDD who had not improved after an adequate SSRI trial (N = 334) were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial. Analyses examined substance use (via the Drug Use Severity Index) and changes therein in relation to treatment and depressive symptoms. Adolescents meeting SUD criteria via the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version at baseline were excluded.
Substance use was common: 28.1% reported repeated experimentation at baseline. Substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. There was significant improvement in substance-related impairment among adolescents who responded to MDD treatment. Baseline suicidal ideation was higher among subjects who progressed to high substance-related impairment (≥75th percentile) versus those whose substance-related impairment remained low (<75th percentile), and parental depressive symptoms predicted persistence of high substance-related impairment during the study. MDD response was best among adolescents with low 12-week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairment. There were no significant differential effects of specific treatments, pharmacological or CBT, on substance use.
Substance use is common among adolescents with treatment-resistant MDD. Subjects who had persistently low substance-related impairment or who demonstrated reduced substance-related impairment had better MDD treatment response, although the direction of this association is uncertain.
substance use; depression; adolescents; treatment
Despite increased risk, most offspring of parents with bipolar disorder (BP) do not manifest BP. The identification of risk factors for BP among offspring could improve preventive and treatment strategies. We examined this topic in the Pittsburgh Bipolar Offspring Study (BIOS).
Subjects included 388 offspring, ages 7–17 years, of 233 parents with BP-I or BP-II (via the Structured Clinical Interview for DSM-IV). Offspring diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime version (KSADS-PL). Analyses focused on the 41 offspring who were diagnosed with BP-I (N=9), BP-II (N=5), or BP-NOS (N=27).
Offspring with BP had proband parents who were significantly younger at the time of their birth, were more likely to be female, and had lower socio-economic status, versus proband parents of offspring without BP. Parental clinical variables and obstetrical variables were not significantly associated with BP among offspring. History of physical and/or sexual abuse, exposure to antidepressants, and exposure to stimulants was significantly greater among offspring with versus without BP. There was significantly greater prevalence of attention-deficit hyperactivity disorder, anxiety disorders, oppositional-defiant/conduct disorders (ODD/CD), and exposure to stimulants and antidepressants among offspring with versus without BP. Variables significantly associated with BP among offspring in regression analyses were: older offspring age, younger parent age at birth, offspring anxiety disorders and ODD/CD, and biological co-parent with BP.
History of anxiety and/or disruptive behavior disorders, as well as presence of bi-lineal parental BP, is associated with elevated risk of bipolar spectrum disorders among offspring. If replicated prospectively, these findings could have implications for the diagnosis and treatment of psychopathology among BP offspring.
bipolar disorder; high risk; offspring; familial
To evaluate lifetime prevalence and specificity of DSM-IV psychiatric disorders and severity of depressive and manic symptoms at intake in preschool offspring of parents with Disorder I–II.
121 offspring ages 2–5 years old of 83 parents with Bipolar Disorder and 102 offspring of 65 demographically matched control parents (29 with non-Bipolar psychiatric disorders and 36 without any lifetime psychopathology) were recruited. Parents with Bipolar Disorder were recruited through advertisement and adult outpatient clinics and control parents were ascertained at random from the community. Subjects were evaluated with standardized instruments. All staff were blind to parental diagnoses.
After adjusting for within-family correlations and both biological parents’ non-Bipolar psychopathology, compared to the offspring of the control parents, offspring of parents with Bipolar Disorder, particularly those older than 4 years old, showed an 8-fold increased life-time prevalence of Attention Deficit Hyperactive Disorder (ADHD) and significantly higher rates of ≥ 2 psychiatric disorders. While only 3 offspring of parents with Bipolar Disorder had mood disorders, offspring of parents with Bipolar Disorder, especially those with ADHD and Oppositional-Defiant Disorder, had significantly more severe current manic and depressive symptomatology than the offspring of the controls.
Preschool offspring of parents with Bipolar Disorder are at increased risk for ADHD and demonstrate increased subthreshold manic and depressive symptomatology. Longitudinal follow-up is warranted to evaluate whether these children are at high-risk to develop mood and other psychiatric disorders.
Epidemiologic studies have found that major depressive disorder (MDD) and anxiety disorders are associated with pain. However, little is known regarding the prevalence and correlates of pain in bipolar I disorder (BD).
The 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample (N = 43,093) of the U.S. adult population, was used to determine if 1) prevalence of moderate-or-greater pain interference is elevated among subjects with 12-month history of BD, and 2) psychiatric and medical comorbidities independently contribute to increased pain interference in BD.
Subjects with BD were significantly more likely to report pain interference of at least moderate severity compared to subjects without BD (24.8% versus 11.9%, p<0.001). Moderate or greater pain interference is also significantly more common among subjects with BD than those with MDD (20.3%) or anxiety disorders (19.3%; p<0.001). Logistic regression analyses adjusting for potential confounding variables indicated that BD is independently associated with increased pain interference (adjusted odds ratio 1.57, 95% confidence interval 1.39–1.78). Factors associated with pain interference in BD included greater age, non-white race, lower income, increased frequency of arthritis and other medical problems, comorbid anxiety disorders, and comorbid substance use disorders.
