Multiple Anxiety Disorders Research Articles

Psychopathology in Adolescent Offspring of Parents With Panic Disorder, Major Depression, or Both: A 10-Year Follow-Up

The authors examined the specificity and course of psychiatric disorders from early childhood through adolescence in offspring of parents with confirmed panic disorder and major depressive disorder. The authors examined rates of psychiatric disorders at 10-year-follow-up (mean age, 14 years) in four groups: offspring of referred parents with panic and depression (N=137), offspring of referred parents with panic without depression (N=26), offspring of referred parents with depression without panic (N=48), and offspring of nonreferred parents with neither disorder (N=80). Follow-up assessments relied on structured interviews with the adolescents and their mothers; diagnoses were rated present if endorsed by either. Parental panic disorder, independently of parental depression, predicted lifetime rates in offspring of multiple anxiety disorders, panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Parental depression independently predicted offspring bipolar, drug use, and disruptive behavior disorders. Parental panic and depression interacted to predict specific phobia and major depressive disorder. Phobias were elevated in all at-risk groups, and depression was elevated in both offspring groups of parents with depression (with or without panic disorder), with the highest rates in the offspring of parents with depression only. Parental depression independently predicted new onset of depression, parental panic disorder independently predicted new onset of social phobia, and the two interacted to predict new onset of specific phobia and generalized anxiety disorder. At-risk offspring continue to develop new disorders as they progress through adolescence. These results support the need to screen and monitor the offspring of adults presenting for treatment of panic disorder or major depressive disorder.

Two‐year course of anxiety disorders: different across disorders or dimensions?

This study compares diagnostic and symptom course trajectories across different anxiety disorders, and examines the role of anxiety arousal vs. avoidance behaviour symptoms in course prediction. Data were from 834 subjects with a current anxiety disorder from the Netherlands Study of Depression and Anxiety (NESDA) who were re-interviewed after 2 years. DSM-IV-based diagnostic interviews and Life Chart Interviews (LCI) were used to assess the diagnostic and symptom course trajectory over 2 years. Anxiety arousal and avoidance behaviour symptoms were measured with LCI, Beck Anxiety Inventory and Fear Questionnaire. Prognosis varied across disorders, with favourable remittance rates of 72.5% for panic disorder without agoraphobia and 69.7% for generalized anxiety disorder; gradually declining to 53.5% for social phobia and 52.7% for panic disorder with agoraphobia. Only 42.9% of those with multiple anxiety disorder remitted, and this group showed a more chronic course than pure anxiety disorders. Both baseline duration and severity were course predictors. Avoidance behaviour symptoms predicted the outcome better than anxiety arousal symptoms. These data suggest that the specific anxiety disorders such as recognized by DSM-IV are useful in predicting the outcome and that this may be determined largely by the relative severity of avoidance behaviour that patients have developed.

Psychiatric Comorbidity and Functioning in a Clinically Referred Population of Adults with Autism Spectrum Disorders: A Comparative Study

To systematically examine the patterns of psychiatric comorbidity and functioning in clinically referred adults with autism spectrum disorders (ASD). Psychiatrically referred adults with and without ASD were compared on measures assessing for psychiatric comorbidity and psychosocial functioning. Sixty-three adults with ASD participated in the study (mean age: 29±11years). Adults with ASD in their lifetime suffered from a higher burden of psychiatric disorders (6±3.4 vs. 3.5±2.7; p<0.001) including major depressive disorder and multiple anxiety disorders, and were functionally more impaired with a significant proportion having received both counseling and pharmacotherapy. Adults with ASD have high levels of psychiatric comorbidity and dysfunction comparable to a clinically referred population of adults without ASD.

