Contextual Triggers and Tic Severity Across Life Periods: A Retrospective Analysis in Adults with Tic Disorders.

In tic disorders (TD), tic expression varies across the lifespan and as a function of contextual factors. This study explored connections between tic expression and contextual triggers across life periods in 74 adults (Mage = 23.2) with TDs. The Tic History and Coping Strategies form assessed retrospective self-reports of contextual antecedents, consequences, and tic severity during four life periods (middle school; 9th/10th grade; 11th/12th grade; college/work) and past month. Tics reportedly worsened during and after school in school-aged years and worsened in the evening during college/work years. Stress and anxiety were reported to consistently trigger tics across time. The impact of activities, places, and emotions did not differ across life periods. Attention-based consequences, most prevalent during middle school, were more common than escape- or avoidance-related consequences across all periods. Findings illuminate how contextual factors may influence tics across life periods and underscore the consistent impact of tic-triggering emotions and attention-related consequences.

Anxiety symptom trajectories from treatment to 5- to 12-year follow-up across childhood and adolescence.

OBJECTIVE: The current study examined trajectories of anxiety during (a) acute treatment and (b) extended follow-up to better characterize the long-term symptom trajectories of youth who received evidence-based intervention for anxiety disorders using a person-centered approach. METHOD: Participants were 319 youth (age 7-17 years at enrollment), who participated in a multicenter randomized controlled trial for the treatment of pediatric anxiety disorders, Child/Adolescent Anxiety Multimodal Study, and a 4-year naturalistic follow-up, Child/Adolescent Anxiety Multimodal Extended Long-term Study, an average of 6.5 years later. Using growth mixture modeling, the study identified distinct trajectories of anxiety across acute treatment (Weeks 0-12), posttreatment (Weeks 12-36), and the 4-year-long follow-up, and identified baseline predictors of these trajectories. RESULTS: Three nonlinear anxiety trajectories emerged: "short-term responders" who showed rapid treatment response but had higher levels of anxiety during the extended follow-up; "durable responders" who sustained treatment gains; and "delayed remitters" who did not show an initial response to treatment, but showed low levels of anxiety during the maintenance and extended follow-up periods. Worse anxiety severity and better family functioning at baseline predicted membership in the delayed remitters group. Caregiver strain differentiated short-term responders from durable responders. CONCLUSIONS: Findings suggest that initial response to treatment does not guarantee sustained treatment gains over time for some youth. Future follow-up studies that track treated youth across key developmental transitions and in the context of changing social environments are needed to inform best practices for the long-term management of anxiety.

Repetitive Transcranial Magnetic Stimulation for Generalized Anxiety Disorder: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Anxiety disorders such as generalized anxiety disorder (GAD) impact 10% of the US population, and many patients do not completely respond to first-line treatments (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and psychotherapy). Given the dearth of evidence for non-pharmacologic, non-psychotherapeutic interventions, we performed a systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) in adults with GAD. METHODS: A systematic literature review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was conducted. Pre- and post-treatment anxiety scores were extracted, and a random-effects meta-analysis was conducted to determine the magnitude of improvement (standardized mean difference). Standard assessments of heterogeneity (e.g., Q-statistic, I2, and τ 2) and publication bias were performed. RESULTS: The initial search resulted in 3194 citations, of which 6 studies were included in the meta-analysis. In total, 152 patients were studied, including 97 patients who received active treatment and 55 who received sham treatment, and heterogeneity was modest (I2 13.32, Q = 5.77). In patients with GAD, rTMS produced a standardized mean difference of -1.857 (confidence interval: -2.219 to -1.494; P < .001) with a prediction interval of -2.55 to -1.16. CONCLUSIONS: The results suggest a robust effect of rTMS in GAD in the context of limited, heterogenous studies. Rigorously designed, randomized controlled trials of rTMS for GAD and related anxiety disorders are urgently needed. These studies will provide opportunities for biomarker development and integration of concurrent evidence-based psychotherapy to maximize results.

