Can Emotional and Behavioral Dysregulation in Youth Be Decoded from Functional Neuroimaging?

INTRODUCTION: High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points. METHODS: A sample of fifty-seven youth (mean age: 14.5 years; 32 males) was selected from a multi-site study of youth with parent-reported behavioral and emotional dysregulation. Participants performed a block-design reward paradigm during functional Magnetic Resonance Imaging (fMRI). Pattern regression analyses consisted of Relevance Vector Regression (RVR) and two cross-validation strategies implemented in the Pattern Recognition for Neuroimaging toolbox (PRoNTo). Medication was treated as a binary confounding variable. Decoded and actual clinical scores were compared using Pearson's correlation coefficient (r) and mean squared error (MSE) to evaluate the models. Permutation test was applied to estimate significance levels. RESULTS: Relevance Vector Regression identified patterns of neural activity associated with symptoms of behavioral and emotional dysregulation at the initial study screen and close to the fMRI scanning session. The correlation and the mean squared error between actual and decoded symptoms were significant at the initial study screen and close to the fMRI scanning session. However, after controlling for potential medication effects, results remained significant only for decoding symptoms at the initial study screen. Neural regions with the highest contribution to the pattern regression model included cerebellum, sensory-motor and fronto-limbic areas. CONCLUSIONS: The combination of pattern regression models and neuroimaging can help to determine the severity of behavioral and emotional dysregulation in youth at different time points.

White matter structure in youth with behavioral and emotional dysregulation disorders: a probabilistic tractographic study.

IMPORTANCE: Psychiatric disorders in youth characterized by behavioral and emotional dysregulation are often comorbid and difficult to distinguish. An alternative approach to conceptualizing these disorders is to move toward a diagnostic system based on underlying pathophysiologic processes that may cut across conventionally defined diagnoses. Neuroimaging techniques have potentials for the identification of these processes. OBJECTIVE: To determine whether diffusion imaging, a neuroimaging technique examining white matter (WM) structure, can identify neural correlates of emotional dysregulation in a sample of youth with different psychiatric disorders characterized by behavioral and emotional dysregulation. DESIGN, SETTING, AND PARTICIPANTS: Using global probabilistic tractography, we examined relationships between WM structure in key tracts in emotional regulation circuitry (ie, cingulum, uncinate fasciculus, and forceps minor) and (1) broader diagnostic categories of behavioral and emotional dysregulation disorders (DDs) and (2) symptom dimensions cutting across conventional diagnoses in 120 youth with behavioral and/or emotional DDs, a referred sample of the Longitudinal Assessment of Manic Symptoms (LAM) study. Thirty age- and sex-matched typically developing youth (control participants) were included. Multivariate multiple regression models were used. The study was conducted from July 1, 2010, to February 28, 2014. MAIN OUTCOMES AND MEASURES: Fractional anisotropy as well as axial and radial diffusivity were estimated and imported into a well-established statistical package. We hypothesized that (1) youth with emotional DDs and those with both behavioral and emotional DDs would show significantly lower fractional anisotropy compared with youth with behavioral DDs in these WM tracts and (2) that there would be significant inverse relationships between dimensional measures of affective symptom severity and fractional anisotropy in these tracts across all participants. RESULTS: Multivariate multiple regression analyses revealed decreased fractional anisotropy and decreased axial diffusivity within the uncinate fasciculus in youth with emotional DDs vs those with behavioral DDs, those with both DDs, and the controls (F6,160 = 2.4; P = .032; all pairwise comparisons, P < .002). In the same model, greater severity of manic symptoms was positively associated with higher fractional anisotropy across all affected youth (F3,85 = 2.8; P = .044). CONCLUSIONS AND RELEVANCE: These findings suggest that abnormal uncinate fasciculus and cingulum WM structure may underlie emotional, but not behavioral, dysregulation in pediatric psychiatric disorders and that a different neural mechanism may exist for comorbid emotional and behavioral DDs.

Decreased amygdala-insula resting state connectivity in behaviorally and emotionally dysregulated youth.

The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, and Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala-right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders.

Improving Clinical Prediction of Bipolar Spectrum Disorders in Youth.