Developmental Pathways for Different Subtypes of Early-Onset Bipolarity in Youths

Two main patterns of comorbidity have been described in bipolar disorder in children and adolescents: the first including preexisting attention-deficit/hyperactivity disorder (ADHD) and related disruptive behavior disorders and the second including anxiety disorders, namely, the association of co-occurring multiple anxiety disorders, usually predating the onset of bipolarity. This study was aimed at exploring whether ADHD and multiple anxiety disorders may exhibit different pathways to specific bipolar phenotypes. We compared 49 youths (7 to 18 years) with bipolar disorder + ADHD without anxiety, 76 youths with bipolar disorder + multiple anxiety disorders without ADHD, and 52 youths with bipolar disorder without ADHD or multiple anxiety disorders who were referred to a third-level hospital and diagnosed according to DSM-IV-TR in the period 2005-2011. Subjects were evaluated for current and lifetime Axis I psychiatric disorders by using a structured clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version) and followed up for at least 6 months. Compared to both patients with bipolar disorder + multiple anxiety disorders and patients with bipolar disorder without ADHD and multiple anxiety disorders, patients with bipolar disorder + ADHD without anxiety were more frequently male, were younger, had an earlier onset of bipolar disorder, had a prevalent chronic course and irritable mood, were more likely to present with a bipolar disorder not otherwise specified diagnosis, had a greater clinical severity and functional impairment, had a manic/mixed index episode, had a higher risk of conduct disorder, and were more resistant to treatments, according to the CGI-Improvement scores (P < .0001). Patients with bipolar disorder + multiple anxiety disorders were similar to those with bipolar disorder without ADHD or multiple anxiety disorders, except for a higher rate of diagnosis of bipolar II disorder, more use of antidepressants, and less use of atypical antipsychotics. The presence of comorbid ADHD versus anxiety disorders is indicative of fundamental differences in the phenomenology of bipolar disorder in youth. While ADHD prior to bipolar disorder is associated with a specific bipolar phenotype, bipolar patients with multiple anxiety disorders are similar to "typical" bipolar patients.

Empirically derived subtypes of lifetime anxiety disorders: developmental and clinical correlates in U.S. adolescents.

The current study examined the sex- and age-specific structure and comorbidity of lifetime anxiety disorders among U.S. adolescents. The sample consisted of 2,539 adolescents (1,505 females and 1,034 males) from the National Comorbidity Survey-Adolescent Supplement who met criteria for Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev. [DSM-IV-TR]) lifetime anxiety disorders (American Psychiatric Association, 2000). Adolescents ranged in age from 13 to 18 years (M = 15.2 years, SE = 0.08 years) and were 39% non-White. Multiple-group latent class analysis was conducted by adolescent sex and age to identify subgroups of adolescents with similar anxiety disorder profiles. Developmental and clinical correlates of empirically derived classes were also examined to assess the nomological validity of identified subgroups. A 7-class solution provided the best fit to the data, with classes defined primarily by one rather than multiple anxiety disorders. Results also indicated that classes displayed similar diagnostic profiles across age, but varied by sex. Classes characterized by multiple anxiety disorders were consistently associated with a greater degree of persistence, clinical severity, impairment, and comorbidity with other DSM-IV-TR psychiatric disorders. The presentation of lifetime anxiety disorders among adolescents and the observation of unique correlates of specific classes provide initial evidence for the utility of individual DSM-IV-TR anxiety disorder categories. Although findings of the present study should be considered preliminary, results emphasize the potential value of early intervention and gender-specific conceptualization and treatment of anxiety disorders.

Factors Associated With the Persistence and Onset of New Anxiety Disorders in Youth With Bipolar Spectrum Disorders

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.

Relationships between anxiety severity, diagnosis of multiple anxiety disorders, and comorbid major depressive disorder