Academic, Interpersonal, Recreational, and Family Impairment in Children with Tourette Syndrome and Attention-Deficit/Hyperactivity Disorder.

This study describes impairment in academic, interpersonal, recreational, and family financial or occupational domains across children in three mutually exclusive diagnostic groups: ever diagnosed with Tourette syndrome (TS), attention-deficit/hyperactivity disorder (ADHD), and both disorders. In 2014, parents reported on impairment and diagnostic status of children aged 4-17 years (n = 3014). Weighted analysis and pairwise t-tests showed more children with ADHD (with or without TS) experienced impairment in overall school performance, writing, and mathematics, relative to children with TS but not ADHD. More children with TS and ADHD had problematic handwriting relative to children with ADHD but not TS. More children with TS and ADHD had problematic interpersonal relationships relative to those with ADHD but not TS. Children with TS and ADHD had higher mean impairment across domains than children with either TS or ADHD. Findings suggest assessing disorder-specific contributions to impairment could inform targeted interventions for TS and ADHD.

Research Review: Pediatric anxiety disorders - what have we learnt in the last 10 years?

BACKGROUND: Anxiety disorders first emerge during the critical developmental periods of childhood and adolescence. This review synthesizes recent findings on the prevalence, risk factors, and course of the anxiety disorders; and their neurobiology and treatment. METHODS: For this review, searches were conducted using PubMed, PsycINFO, and clinicaltrials.gov. Findings related to the epidemiology, neurobiology, risk factors, and treatment of pediatric anxiety disorders were then summarized. FINDINGS: Anxiety disorders are high prevalence, and early-onset conditions associated with multiple risk factors including early inhibited temperament, environment stress, and structural and functional abnormalities in the prefrontal-amygdala circuitry as well as the default mode and salience networks. The anxiety disorders are effectively treated with cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). CONCLUSIONS: Anxiety disorders are high prevalence, early-onset conditions associated with a distinct neurobiological fingerprint, and are consistently responsive to treatment. Questions remain regarding who is at risk of developing anxiety disorders as well as the way in which neurobiology predicts treatment response.

Effect of behavior therapy for Tourette's disorder on psychiatric symptoms and functioning in adults.

BACKGROUND: Although behavior therapy reduces tic severity, it is unknown whether it improves co-occurring psychiatric symptoms and functional outcomes for adults with Tourette's disorder (TD). This information is essential for effective treatment planning. This study examined the effects of behavior therapy on psychiatric symptoms and functional outcomes in older adolescents and adults with TD. METHOD: A total of 122 individuals with TD or a chronic tic disorder participated in a clinical trial comparing behavior therapy to psychoeducation and supportive therapy. At baseline, posttreatment, and follow-up visits, participants completed assessments of tic severity, co-occurring symptoms (inattention, impulsiveness, hyperactivity, anger, anxiety, depression, obsessions, and compulsions), and psychosocial functioning. We compared changes in tic severity, psychiatric symptoms, and functional outcomes using repeated measure and one-way analysis of variance. RESULTS: At posttreatment, participants receiving behavior therapy reported greater reductions in obsessions compared to participants in supportive therapy ($\eta _p^2 $ = 0.04, p = 0.04). Across treatments, a positive treatment response on the Clinical Global Impression of Improvement scale was associated with a reduced disruption in family life ($\eta _p^2 $ = 0.05, p = 0.02) and improved functioning in a parental role ($\eta _p^2 $ = 0.37, p = 0.02). Participants who responded positively to eight sessions of behavior therapy had an improvement in tic severity ($\eta _p^2 $ = 0.75, p < 0.001), inattention ($\eta _p^2 $ = 0.48, p < 0.02), and functioning ($\eta _p^2 $ = 0.39-0.42, p < 0.03-0.04) at the 6-month follow-up. CONCLUSION: Behavior therapy has a therapeutic benefit for co-occurring obsessive symptoms in the short-term, and reduces tic severity and disability in adults with TD over time. Additional treatments may be necessary to address co-occurring symptoms and improve functional outcomes.

