Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Validation of the Seven Up Seven Down Inventory in bipolar offspring: screening and prediction of mood disorders. Findings from the Dutch Bipolar Offspring Study.

OBJECTIVE: To validate the Seven Up Seven Down (7U7D), an abbreviated version of the General Behavior Inventory (GBI), as screener for mood disorders and test its ability to predict mood disorders over time in individuals at risk for bipolar disorder (BD). METHODS: Bipolar offspring (n=108) were followed from adolescence into adulthood and assessed at baseline, 1-, 5- and 12 years follow-up (T1-T4 respectively). Offspring were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime Version, Structured Clinical Interview for DSM-IV Axis I Disorders and the GBI. RESULTS: Performance of the GBI and 7U7D was functionally similar for the depression (7D) scale, but variable for the mania (7U) scale. As screener for mood disorders (T4), the 7D showed fair diagnostic efficiency (area under the curve (AUC) 0.68, p<0.01, OR 1.53, 95% CI 1.15-2.03). The discriminative validity for BD and unipolar disorder was only close to significant (7D AUC 0.66, p=0.078; 7U AUC 0.67, p=0.067). In terms of prediction of mood disorder onset between T1 and T4, the 7D, but not the 7U, was associated with new onset (AUC 0.67, p<0.05; HR 1.14, 95% CI 1.07-1.23). The 7U7D did not achieve significant prediction of BD. LIMITATIONS: Relative small sample size and limited generalizability. CONCLUSIONS: Based on the current study, the 7U7D shows limited potential as screening instrument for mood disorders in bipolar offspring. The clinical utility of the 7U7D needs further exploration for use in clinical and research settings.

Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth.

BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth.

New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder.

The rapid cycling variant of bipolar disorder is defined as the occurrence of four periods of either manic or depressive illness within 12 months. Patients suffering from this variant of bipolar disorder have an unmet need for effective treatment. This review examines two major studies in an attempt to update understanding of the current therapies available to treat rapid cycling patients. The first trial compares lamotrigine versus placebo in 182 patients studied for 6 months. The second is a recently completed, 20-month trial comparing divalproate and lithium in 60 patients. Both trials had a double-blind, randomized parallel-group design. The data from the latter study indicate that there are no large differences in efficacy between lithium and divalproate in the long-term treatment of rapid cycling bipolar disorder. In addition, lamotrigine has the potential to complement the spectrum of lithium and divalproate through its greater efficacy for depressive symptoms.

Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder.

OBJECTIVES: The primary purpose of this study was to describe the clinical presentation of bipolar I disorder (BP-I) as it occurs in children and adolescents and to assess whether the manifestations of BP-I were similar in both age groups. METHOD: Ninety youths between the ages of 5 and 17 years meeting full diagnostic symptom criteria for BP-I were included in this study. The diagnosis of BP-I was established for these youths based on the results of a semi-structured diagnostic interview and a clinical assessment by a child and adolescent psychiatrist. The course of a subset of these youngsters' illnesses was assessed using the Life Charting Method (LCM). Data regarding the clinical presentation, longitudinal history, psychiatric co-morbidities and parental psychopathology were also obtained. RESULTS: The clinical presentation of BP-I was similar in children and adolescents. Youths meeting diagnostic criteria for BP-I developed an average of approximately 5.8 of the 7 symptoms of mania during periods of elevated or irritable mood. BP-I was found to be a cyclic disorder characterized by high rates of rapid cycling (50%) with almost no inter-episode recovery. Almost 75% of these subjects also met diagnostic symptom criteria for a disruptive behavior disorder. High rates of mood disorders were found in fathers. CONCLUSIONS: These data suggest that the presentation of juvenile BP-I is a cyclic and valid clinical condition with manifestations on a continuum with the later-onset forms of this illness.

Discriminative validity of parent report of hypomanic and depressive symptoms on the General Behavior Inventory.