Patients with anxiety disorder (AD) are more likely to be concurrently comorbid with other ADs or major depressive disorder (MDD). However, it is unknown whether such patients show more severe anxiety symptoms than patients with single AD. We compared anxiety severity among patients with single AD, multiple ADs, and multiple ADs plus MDD. Subjects were 136 consecutive outpatients with any AD who were comprehensively diagnosed. Symptom severity of panic disorder (PD), social anxiety disorder (SAD), obsessive–compulsive disorder (OCD), and generalized anxiety disorder (GAD) was measured using self-rating questionnaires, and the scores were compared among the 3 comorbidity conditions (single AD vs. multiple ADs vs. multiple ADs plus MDD). PD and SAD scores in the multiple ADs and the multiple ADs plus MDD conditions were significantly greater than the scores in the single AD condition regardless of diagnosis of PD and SAD. OCD scores did not differ among the 3 conditions while the scores in patients with OCD were significantly greater than those in patients without OCD. GAD scores in the multiple ADs plus MDD condition were significantly greater than those in the single AD and the multiple AD conditions. Moreover, in patients with MDD, the GAD scores in patients with GAD were not greater than those in patients without GAD. The results suggest that symptoms of PD, SAD, and GAD but not OCD are affected by the diagnosis of multiple ADs or comorbid MDD and that diagnosis of comorbid MDD affects GAD symptoms more strongly than diagnosis of GAD.

Trait Versus Situation-Specific Intolerance of Uncertainty in a Clinical Sample with Anxiety and Depressive Disorders

Intolerance of uncertainty (IU) has been most heavily implicated in the development and maintenance of generalised anxiety disorder; however, recent research has supported the transdiagnostic conceptualisation of IU by demonstrating that IU contributes to a broad array of symptoms associated with multiple anxiety and depressive disorders. The aim of this study was to examine IU firstly as a trait variable and secondly in reference to a regularly occurring, diagnostically relevant situation in a large clinical sample (N = 218). A measure of situation-specific IU (the Intolerance of Uncertainty Scale–Situation-Specific Version; IUS-SS) is presented. The IUS-SS was found to have a unitary factor structure and high internal consistency. Participants reported significantly more situation-specific IU compared to trait IU. Discriminant validity was indicated by lack of significant relationships with measures of extraversion and alcohol use. Supporting the convergent validity and transdiagnostic nature of the scale, the IUS-SS was positively associated with neuroticism and symptoms of generalised anxiety disorder and social phobia, and explained unique variance in symptoms of depression and panic disorder above and beyond trait IU. Theoretical and clinical implications are discussed.

Empirically derived subgroups of bipolar I patients with different comorbidity patterns of anxiety and substance use disorders in Han Chinese population

Bipolar-I disorder (BPI) often co-occurred with anxiety (ANX) and substance use disorders (SUD), which poses challenges in public health and clinical treatment, and adds complexity in searching for relevant etiologic factors. The present study sought to identify subgroups of BPI patients using comorbidity patterns with ANX and SUD. Clinical patients (N=306) diagnosed with BPI were recruited and interviewed using the Composite International Diagnostic Interview to collect data on demographics and clinical features, including episodic information, impairments, and lifetime diagnoses of ANX (panic, agoraphobia, generalized anxiety disorder, specific and social phobia) and SUD (nicotine dependence, alcohol use and drug use disorder). We applied latent class analysis to empirically derive classes of BPI. A number of exogenous variables were examined for each class. A three-class model provides excellent discriminability for subgrouping BPI patients with different comorbidity patterns. The BPI-LOW class (83.99%) had more pure mania without most lifetime comorbidity, higher numbers of last year mania episodes, and less suicidality and impairments. The BPI-ANX class (3.60%) was female predominant, tended to comorbid with multiple anxiety disorders but no SUD, and had early onset age. The BPI-SUD class (12.42%) was male predominant, had high prevalence of lifetime SUD and frequent mood episodes in the last year. Both the BPI-ANX and BPI-SUD classes had severe functional impairments and suicidal behaviors. Clinical information was retrospectively collected. Besides, we did not comprehensively access lifetime comorbidity for all psychiatric disorders. The three empirically identified subgroups of BPI patients exhibited distinguished comorbidity patterns and clinical features, including suicidal behaviors, frequent mood episodes and functional impairments. Our findings have clinical implication in intervention and treatment as well as to explore their different underlying mechanisms.