Symptom-specific effects of cognitive-behavioral therapy, sertraline, and their combination in a large randomized controlled trial of pediatric anxiety disorders.

BACKGROUND: Pediatric anxiety disorders are highly prevalent and associated with significant functional disabilities and lifelong morbidity. Cognitive-behavioral therapy (CBT), sertraline, and their combination are effective treatments, but little is known about how these treatments exert their effects. METHODS: Using network intervention analysis (NIA), we analyzed data from the largest randomized controlled treatment trial of pediatric anxiety disorders (Child/Adolescent Anxiety Multimodal Study, NCT00052078, clinicaltrials.gov/ct2/show/NCT00052078) and outlined the causal symptom domain-specific effects of CBT, sertraline, and their combination over the course of the 12-week treatment while taking into account both specificity and overlap between symptom domains. RESULTS: All active treatments produced positive effects with the most pronounced and consistent effects emerging in relation to psychological distress, family interference, and avoidance. Psychological distress was consistently the most and physical symptoms the least central symptom domain in the disorder network. CONCLUSIONS: All active treatments showed beneficial effects when compared to placebo, and NIA identified that these effects were exerted similarly across treatments and primarily through a reduction of psychological distress, family interference, and avoidance. CBT and sertraline may have differential mechanisms of action in relation to psychological distress. Given the lack of causal effects on interference outside family and physical symptoms, interventions tailored to target these domains may aid in the building of more effective treatments. Psychological distress and avoidance should remain key treatment focuses because of their central roles in the disorder network. The findings inform and promote developing more effective interventions.

Person-Centered Profiles Among Treatment-Seeking Children and Adolescents with Anxiety Disorders.

Latent profile analysis (LPA) was used to derive homogeneous subgroups within the Child/Adolescent Anxiety Multimodal Study sample (N = 488; 7-17 years, M = 10.69, SD = 2.80) and examine whether class membership predicted or moderated treatment response. Subgroups were identified on baseline multi-informant measures of variables most consistently associated with outcome (youth anxiety/diagnosis, impairment, family psychopathology/functioning). Subgroup membership was examined as a predictor/moderator of outcome across the four treatment conditions (CBT, Sertraline, CBT+Sertraline, pill placebo) at posttreatment (12 weeks) and open-extension follow-up (24 weeks). Four subgroups emerged: mild symptoms/impairment, moderate symptoms/impairment, moderate symptoms/impairment with family dysfunction/parental psychopathology, and severe symptoms/impairment. There were significant between-class differences on socioeconomic status (SES; lower reported SES in the moderate with family dysfunction/parental psychopathology class compared to the mild and moderate class) and age (older age in the severe symptoms class compared to the other three classes). Youth in the mild symptoms/impairment class showed lower posttreatment anxiety across conditions but reported significantly lower symptom severity at baseline. Controlling for demographic differences, response to treatment type did not differ across classes. Analyses indicate that elevated family dysfunction/parental psychopathology clusters primarily within one subgroup of anxious youth rather than mapping onto symptom severity, highlighting the utility of LPA for clarifying within-person combinations of predictor/moderator variables. Implications for development of interventions targeting class-relevant variables are discussed.

Psychotic symptoms and suicidal ideation in child and adolescent bipolar I disorder.

OBJECTIVES: The purpose of this study was to explore associations between specific types of hallucinations and delusions and suicidal ideation in a sample of children and adolescents with bipolar I disorder. METHODS: Participants (N = 379) were children and adolescents aged 6-15 years (M = 10.2, SD = 2.7) with DSM-IV diagnoses of bipolar I disorder, mixed or manic phase. The study sample was 53.8% female and primarily White (73.6% White, 17.9% Black, and 8.5% Other). Presence and nature of psychotic symptoms, suicidal ideation, and functioning level were assessed through clinician-administered measures. A series of logistic regressions was performed to assess the contribution of each subtype of psychotic symptom to the presence of suicidal ideation above and beyond age, sex, socio-economic status, age at bipolar disorder onset, and global level of functioning. RESULTS: Hallucinations overall, delusions of guilt, and number of different psychotic symptom types were uniquely associated with increased odds of suicidal ideation after accounting for covariates. Other forms of delusions (eg, grandiose) and specific types of hallucinations (eg, auditory) were not significantly uniquely associated with the presence of suicidal ideation. CONCLUSIONS: Findings of this study suggest the presence of hallucinations as a whole, delusions of guilt specifically, and having multiple concurrent types of psychotic symptoms are associated with the presence of suicidal ideation in children and adolescents with bipolar I disorder. Psychotic symptom subtypes, as opposed to psychosis as a whole, are an under-examined, potentially important, area for consideration regarding suicidal ideation in pediatric bipolar I disorder.