This report evaluates whether classification tree algorithms (CTA) may improve the identification of individuals at risk for bipolar spectrum disorders (BPSD). Analyses used the Longitudinal Assessment of Manic Symptoms (LAMS) cohort (629 youth, 148 with BPSD and 481 without BPSD). Parent ratings of mania symptoms, stressful life events, parenting stress, and parental history of mania were included as risk factors. Comparable overall accuracy was observed for CTA (75.4%) relative to logistic regression (77.6%). However, CTA showed increased sensitivity (0.28 vs. 0.18) at the expense of slightly decreased specificity and positive predictive power. The advantage of CTA algorithms for clinical decision making is demonstrated by the combinations of predictors most useful for altering the probability of BPSD. The 24% sample probability of BPSD was substantially decreased in youth with low screening and baseline parent ratings of mania, negative parental history of mania, and low levels of stressful life events (2%). High screening plus high baseline parent-rated mania nearly doubled the BPSD probability (46%). Future work will benefit from examining additional, powerful predictors, such as alternative data sources (e.g., clinician ratings, neurocognitive test data); these may increase the clinical utility of CTA models further.

Three-year latent class trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms in a clinical sample not selected for ADHD.

OBJECTIVE: This study aims to examine trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms in the Longitudinal Assessment of Manic Symptoms (LAMS) sample. METHOD: The LAMS study assessed 684 children aged 6 to 12 years with the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS) and rating scales semi-annually for 3 years. Although they were selected for elevated manic symptoms, 526 children had baseline ADHD diagnoses. With growth mixture modeling (GMM), we separately analyzed inattentive and hyperactive/impulsive symptoms, covarying baseline age. Multiple standard methods determined optimal fit. The χ(2) and Kruskal-Wallis analysis of variance compared resulting latent classes/trajectories on clinical characteristics and medication. RESULTS: Three latent class trajectories best described inattentive symptoms, and 4 classes best described hyperactive/impulsive symptoms. Inattentive trajectories maintained their relative position over time. Hyperactive/impulsive symptoms had 2 consistent trajectories (least and most severe). A third trajectory (4.5%) started mild, then escalated; and a fourth (14%) started severe but improved dramatically. The improving trajectory was associated with the highest rate of ADHD and lowest rate of bipolar diagnoses. Three-fourths of the mildest inattention class were also in the mildest hyperactive/impulsive class; 72% of the severest inattentive class were in the severest hyperactive/impulsive class, but the severest inattention class also included 62% of the improving hyperactive-impulsive class. CONCLUSION: An ADHD rather than bipolar diagnosis prognosticates a better course of hyperactive/impulsive, but not inattentive, symptoms. High overlap of relative severity between inattention and hyperactivity/impulsivity confirms the link between these symptom clusters. Hyperactive/impulsive symptoms wane more over time. Group means are insufficient to understand individual ADHD prognosis. A small subgroup deteriorates over time in hyperactivity/impulsivity and needs better treatments than currently provided.

Use of outpatient mental health services among children of different ages: are younger children more seriously ill?

OBJECTIVE: The study compared use of specialty outpatient mental services among children ages six and seven and children ages eight through 12 and investigated predictors of differences in the patterns of service use by age. METHODS: Eligible children were first-time patients of clinics participating in the Longitudinal Assessment of Manic Symptoms who were between ages six and 12 and who were English speaking. Children who screened positive for symptoms of mania (N=1,124) were invited to participate, and families of 621 (55%) children consented. A matched sample of 86 children without a positive screen for mania also participated. Baseline interviews assessed sociodemographic characteristics of the child and family and the child's functioning, diagnoses, and use of services. RESULTS: Of the 707 children, 30% were younger, and 50% used multiple types of specialty outpatient services. Younger children were more likely to be male, have Medicaid insurance, and have two parents with mental health problems. Use of multiple types of services was related to study site, high depression scores, fewer minor health issues, and fewer stressful life events among younger children and with parental stress, primary diagnosis, poor functioning, and not living with both parents among older children. Younger children were much more likely than older children to have used services before age six. CONCLUSIONS: Younger children showed very early use of multiple types of services for mental health problems and a pattern of persistent impairment despite long-standing use of services. These data argue strongly for focusing on emotional and behavioral issues among young children.