The Study of Fear Extinction: Implications for Anxiety Disorders

In this review, the authors propose that the fear extinction model can be used as an experimental tool to cut across symptom dimensions of multiple anxiety disorders to enhance our understanding of the psychopathology of these disorders and potentially facilitate the detection of biomarkers for them. The authors evaluate evidence for this proposition from studies examining the neurocircuitry underlying fear extinction in rodents, healthy humans, and clinical populations. The authors also assess the potential use of the fear extinction model to predict vulnerability for anxiety and treatment response and to improve existing treatments or develop novel ones. Finally, the authors suggest potential directions for future research that will help to further validate extinction as a biomarker for anxiety across diagnostic categories and to bridge the gap between basic neuroscience and clinical practice.

Symptomatology and markers of anxiety disorders in Parkinson's disease: A cross‐sectional study

Anxiety is understudied in Parkinson's disease (PD), which is not justified by the prevalence and impact of anxiety disorders on quality of life in PD patients. In this cross-sectional study, 342 patients suffering from idiopathic PD underwent a research-based assessment including DSM IV criteria for anxiety disorders, the Hamilton anxiety rating scale (HARS) and the beck anxiety inventory (BAI). Thirty-four percent (34%) of subjects met the DSM IV criteria for at least one anxiety disorder; 11.8% met criteria for multiple anxiety disorders; and 11.4% had clinically relevant anxiety symptoms without meeting the criteria for any specific anxiety disorder. Score profiles on the HARS and BAI differed significantly between the disorders, but these differences were associated with different scores on a limited number of items, and the respective symptom profiles were not readily interpretable. Female sex, the presence of motor fluctuations, as well as a previous history of an anxiety disorder were markers for anxiety disorders. The use of a mono-amino oxidase (MAO)-B inhibitor was associated with a reduced prevalence of anxiety disorders. Research into anxiety in PD is hampered by the questionable validity of DSM IV defined anxiety disorders in this population. A first focus for research should therefore be the identification of clinically useful anxiety presentations and their validation in PD.

Diagnosis of multiple anxiety disorders predicts the concurrent comorbidity of major depressive disorder

Diagnosis of multiple anxiety disorders predicts the concurrent comorbidity of major depressive disorder

Anger problems across the anxiety disorders: findings from a population-based study

Previous research examining anger problems among the anxiety disorders has been limited by the use of nonrepresentative samples, univariate analyses, as well as low sample size. The current study examined the association between posttraumatic stress disorder (PTSD), panic disorder (PD), social anxiety disorder, specific phobia (SP), and generalized anxiety disorder (GAD) and anger experience and expression. We hypothesized that greater anger experience and expression would be associated with all anxiety disorders, but that it would be most consistently associated with PTSD and PD diagnoses, and that these relationships would remain significant after controlling for demographics (i.e. age, gender, ethnicity, marital status, and income) and comorbid disorders. Participants included 5,692 (54% female) adults from the National Comorbidity Survey-Replication, a large, nationally representative survey. Our data suggest that there are unique relationships between multiple anxiety disorders and various indices of anger experience and expression that are not better accounted for by psychiatric comorbidity. Contrary to predictions, PTSD and PD were not consistently associated with anger experience and expression. Overall, these findings lend support to the emerging literature demonstrating a potentially important relationship between anxiety disorders and anger problems.

Coordinated multi-component treatment in primary care improves anxiety in adults with multiple anxiety disorders compared with usual care

Coordinated multi-component treatment in primary care improves anxiety in adults with multiple anxiety disorders compared with usual care

Clinical characteristics of comorbid obsessive‐compulsive disorder and bipolar disorder in children and adolescents

To explore bidirectional comorbidity between bipolar disorder (BPD) and obsessive-compulsive disorder (OCD) in youth and to examine the symptom profile and clinical correlates of both disorders in the context of reciprocal comorbidity and ascertainment status. Two samples of consecutively referred youth (ages 6-17 years) ascertained contemporaneously for respective studies of BPD and OCD were compared using clinical and scalar assessment and structured diagnostic interviews. A total of 21% (17/82) of the BPD subjects and 15% (19/125) of the OCD subjects met DSM-III-R diagnostic criteria for both disorders. In the presence of BPD, youth with OCD more frequently experienced hoarding/saving obsessions and compulsions along with a clinical profile of greater comorbidity, poorer global functioning, and higher rate of hospitalization that is characteristic of BPD. Multiple anxiety disorders (> or = 3), especially generalized anxiety disorder and social phobia, were present at a higher frequency when OCD and BPD were comorbid than otherwise. In subjects with comorbid OCD and BPD, the primary disorder of ascertainment was associated with an earlier onset and more severe impairment. An unexpectedly high rate of comorbidity between BPD and OCD was observed in youth irrespective of primary ascertainment diagnosis. In youth with comorbid OCD and BPD, the clinical characteristics of each disorder run true and are analogues to their clinical presentation in youth without reciprocal comorbidity, with the exception of increased risk for obsessions and compulsions of hoarding/saving and comorbidity with other anxiety disorders.