Integrating evidence-based assessment into clinical practice for pediatric anxiety disorders.

BACKGROUND: Although evidence-based assessments are the cornerstone of evidence-based treatments, it remains unknown whether incorporating evidence-based assessments into clinical practice enhances therapists' judgment of therapeutic improvement. This study examined whether the inclusion of youth- and parent-reported anxiety rating scales improved therapists' judgment of treatment response and remission compared to the judgment of treatment-masked independent evaluators (IEs) after (a) weekly/biweekly acute treatment and (b) monthly follow-up care. METHODS: Four hundred thirty six youth received cognitive-behavioral therapy (CBT), medication, CBT with medication, or pill placebo through the Child/Adolescent Anxiety Multimodal Study. Participants and parents completed the following anxiety scales at pretreatment, posttreatment, and follow-up: Screen for Childhood Anxiety and Related Disorders (SCARED) and Multidimensional Anxiety Scale for Children (MASC). IEs rated anxiety on the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) at posttreatment and follow-up. Therapists rated anxiety severity and improvement using scales that paralleled IE measures. RESULTS: Fair-to-moderate agreement was found between therapists and IEs after acute treatment (κ = 0.38-0.48), with only slight-to-fair agreement found after follow-up care (κ = 0.07-0.33). Optimal algorithms for determining treatment response and remission included the combination of therapists' ratings and the parent-reported SCARED after acute (κ = 0.52-0.54) and follow-up care (κ = 0.43-0.48), with significant improvement in the precision of judgments after follow-up care (p < .02-.001). CONCLUSION: Therapists are good at detecting treatment response and remission, but the inclusion of the parent-report SCARED optimized agreement with IE rating-especially when contact was less frequent. Findings suggest that utilizing parent-report measures of anxiety in clinical practice improves the precision of therapists' judgment.

Dysregulated Irritability as a Window on Young Children's Psychiatric Risk: Transdiagnostic Effects via the Family Check-Up.

Building on prior work using Tom Dishion's Family Check-Up, the current article examined intervention effects on dysregulated irritability in early childhood. Dysregulated irritability, defined as reactive and intense response to frustration, and prolonged angry mood, is an ideal marker of neurodevelopmental vulnerability to later psychopathology because it is a transdiagnostic indicator of decrements in self-regulation that are measurable in the first years of life that have lifelong implications for health and disease. This study is perhaps the first randomized trial to examine the direct effects of an evidence- and family-based intervention, the Family Check-Up (FCU), on irritability in early childhood and the effects of reductions in irritability on later risk of child internalizing and externalizing symptomatology. Data from the geographically and sociodemographically diverse multisite Early Steps randomized prevention trial were used. Path modeling revealed intervention effects on irritability at age 4, which predicted lower externalizing and internalizing symptoms at age 10.5. Results indicate that family-based programs initiated in early childhood can reduce early childhood irritability and later risk for psychopathology. This holds promise for earlier identification and prevention approaches that target transdiagnostic pathways. Implications for future basic and prevention research are discussed.

Do Children with Special Health Care Needs with Anxiety have Unmet Health Care Needs? An Analysis of a National Survey.