It often is difficult clinically to differentiate bipolar disorder from other mental health conditions in young people. This study evaluated a parent report measure of depressive and hypomanic/biphasic symptoms. Parents of 196 youths, who were 5 to 17 years old and presented at an outpatient research center, completed an adapted General Behavior Inventory (GBI). Factor analyses suggested two dimensions, depression (alpha = .97) and biphasic/hypomania (alpha = .95). Logistic regressions using these scales discriminated mood disorder versus disruptive behavior disorder or no diagnosis, unipolar versus bipolar disorder, and bipolar versus disruptive behavior disorder based on structured interviews. Classification rates exceeded 80%, and receiver operating characteristic analyses showed good diagnostic efficiency for the scales, with areas under the curve greater than .80. Results indicate that clinicians can use the parent-completed GBI to derive clinically meaningful information about mood disorders in youths.

Predictors of violence exposure among inner-city youth.

Examined the ability of demographic variables and risk factors (parental substance use, number of people in the home, out-of-home placements, grades repeated, arrest history, and total life stress) to predict exposure to community violence among 342 high school students from inner-city Baltimore referred for mental health care in community centers or in the schools. Over 90% of the sample knew at least 1 victim of a violent act, 77% reported witnessing a violent act, and 47% reported past victimization by violence. Risk variables were more powerful regression predictors of violence exposure than demographic characteristics such as race, sex, or clinical setting. Even after controlling for demographic differences in violence exposure, risk factors as a group accounted for another 10% to 15% of variance. Life stress was the most consistent predictor of violence exposure for this sample, and life stress was the only variable to make a significant unique contribution to the prediction of all 4 violence criteria.

Emotion knowledge in economically disadvantaged children: self-regulatory antecedents and relations to social difficulties and withdrawal.

We examined the relations of verbal ability and self-regulation in preschool to emotion knowledge in first grade, and concurrent relations between emotion knowledge and indexes of social functioning in 143 children from low-income families. After controlling for children's verbal ability in preschool, teacher reports of attentional control and caregiver reports of behavioral control in preschool predicted children's emotion expression knowledge and emotion situation knowledge 2 years later. After controlling for verbal ability and attentional and behavioral control, children's emotion knowledge predicted concurrent teacher-reported social problems and social withdrawal. Results suggest that low levels of emotion knowledge co-occur with many important aspects of children's early social adaptation.

The frequency of reliable component difference scores for the Wechsler Intelligence Scale for Children--Third edition in two samples.

The cumulative percentage frequencies are presented for differences among reliable component analysis (RCA) scores for the verbal comprehension, perceptual organization, freedom from distractibility, and processing speed constructs assessed by the Wechsler Intelligence Scale for Children--Third edition (WISC-III) for the standardization sample and a learning disabled sample. Using RCA scores to form differences has several advantages over traditional equally weighted scores for the WISC-III. J. C. Caruso and N. Cliff (2000) presented tables to assess the statistical significance of differences among the RCA scores for the WISC-III. It is important, however, to use a dual approach in interpreting difference scores; both the statistical significance of a difference and the frequency with which it occurred in a relevant comparison group should be determined. This article contains the information necessary for practitioners to use the recommended dual approach to interpreting RCA difference scores for the WISC-III.

Contextual risk, caregiver emotionality, and the problem behaviors of six- and seven-year-old children from economically disadvantaged families.

This study explored the relations between additive and cumulative representations of contextual risk, caregiver emotionality, child adaptability, and teacher reports of the problem behaviors of 6- and 7-year-old children (N = 155) from economically disadvantaged families. The results showed relations between both risk representations and child problem scores and provided evidence that the relation for cumulative risk may be moderated by caregiver negative emotionality and caregiver positive emotionality and partially mediated by child adaptability. The results suggest the importance of exploring alternative representations of contextual risk and the conditions under which contextual risk influences child behavior.

Depression and disability in Parkinson's disease.

The relationship between depression and disability in idiopathic Parkinson's disease (PD) was examined in 31 outpatients. Thirteen percent had current major depression (MD), 10% dysthymia, and 32% a lifetime history of MD. Depression was significantly related to both illness severity and functional impairment. Male patients with early-onset PD (before age 55) had more mood and anxiety disorders than late-onset male patients. Patients with right-sided PD had significantly more depressive symptoms than those with left-sided PD. On multiple regression analyses, depression predicted impaired social, role, and physical functioning for men (but not for women), independent of the impact of illness severity. The results suggest that treatment of depression may improve function; however, findings of gender differences will require replication.