Clinical decision making about child and adolescent anxiety disorders using the Achenbach system of empirically based assessment.

Anxiety disorders are common among children but can be difficult to diagnose. An actuarial approach to the diagnosis of anxiety may improve the efficiency and accuracy of the process. The objectives of this study were to determine the clinical utility of the Achenbach Child Behavior Checklist (CBCL) and Youth Self Report (YSR), two widely used assessment tools, for diagnosing anxiety disorders in youth and to aid clinicians in incorporating scale scores into an actuarial approach to diagnosis through a clinical vignette. Demographically diverse youth, 5 to 18 years of age, were drawn from two samples; one (N = 1,084) was recruited from a research center, and the second (N = 651) was recruited from an urban community mental health center. Consensus diagnoses integrated information from semistructured interview, family history, treatment history, and clinical judgment. The CBCL and YSR internalizing problems T scores discriminated cases with any anxiety disorder or with generalized anxiety disorder from all other diagnoses in both samples (ps < .0005); the two scales had equivalent discriminative validity (ps > .05 for tests of difference). No other scales, nor any combination of scales, significantly improved on the performance of the Internalizing scale. In the highest risk group, Internalizing scores greater than 69 (CBCL) or greater than 63 (YSR) resulted in a Diagnostic Likelihood Ratio of 1.5; low scores reduced the likelihood of anxiety disorders by a factor of 4. Combined with other risk factor information in an actuarial approach to assessment and diagnosis, the CBCL and YSR Internalizing scales provide valuable information about whether a youth is likely suffering from an anxiety disorder.

Parsing dimensional vs diagnostic category-related patterns of reward circuitry function in behaviorally and emotionally dysregulated youth in the Longitudinal Assessment of Manic Symptoms study.

IMPORTANCE: Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs disorder-specific pathophysiologic features. OBJECTIVE: To identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that (1) are associated with behavioral and emotional dysregulation pathologic dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10-Item Mania Scale [PGBI-10M], mania, depression, and anxiety) or (2) differentiate diagnostic categories (bipolar spectrum disorders, attention-deficit/hyperactivity disorder, anxiety, and disruptive behavior disorders). DESIGN, SETTING, AND PARTICIPANTS: A multisite neuroimaging study was conducted from February 1, 2011, to April 15, 2012, at 3 academic medical centers: University Hospitals Case Medical Center, Cincinnati Children's Hospital Medical Center, and University of Pittsburgh Medical Center. Participants included a referred sample of behaviorally and emotionally dysregulated youth from the Longitudinal Assessment of Manic Symptoms (LAMS) study (n = 85) and healthy youth (n = 20). MAIN OUTCOMES AND MEASURES: Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (win, loss, and control conditions), symptom dimensions, and diagnostic categories. RESULTS: Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical activity (r = 0.28) and anxiety with greater right dorsal anterior cingulate cortical (r = 0.27) activity to win. The 20 highest (t = 2.75) and 20 lowest (t = 2.42) PGBI-10M-scoring youth showed significantly greater left middle prefrontal cortical activity to win compared with 20 healthy youth. Disruptive behavior disorders were associated with lower left ventrolateral prefrontal cortex activity to win (t = 2.68) (all P < .05, corrected). CONCLUSIONS AND RELEVANCE: Greater PGBI-10M-related left middle prefrontal cortical activity and anxiety-related right dorsal anterior cingulate cortical activity to win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth regardless of diagnosis. Reduced left ventrolateral prefrontal cortex activity to win may reflect reward insensitivity in youth with disruptive behavior disorders. Despite a distinct reward-related neurophysiologic feature in disruptive behavior disorders, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.

Emotional face processing in pediatric bipolar disorder: evidence for functional impairments in the fusiform gyrus.