The prevalence of pain interference is elevated in BD, even compared to MDD or anxiety disorders, and is associated with both medical and psychiatric comorbidities. Interference from pain may be an important variable to consider in the assessment and treatment of BD. Future prospective studies are needed to determine the direction of the observed associations.
pain; bipolar disorder; comorbidity; epidemiologic
To study the relationship between negative life events and demographic and clinical variables in youth with bipolar I disorder, bipolar II disorder, and bipolar disorder not otherwise specified (NOS), as well as to compare the rates of life events in youth with bipolar disorder, depressive and/or anxiety disorders (DEP-ANX), and healthy controls.
Subjects included 446 youth, aged 7 to 17 years, meeting DSM-IV criteria for bipolar I, bipolar II, or an operationalized definition of bipolar disorder NOS, and were enrolled in the Course and Outcome of Bipolar Illness in Youth study. Subjects completed the Life Events Checklist. Sixty-five DEP-ANX and 65 healthy youth were obtained from previous studies using similar methodology. The study was conducted from October 2000 to July 2006.
Older age, lower socioeconomic status, living with nonintact family, non-Caucasian race, anxiety, and disruptive disorders were associated with greater number of total negative life events. Specifically, increased independent, dependent, and uncertain negative life events were associated with lower socioeconomic status, nonintact family, and comorbid disruptive disorders. Increased independent negative life events were additionally associated with non-Caucasian race and comorbid anxiety disorders. Increased dependent and uncertain negative life events were also associated with older age. DEP-ANX youth reported a similar rate of negative life events as bipolar youth, and both groups had more negative life events than the healthy controls. Bipolar youth reported fewer total and dependent positive life events compared to DEP-ANX and healthy youths.
Similar to DEP-ANX youth, bipolar youth are exposed to excessive negative independent and dependent life events which may have implications in the long-term outcome and negative consequences associated with this disorder.
To determine whether some children with bipolar disorder (BP) manifest irritability without elation and whether these children differ on socio-demographic, phenotypic, and familial features from those who have elation and no irritability and from those who have both.
361 BP youth recruited from three sites, University of Pittsburgh, Brown, and UCLA were assessed at baseline and for most severe past symptomatology using standardized semi-structured interviews. BP subtype was identified and frequency and severity of manic symptoms quantified. Subjects were required to have episodic mood disturbance to be diagnosed with BP. The sample was then re-classified, and compared, based upon the most severe lifetime manic episode into three subgroups: elated only, irritable only, and both elated and irritable.
Irritable only and elated only subgroups constituted 10% and 15% of the sample, respectively. Except for the irritable only subjects being significantly younger than the other two subgroups, there were no other between groups socio-demographic differences. There were no significant between-group differences in the BP subtype, rate of psychiatric comorbidities, severity of illness, duration of illness, and family history of mania in first/second-degree relatives and other psychiatric disorders in first degree relatives with the exception of depression and alcohol abuse occurring more frequently in the irritability only subgroup. The elated only group had higher scores on most DSM-IV mania criterion B items.
The results of this study support the DSM-IV A criteria for mania in youth. Irritable-only mania exists, particularly in younger children, but similar to elated-only mania it occurs infrequently. The fact that the irritable only subgroup has similar clinical characteristics and family histories of BP, as compared to subgroups with predominant elation, provides support for continuing to consider episodic irritability in the diagnosis of pediatric BP.
Overweight (OW) and obesity (OB) is highly prevalent among adults with bipolar disorder (BP), and has been associated with illness severity. Little is known regarding OW/OB among youth with BP.
Subjects were 348 youth ages 7 to 17 years old, with BP-I, BP-II, or study-operationalized criteria for BP-NOS enrolled in the Course and Outcome of Bipolar Youth study. Ageand sex-adjusted body mass index (BMI) was computed according to International Obesity Task Force cut points, based on self- and parent-reported height and weight, to determine OW/OB.
OW/OB was prevalent among 42% of subjects. The most robust predictors of OW/OB in a logistic regression model were younger age, non-Caucasian race, lifetime physical abuse, substance use disorders, psychiatric hospitalizations, and exposure to ≥2 medication classes associated with weight-gain.
The prevalence of OW/OB among youth with BP may be modestly greater than the general population. Moreover, similar to adults, OW/OB among youth with BP may be associated with increased psychiatric burden. These preliminary findings underscore the importance of early identification of OW/OB among youth with BP. Future studies are needed to clarify the direction of the associations between OW/OB and the identified predictors, and to compare the prevalence of OW/OB among youth with BP versus other psychiatric disorders.
bipolar disorder; child; adolescent; pediatric; overweight; obesity