The role of genes and environment in shaping co-occurrence of DSM-IV defined anxiety dimensions among Italian twins aged 8–17

This study investigated the ultimate causes of co-variation between symptoms of four common DSM-IV anxiety dimensions – Generalized Anxiety, Panic, Social Phobia and Separation Anxiety disorder – assessed with the Italian version of the Screen for Child Anxiety-Related Emotional Disorders questionnaire in a sample of 378 twin pairs aged 8–17 from the population-based Italian Twin Register. Genetic and environmental proportions of covariance between the targeted anxiety dimensions were estimated by multivariate twin analyses. Genetic influences (explaining from 58% to 99% of covariance) and unique environmental factors were the sole sources of co-variation for all phenotypes under study. Genetic influences associated with different anxiety dimensions coincide remarkably, as indicated by genetic correlations ranging from 0.40 to 0.61, while unique environmental overlap is less substantial. Thus, while additive genetic effects are important in explaining why children report symptoms from multiple anxiety disorders, environmental idiosyncratic factors seem to play a marginal role in shaping the co-occurrence of different anxiety dimensions in childhood.

Functioning and disability levels in primary care out-patients with one or more anxiety disorders

Anxiety disorders are the most prevalent mental health disorders and are associated with substantial disability and reduced well-being. It is unknown whether the relative impact of different anxiety disorders is due to the anxiety disorder itself or to the co-occurrence with other anxiety disorders. This study compared the functional impact of combinations of anxiety disorders in primary care out-patients. A total of 1004 patients with panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) or post-traumatic stress disorder (PTSD) provided data on their mental and physical functioning, and disability. Multivariate regressions compared functional levels for patients with different numbers and combinations of disorders. Of the patients, 42% had one anxiety disorder only, 38% two, 16% three and 3% all four. There were few relative differences in functioning among patients with only one anxiety disorder, although those with SAD were most restricted in their work, social and home activities and those with GAD were the least impaired. Functioning levels tended to deteriorate as co-morbidity increased. Of the four anxiety disorders examined, GAD appears to be the least disabling, although they all have more in common than in distinction when it comes to functional impairment. A focus on unique effects of specific anxiety disorders is inadequate, as it fails to address the more pervasive impairment associated with multiple anxiety disorders, which is the modal presentation in primary care.

Delivery of Evidence-Based Treatment for Multiple Anxiety Disorders in Primary Care