OBJECTIVE: Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder. METHOD: Youth with a bipolar spectrum diagnosis (n = 20) were matched to a nonbipolar clinical group (n = 20), with similar demographics and comorbid diagnoses, and a healthy control group (n = 20). Youth participated in a functional magnetic resonance imaging (fMRI) scanning which employed a task-irrelevant emotion processing design in which processing of facial emotions was not germane to task performance. RESULTS: Hypoactivation, isolated to the fusiform gyrus, was found when viewing animated, emerging facial expressions of happiness, sadness, fearfulness, and especially anger in pediatric bipolar participants relative to matched clinical and healthy control groups. CONCLUSIONS: The results of the study imply that differences exist in visual regions of the brain's face processing system and are not solely isolated to emotional brain regions such as the amygdala. Findings are discussed in relation to facial emotion recognition and fusiform gyrus deficits previously reported in the autism literature. Behavioral interventions targeting attention to facial stimuli might be explored as possible treatments for bipolar disorder in youth.

Prescription of psychiatric medications and polypharmacy in the LAMS cohort.

OBJECTIVE: This study evaluated demographic and clinical correlates and predictors of polypharmacy at baseline assessment in the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a cohort of children age six to 12 years at their first outpatient mental health visit at university-affiliated clinics. METHODS: Use of medications in four classes (mood stabilizers, antidepressants, antipsychotics, and stimulants) was assessed, and the Service Assessment for Children and Adolescents classified lifetime and current use of various services. Analyses examined correlates of the number of medications prescribed and odds of polypharmacy, defined as use of two or more concurrent medications. RESULTS: In the total sample, 201 of 698 participants (29%) were prescribed two or more medications. These participants had lower Children's Global Assessment Scale scores, more comorbid disorders, and higher baseline parent-reported mood symptoms than those prescribed no or one medication. White youths were three times as likely as nonwhite youths to be receiving two or more psychotropics, even after adjustment for other demographic and clinical characteristics. Of 262 participants (38% of sample) not being treated with medications, 252 (96%) had a diagnosis of at least one psychiatric disorder (74% had two or more). CONCLUSIONS: Findings suggest that patients with greater severity and comorbidity were more likely to receive two or more medications. However, 38% of these children with serious disorders were not receiving psychotropic medication at the time of this assessment. Results counter findings suggesting overtreatment with medications of children with psychiatric disorders in the community.

The 24-month course of manic symptoms in children.

OBJECTIVES: The Longitudinal Assessment of Manic Symptoms (LAMS) study was designed to investigate phenomenology and establish predictors of functional outcomes in children with elevated manic symptoms. The purpose of this series of analyses was to determine whether the participants demonstrated different trajectories of parent-reported manic and biphasic symptoms over the first 24 months of follow-up and to describe the clinical characteristics of the trajectories. METHODS: The 707 participants were initially aged 6-12 years and ascertained from outpatient clinics associated with the four university-affiliated LAMS sites. There were 621 children whose parents/guardians' ratings scored ≥ 12 on the Parent General Behavior Inventory-10-item Mania Form (PGBI-10M) and a matched random sample of 86 children whose parents/guardians' ratings scored ≤ 11 on the PGBI-10M. Participants were seen every six months after the baseline and their parents completed the PGBI-10M at each visit. RESULTS: For the whole sample, manic symptoms decreased over 24 months (linear effect B = -1.15, standard error = 0.32, t = -3.66, p < 0.001). Growth mixture modeling revealed four unique trajectories of manic symptoms. Approximately 85% of the cohort belonged to two classes in which manic symptoms decreased. The remaining ~15% formed two classes (high and rising and unstable) characterized by the highest rates of diagnostic conversion to a bipolar disorder (all p-values < 0.001). CONCLUSIONS: Outcomes are not uniform among children with symptoms of mania or at high risk for mania. A substantial minority of clinically referred children shows unstable or steadily increasing manic symptoms, and these patterns have distinct clinical correlates.

Phenomenology of bipolar disorder not otherwise specified in youth: a comparison of clinical characteristics across the spectrum of manic symptoms.

OBJECTIVES: Controversy surrounds the diagnostic categorization of children with episodic moods that cause impairment, but do not meet DSM-IV criteria for bipolar I (BD-I) or bipolar II (BD-II) disorder. This study aimed to characterize the degree to which these children, who meet criteria for bipolar disorder not otherwise specified (BD-NOS), are similar to those with full syndromal BD, versus those with no bipolar spectrum diagnosis (no BSD). METHODS: Children aged 6-12 years were recruited from nine outpatient clinics, preferentially selected for higher scores on a 10-item screen for manic symptoms. Interviews with the children and their primary caregivers assessed a wide array of clinical variables, as well as family history. RESULTS: A total of 707 children [mean ± standard deviation (SD) 9.4 ± 1.9 years old] were evaluated at baseline, and were diagnosed with BD-I (n = 71), BD-II (n = 3), BD-NOS (including cyclothymia; n = 88), or no BSD (n = 545). Compared to BD-I, the BD-NOS group had less severe past functional impairment. However, current symptom severity and functional impairment did not differ between BD-NOS and BD-I, even though both groups were significantly more symptomatic and impaired than the no BSD group. Parental psychiatric history was similar for the BD-NOS and BD-I groups, and both were more likely than the no BSD group to have a parent with a history of mania. Rates of elated mood did not differ between BD-NOS and BD-I youth. CONCLUSIONS: Children with BD-NOS and BD-I are quite similar, but different from the no BSD group, on many phenomenological measures. These findings support the hypothesis that BD-NOS is on the same spectrum as BD-I.

Examining the validity of cyclothymic disorder in a youth sample: replication and extension.

DSM-IV-TR defines four subtypes of bipolar disorder (BP): bipolar I, bipolar II, cyclothymic disorder and bipolar not otherwise specified (NOS). However, cyclothymic disorder in children is rarely researched, or often subsumed in an "NOS" category. The present study tests the replicability of findings from an earlier study, and expands on the criterion validity of cyclothymic disorder in youth. Using the Robins and Guze (1970) framework we examined the validity of cyclothymic disorder as a subtype of BP. Using a youth (ages 5-17) outpatient clinical sample (N = 894), participants with cyclothymic disorder (n = 53) were compared to participants with other BP spectrum disorders (n = 399) and to participants with non-bipolar disorders (n = 442). Analyses tested differences in youth with cyclothymic disorder and bipolar disorder not otherwise specified who do, and those who do not, have a parent with BP. Compared to youth with non-bipolar disorders, youth with cyclothymic disorder had higher irritability (p < 0.001), more comorbidity (p < 0.001), greater sleep disturbance (p < 0.005), and were more likely to have a family history of BP (p < 0.001). Cyclothymic disorder was associated with a younger age of onset compared to depression (p < 0.001) and bipolar II (p = 0.05). Parental BP status was not significantly associated with any variables. Results support that cyclothymic disorder belongs on the bipolar spectrum. Epidemiological studies indicate that cyclothymic disorder is not uncommon and involves significant impairment. Failing to differentiate between cyclothymic disorder and bipolar NOS limits our knowledge about a significant proportion of cases of bipolarity.

Age differences in the phenomenology of pediatric bipolar disorder.

BACKGROUND: The primary purpose of this study was to explore whether age differences in the phenomenology of bipolar disorders from 4 to 17 years of age exist. METHODS: Outcome measures included questionnaires pertaining to mood symptoms, psychosocial functioning, and family history of psychiatric illness. Phenomenology was examined in two diagnostic groups: syndromal bipolar disorder (bipolar I or II) and subsyndromal bipolar disorder (bipolar disorder not otherwise specified or cyclothymia) and across six age cohorts: 4-6, 7-8, 9-10, 11-13, and 14-17 years. Analyses examined linear and non-linear age effects on clinician-rated measures of mood and psychosocial functioning. RESULTS: Participants were 535 outpatients (339 males) ages 4-17 years. The proportion diagnosed with comorbid ADHD was significantly lower in the oldest age group. Age groups showed significant moderate decreases in motor activity, aggression, and irritability with age. Many symptoms of depression showed significant increases with age. BP I cases showed much higher manic symptoms, and BP I and BP II cases indicated slightly to moderately higher depressive symptoms, compared to subsyndromal cases. These patterns held after adjusting for comorbid ADHD, and age did not interact with syndrome status. There were also age differences in total scores for measures of mood symptoms and psychosocial functioning. LIMITATIONS: Mood ratings were completed based on the same interview that informed the research diagnoses. Also, mood episode at time of interview was not captured. CONCLUSIONS: These findings affirm the existence of bipolar disorder from pre-school children through adolescence, with a similar clinical presentation across a wide developmental age span.

Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study.

OBJECTIVE: To examine the proposed disruptive mood dysregulation disorder (DMDD) diagnosis in a child psychiatric outpatient population. Evaluation of DMDD included 4 domains: clinical phenomenology, delimitation from other diagnoses, longitudinal stability, and association with parental psychiatric disorders. METHOD: Data were obtained from 706 children aged 6-12 years who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) study (sample was accrued from November 2005 to November 2008). DSM-IV criteria were used, and assessments, which included diagnostic, symptomatic, and functional measures, were performed at intake and at 12 and 24 months of follow-up. For the current post hoc analyses, a retrospective diagnosis of DMDD was constructed using items from the K-SADS-PL-W, a version of the Schedule for Affective Disorders and Schizophrenia for School-Age Children, which resulted in criteria closely matching the proposed DSM-5 criteria for DMDD. RESULTS: At intake, 26% of participants met the operational DMDD criteria. DMDD+ vs DMDD- participants had higher rates of oppositional defiant disorder (relative risk [RR] = 3.9, P < .0001) and conduct disorder (RR = 4.5, P < .0001). On multivariate analysis, DMDD+ participants had higher rates of and more severe symptoms of oppositional defiant disorder (rate and symptom severity P values < .0001) and conduct disorder (rate, P < .0001; symptom severity, P = .01), but did not differ in the rates of mood, anxiety, or attention-deficit/hyperactivity disorders or in severity of inattentive, hyperactive, manic, depressive, or anxiety symptoms. Most of the participants with oppositional defiant disorder (58%) or conduct disorder (61%) met DMDD criteria, but those who were DMDD+ vs DMDD- did not differ in diagnostic comorbidity, symptom severity, or functional impairment. Over 2-year follow-up, 40% of the LAMS sample met DMDD criteria at least once, but 52% of these participants met criteria at only 1 assessment. DMDD was not associated with new onset of mood or anxiety disorders or with parental psychiatric history. CONCLUSIONS: In this clinical sample, DMDD could not be delimited from oppositional defiant disorder and conduct disorder, had limited diagnostic stability, and was not associated with current, future-onset, or parental history of mood or anxiety disorders. These findings raise concerns about the diagnostic utility of DMDD in clinical populations.

An update on antidepressant use and suicidality in pediatric depression.

INTRODUCTION: In 2003, public health advisories in North America and Europe regarding suicidality associated with selective serotonin reuptake inhibitors (SSRIs) led to the addition of black box warnings to antidepressant package inserts in 2004. Subsequently, a series of events appeared to result from these regulatory actions. AREAS COVERED: This review provides an overview of the temporal associations of regulatory agencies' actions in North America and Europe with rates of depression diagnoses, pediatric antidepressant prescription rates, follow-up visits to physicians prescribing antidepressants, and rates of completed suicide and suicidal ideation in children and adolescents. In addition, evidence-based predictors of suicidal behavior and suicide risk, as provided by large, multisite studies of depressed children and adolescents, are outlined. Finally, this review considers key advancements in the study of young patients at risk for suicide and describes innovations in current research methodology, to more accurately identify suicidality and the relationship to antidepressant use within this vulnerable patient population. EXPERT OPINION: Evaluating the role of antidepressants in those youths who do not respond to evidence-based psychotherapeutic interventions may be a useful future research direction. Until more data are available, however, closely monitored antidepressant treatment in combination with CBT may provide the most benefit.

What differentiates children visiting outpatient mental health services with bipolar spectrum disorder from children with other psychiatric diagnoses?