OBJECTIVE: To describe differences in health care needs between Children with Special Health Care Needs (CSHCN) with and without anxiety and examine the association between anxiety and unmet health care needs. METHODS: We analyzed data from the 2009/2010 national survey of CSHCN. The independent variable was anxiety. The main outcomes were health care needs and unmet needs. Covariates included demographics, other co-morbid conditions, and the presence and quality of a medical home. We used bivariate analyses and multivariable logistic regression to assess the relationships among anxiety, covariates, and the outcomes. We stratified our analysis by age (6-11 years, 12-17 years). Propensity score matched paired analysis was used as a sensitivity analysis. RESULTS: Our final sample included 14,713 6-11 year-olds and 15,842 12-17-year-olds. Anxiety was present in 16% of 6-11 year-olds and 23% or 12-17 year-olds. In bivariate analyses, CSHCN with anxiety had increased health care needs and unmet needs, compared to CSHCN without anxiety. In multivariable analyses, only children 12-17 years old with anxiety had increased odds of having an unmet health care need compared to those children without anxiety (OR 1.44 [95% CI 1.17-1.78]). This was confirmed in the propensity score matching analysis (OR 1.12, [95% CI 1.02-1.22]). The specific unmet needs for older CSHCN with anxiety were mental health care (OR 1.54 [95% CI 1.09-2.17]) and well child checkups (OR 2.01 [95% CI 1.18-3.44]). CONCLUSION: Better integration of the care for mental and physical health is needed to ensure CSHCN with anxiety have all of their health care needs met.

The Effects of Youth Anxiety Treatment on School Impairment: Differential Outcomes Across CBT, Sertraline, and their Combination.

Youth anxiety disorders are highly prevalent and are associated with considerable school impairment. Despite the identification of well-supported strategies for treating youth anxiety, research has yet to evaluate the differential effects of these treatments on anxiety-related school impairment. The present study leveraged data from the Child/Adolescent Anxiety Multimodal Study to examine differential treatment effects of CBT, sertraline, and their combination (COMB), relative to placebo (PBO), on anxiety-related school impairment among youth (N = 488). Latent growth modeling revealed that all three active treatments demonstrated superiority over PBO in reducing anxiety-related school impairment over time, with COMB showing the most robust effects. According to parent report, medication strategies may have stronger effects on anxiety-related school impairment among males than among females. Results were discrepant across parents and youth. Findings are discussed in terms of clinical implications for anxious youth and the need for continued research to examine treatment effects on anxiety-related school impairment.

Self-esteem in adults with Tourette syndrome and chronic tic disorders: The roles of tic severity, treatment, and comorbidity.

BACKGROUND: Tourette syndrome (TS) and chronic tic disorders (CTD) are stigmatizing disorders that may significantly impact self-esteem. Alternatively, comorbid psychiatric illnesses may affect self-esteem more than tics themselves. Extant research on self-esteem in TS/CTD is limited, has inconsistently examined the effect of comorbidities on self-esteem, and yields mixed findings. METHOD: This study aimed to clarify the roles of tics versus comorbid diagnoses on self-esteem in a large, carefully diagnosed sample of adults with TS/CTD (N = 122) receiving 10 weeks of Comprehensive Behavioral Intervention for Tics (CBIT) or Psychoeducation and Supportive Therapy (PST). RESULTS: Baseline self-esteem did not differ between adults with TS/CTD only and normative means, whereas self-esteem was significantly lower among adults with TS/CTD with a comorbid psychiatric illness. In a multiple regression testing the baseline association between tic severity, presence of comorbid psychiatric illness, and depression severity with self-esteem, comorbidity and depression severity were significantly associated with self-esteem, whereas tic severity was not. Finally, using a generalized linear model, we tested the effects of treatment assignment, comorbidity, and their interaction on changes in self-esteem across treatment, controlling for baseline depression severity. Results showed that for those with a comorbid illness, self-esteem improved significantly more with CBIT than with PST. CONCLUSIONS: Comorbid illnesses appear to affect self-esteem more so than tics among adults with TS/CTD. Therapeutic attention should be paid to treating comorbid diagnoses alongside tics when treating TS/CTD.