Improving the quality of mental health care requires moving clinical interventions from controlled research settings into real-world practice settings. Although such advances have been made for depression, little work has been performed for anxiety disorders. To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders (panic, generalized anxiety, social anxiety, and posttraumatic stress disorders) would be better than usual care (UC). A randomized controlled effectiveness trial of Coordinated Anxiety Learning and Management (CALM) compared with UC in 17 primary care clinics in 4 US cities. Between June 2006 and April 2008, 1004 patients with anxiety disorders (with or without major depression), aged 18 to 75 years, English- or Spanish-speaking, were enrolled and subsequently received treatment for 3 to 12 months. Blinded follow-up assessments at 6, 12, and 18 months after baseline were completed in October 2009. CALM allowed choice of cognitive behavioral therapy (CBT), medication, or both; included real-time Web-based outcomes monitoring to optimize treatment decisions; and a computer-assisted program to optimize delivery of CBT by nonexpert care managers who also assisted primary care clinicians in promoting adherence and optimizing medications. Twelve-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptoms score. Secondary outcomes included proportion of responders (> or = 50% reduction from pretreatment BSI-12 score) and remitters (total BSI-12 score < 6). A significantly greater improvement for CALM vs UC in global anxiety symptoms was found (BSI-12 group mean differences of -2.49 [95% confidence interval {CI}, -3.59 to -1.40], -2.63 [95% CI, -3.73 to -1.54], and -1.63 [95% CI, -2.73 to -0.53] at 6, 12, and 18 months, respectively). At 12 months, response and remission rates (CALM vs UC) were 63.66% (95% CI, 58.95%-68.37%) vs 44.68% (95% CI, 39.76%-49.59%), and 51.49% (95% CI, 46.60%-56.38%) vs 33.28% (95% CI, 28.62%-37.93%), with a number needed to treat of 5.27 (95% CI, 4.18-7.13) for response and 5.50 (95% CI, 4.32-7.55) for remission. For patients with anxiety disorders treated in primary care clinics, CALM compared with UC resulted in greater improvement in anxiety symptoms, depression symptoms, functional disability, and quality of care during 18 months of follow-up. clinicaltrials.gov Identifier: NCT00347269.

Barriers to treatment seeking for anxiety disorders: initial data on the role of mental health literacy

Anxiety disorders represent the single largest mental health problem in the United States [Greenberg et al., 1999. J Clin Psychiatry 60:427-435; Rice and Miller, 1998. Br J Psychiatry 173:4-9]. However most individuals with anxiety disorders never seek treatment [Henderson et al., 2002. Can J Psychiatry 47:819-824; Mojtabai et al., 2002. Arch Gen Psychiatry 59:77-84; Roness et al., 2005. Acta Psychiatr Scand 111:51-58]. Deficits in the ability to recognize anxiety disorders and beliefs about them, (i.e., "mental health literacy") may contribute to low levels of help seeking. Survey data assessing mental health literacy for multiple anxiety disorders and for depression were collected from 284 undergraduate students enrolled in psychology courses at a public university in the United States. Specifically, respondents were presented with vignettes portraying individuals experiencing various forms of mental illness and were asked to label the disorder, its cause and whether or not they would recommend treatment. Findings showed that social phobia and obsessive compulsive disorder (OCD) were associated with recognition rates that were generally high and similar to depression (approximately 80%). In contrast, less than half of the respondents labeled panic disorder or generalized anxiety disorder (GAD) correctly. Symptoms of OCD were attributed to mental illness by approximately 50% of respondents, but such attributions were rare for the other anxiety disorders studied (<12%). Finally, data on help-seeking recommendations suggested that such recommendations are far from universal and varied between different anxiety disorders and according to perceptions of the causes of symptoms. Given that the current sample was well-educated young adults, mental health literacy of the general public may be even lower.

A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity

To estimate the spectrum of familial risk for psychopathology in first-degree relatives of children with unabridged DSM-IV bipolar-I disorder (BP-I). We conducted a blinded, controlled family study using structured diagnostic interviews of 157 children with BP-I probands (n=487 first-degree relatives), 162 attention deficit hyperactivity disorder (ADHD) (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives). The morbid risk (MR) of BP-I disorder in relatives of BP-I probands (MR=0.18) was increased 4-fold [95% confidence interval (CI) 2.3-6.9, p<0.001] over the risk to relatives of control probands (MR=0.05) and 3.5-fold (95% CI 2.1-5.8, p<0.001) over the risk to relatives of ADHD probands (MR=0.06). In addition, relatives of children with BP-I disorder had high rates of psychosis, major depression, multiple anxiety disorders, substance use disorders, ADHD and antisocial disorders compared with relatives of control probands. Only the effect for antisocial disorders lost significance after accounted for by the corresponding diagnosis in the proband. Familial rates of ADHD did not differ between ADHD and BP-I probands. Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I. Relatives of probands with BP-I were also at increased risk for other psychiatric disorders frequently associated with pediatric BP-I. These results support the validity of the diagnosis of BP-I in children as defined by DSM-IV. More work is needed to better understand the nature of the association between these disorders in probands and relatives.