OBJECTIVES: To determine the contribution of parent-reported manic symptoms, family history, stressful life events, and family environment in predicting diagnosis of bipolar spectrum disorders (BPSD) in youth presenting to an outpatient psychiatric clinic. METHODS: A total of 707 6- to 12-year-old children [621 with elevated symptoms of mania (ESM+) based on screening via the Parent General Behavior Inventory 10-item Mania Scale (PGBI-10M) and 86 without ESM (ESM-)] received a comprehensive assessment. RESULTS: Of the 629 with complete data, 24% (n = 148) had BPSD. Compared to those without BPSD (n = 481), children with BPSD: were older (Cohen's d = 0.44) and more likely to be female (Cohen's d = 0.26); had higher parent-endorsed manic symptom scores at screening (Cohen's d = 0.36) and baseline (Cohen's d = 0.76), more biological parents with a history of manic symptoms (Cohen's d = 0.48), and greater parenting stress (Cohen's d = 0.19). Discriminating variables, in order, were: baseline PGBI-10M scores, biological parent history of mania, parenting stress, and screening PGBI-10M scores. Absence of all these factors reduced risk of BPSD from 24% to 2%. CONCLUSIONS: History of parental manic symptoms remains a robust predictor of BPSD in youth seeking outpatient care, even after accounting for parent report of manic symptoms in the child at screening. However, the risk factors identified as associated with BPSD, together had limited value in accurately identifying individual participants with BPSD, highlighting the need for careful clinical assessment.

Parents' perceptions of benefit of children's mental health treatment and continued use of services.

OBJECTIVE: The authors examined the association of demographic and clinical characteristics, family history, and type of treatment among children receiving outpatient mental health services and parents' perception of treatment benefit. They also examined whether perceived benefit was related to continued use of services at six-month follow-up. METHODS: Parents of children age six to 12 years who were first-time patients at one of nine clinics participating in the Longitudinal Assessment of Manic Symptoms (LAMS) study completed the Parent General Behavior Inventory Ten-Item Mania Scale. Parents of children with scores of 12 or higher (N=1,124) were invited to participate in a follow-up study, and 621 agreed. During baseline assessment after the first outpatient visit and at six-month follow-up, the parents were asked about children's sociodemographic and diagnostic characteristics and use of services and asked to rate how much their children had benefited from the most recent outpatient treatment. RESULTS: Data were available for 573 children. At baseline, parents of 167 (29%) children reported that the treatment provided a lot of benefit, and perceived benefit was related to receiving medication (with or without therapy) versus just therapy, higher scores on functioning, LAMS site, no history of comorbid diagnoses, living with both biological parents, and having no parents or siblings with a prior hospitalization for a psychiatric illness. At six-month follow-up, perceived benefit was related to continued use of services (p<.001). CONCLUSIONS: Medication with or without therapy was perceived as more beneficial than therapy alone. Perceived benefit was strongly related to continued use of treatment.

Pediatric bipolar disorder and ADHD: family history comparison in the LAMS clinical sample.

BACKGROUND: Transgenerational association of bipolar spectrum disorder (BPSD) and attention deficit/hyperactivity disorder (ADHD) has been reported, but inconclusively. METHOD: Children ages 6-12 were systematically recruited at first outpatient visit at 9 clinics at four universities and reliably diagnosed; 621 had elevated symptoms of mania (>12 on the Parent General Behavior Inventory 10-Item Mania Scale); 86 had scores below 12. We analyzed baseline data to test a familial association hypothesis: compared to children with neither BPSD nor ADHD, those with either BPSD or ADHD would have parents with higher rates of both bipolar and ADHD symptoms, and parents of comorbid children would have even higher rates of both. RESULTS: Of 707 children, 421 had ADHD without BPSD, 45 BPSD without ADHD, 117 comorbid ADHD+BPSD, and 124 neither. The rate of parental manic symptoms was similar for the comorbid and BPSD-alone groups, significantly greater than for ADHD alone and "neither" groups, which had similar rates. ADHD symptoms in parents of children with BPSD alone were significantly less frequent than in parents of children with ADHD (alone or comorbid), and no greater than for children with neither diagnosis. Family history of manic symptoms, but not ADHD symptoms, was associated with parent-rated child manic-symptom severity over and above child diagnosis. LIMITATIONS: The sample was not epidemiologic, parent symptoms were based on family history questions, and alpha was 0.05 despite multiple tests. CONCLUSIONS: These results do not support familial linkage of BPSD and ADHD; they are compatible with heritability of each disorder separately with coincidental overlap.

Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders.

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12-17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use.