Mediators of Treatment Outcomes for Anxious Children and Adolescents: The Role of Somatic Symptoms.

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors are effective treatments for pediatric anxiety disorders. However, the mechanisms of these treatments are unknown. Previous research indicated that somatic symptoms are reduced following treatment, but it is unclear if their reductions are merely a consequence of treatment gains. This study examined reductions in somatic symptoms as a potential mediator of the relationship between treatment and anxiety outcomes. Participants were 488 anxious youth ages 7-17 (M = 10.7), 50.4% male, 78.9% Caucasian, enrolled in Child/Adolescent Anxiety Multimodal Study, a large randomized control trial comparing 12-week treatments of CBT, sertraline, a combination of CBT and sertraline, and a pill placebo. Causal mediation models were tested in R using data from baseline, 8-, and 12-week evaluations. Somatic symptoms were assessed using the Panic/Somatic subscale from the Screen for Child Anxiety Related Emotional Disorders. Youth outcomes were assessed using the Pediatric Anxiety Rating Scale and Children's Global Assessment Scale. Reductions in somatic symptoms mediated improvement in anxiety symptoms and global functioning for those in the sertraline-only condition based on parent report. Conditions involving CBT and data based on child reported somatic symptoms did not show a mediation effect. Findings indicate that reductions in somatic symptoms may be a mediator of improvements for treatments including pharmacotherapy and not CBT. Although the overall efficacy of sertraline and CBT for anxiety may be similar, the treatments appear to function via different mechanisms.

The Interplay of Familial and Individual Risk in Predicting Clinical Improvements in Pediatric Anxiety Disorders.

Bioecological models of developmental psychopathology underscore the role of familial experiences of adversity and children's individual-level characteristics in heightening risk for pediatric anxiety through direct, combined, and interactive effects. To date, much of the existing research dedicated to pediatric anxiety disorders has largely been examined in bioecological models of diathesis-stress using community samples. This study extends our understanding of children's differential responsiveness to familial adversity by examining the diathesis-stress interaction of cumulative risk and children's individual-level vulnerabilities (negative affectivity and coping efficacy) within a clinic-referred treatment study for pediatric anxiety disorders. A cumulative risk index assessing exposure to familial adversity (e.g., socioeconomic status [SES], parent psychiatric illness) and self-reported measures of children's negative affectivity and coping efficacy were each measured at the intake of a randomized controlled clinical trial for the treatment of pediatric anxiety disorders (N = 488; 7-17 years of age). Trajectories of interviewer-rated anxiety symptoms were assessed across 12 weeks of treatment at baseline, 4 weeks, 8 weeks, and 12 weeks. Consistent with models of temperamental risk for mental health problems, negative affectivity predicted higher anxiety symptoms at intake. A significant diathesis-stress interaction between cumulative risk and coping efficacy emerged, as high risk and perceptions of lower coping efficacy attenuated declines in anxiety across 12 weeks. These patterns did not differ across treatment conditions. The results indicate that for youth experiencing high levels of stress, additional treatment efforts targeting familial stressors and coping efficacy may be important in maximizing treatment outcomes.

Temperamental Characteristics of Withdrawn Behavior Problems in Children.

Withdrawn/depressed behavior (WD) as defined by the Child Behavior Checklist (CBCL) relates to various outcomes in developmental psychopathology such as depression, pervasive developmental disorders, and suicide. We sought to examine the temperamental characteristics of children who concurrently endorse symptoms of WD. Junior Temperament and Characteristic Inventory (JTCI) and CBCL data were collected from 397 children's parents in a family study in the northeastern United States. Linear mixed models were used to test the relations between WD and temperament dimensions (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence) on the JTCI, while controlling for age, sex, item overlap, and co-occurring aggression and attention problems. When controlling for definitional artifact and CBCL aggressive behavior and attention scores, high harm avoidance and low reward dependence were both significant predictors of childhood withdrawn behavior. This study marks the first characterization of a temperamental profile associated with WD in children and adolescents.

Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. METHODS: DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. RESULTS: Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). CONCLUSIONS: These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder.