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.

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.

Lifetime and novel psychiatric disorders after pediatric traumatic brain injury.

OBJECTIVE: To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury (TBI) in children and adolescents. METHOD: Forty-six youths who sustained a TBI between the ages of 6 through 15 years were evaluated at least 1 year post-TBI to identify the presence of lifetime and/or novel psychiatric disorders. Semistructured interviews of the parent and child and standardized parent self-report rating instruments were used. RESULTS: Attention-deficit/hyperactivity disorder and depressive disorders were the most common lifetime and novel diagnoses. A wide variety and high rate of novel psychiatric disorders were identified; 74% of these disorders persisted in 48% of the injured children. Internalizing disorders were more likely to resolve than externalizing disorders. Both interviews and parent ratings were sensitive to current externalizing behaviors; interviews more often detected internalizing disorders, whereas parent ratings also identified cognitive difficulties. CONCLUSIONS: Findings were generally consistent with previous research demonstrating the high rate of novel psychiatric disorders following pediatric TBI. Psychiatric interviews were sensitive in identifying both lifetime and novel disorders.

Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder.

OBJECTIVE: To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years. METHOD: Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS). RESULTS: Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen. CONCLUSIONS: Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

Ultradian rhythms and temporal coherence in sleep EEG in depressed children and adolescents.

BACKGROUND: It has been suggested that a primary ultradian (80-120 minute) rhythm disturbance in EEG underlies sleep abnormalities in adults with depression. The present study evaluated ultradian rhythm disturbances in childhood and adolescent depression. METHODS: Sleep macroarchitecture and temporal coherence in quantitative EEG rhythms were investigated in 50 medication-free outpatients with major depression (25 children and 25 adolescents) and 15 healthy normal controls (5 children and 10 adolescents). RESULTS: Few of the macroarchitectural measures showed significant group effects. In fact, age and sex effects were stronger than disease-dependent components. Temporal coherence of EEG rhythms during sleep did differentiate those with MDD from controls. Both depressed children and adolescents had lower intrahemispheric coherence, whereas interhemispheric was only lower in depressed adolescents in comparison with controls. Gender differences were evident in adolescents, but not children, with MDD with lowest interhemispheric coherence in adolescent girls. CONCLUSIONS: These findings are in keeping with increased risk for depression in females beginning at adolescence and extending throughout adulthood. It was suggested that low temporal coherence in depression reflects a disruption in the fundamental basic rest-activity cycle of arousal and organization in the brain that is strongly influenced by gender.

Acute and continuation pharmacological treatment of children and adolescents with bipolar disorders; a summary of two previous studies.

We report the results of an acute-phase and continuation-phase study of the pharmacological treatment of children and adolescents with bipolar disorders. The acute phase study, with a duration of 6-8 weeks, aimed at developing effect sizes (ES) for lithium, divalproex sodium, and carbamazepine, in the acute phase treatment of Bipolar I or II children and adolescents during a mixed or manic episode. During the acute-phase of treatment, 42 outpatients with a mean age of 11.4 yr. (20 with Bipolar I Disorder and 22 with Bipolar II Disorder) were randomly assigned to 6-8 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly CGI Improvement scores and the Young Mania Rating Scale. Using a ≥ 50% change from baseline to exit in the Y-MRS scores to define response, the effect size for divalproex sodium was 1.63,1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were: sodium divalproex 53%; lithium 38%; and carbamazepine 38% (x 2=0.85, 2 d.f., p=0.60). Thirty-five subjects continued in open, treatment for another 16-18 weeks, for a total of 24 weeks of prospective treatment. Overall, of the thirty-five continuation phase subjects, thirty (85%) were categorized as responders at the end of the continuation phase of treatment. Of these thirty-five subjects, 13 (37%) were only on a single mood stabilizer and no other psychotropic agents at the end of the continuation phase. Thirty-one percent of subjects in continuation were also treated with a stimulant medication in addition to mood stabilizers.

Prediction of response to fluoxetine and placebo in children and adolescents with major depression: a hypothesis generating study.

BACKGROUND: The results of multivariate analyses to identify potential predictors of response to fluoxetine or placebo separately in 96 child and adolescent outpatients with major depressive disorder from a recent controlled trial are presented. METHODS: A variety of clinical, demographic and laboratory factors were examined as possible predictors of response to fluoxetine or placebo using logistic regression models. RESULTS: No single variable or combination of variables strongly predicted response to fluoxetine. For the placebo group, a younger age, a shorter duration of depressive episode, and a lower socioeconomic status predicted response with an overall predictive power of 81%. CONCLUSIONS: This study is limited by the small sample size and should be considered hypothesis generating rather than confirming.

A SPECT HMPAO study of regional cerebral blood flow in depressed adolescents and normal controls.

1. The objective of this study was to compare the relative regional cerebral blood flow (rCBF) patterns of a group of adolescents with major depressive disorder (MDD) to a group of normal controls. 2. Seven adolescent patients with symptomatic MDD and 7 age- and gender-matched normal controls, underwent SPECT imaging with 99mTc-HMPAO while unmedicated and in a resting state. These subject's data were normalized to whole brain counts, oriented in Talairach space, and analyzed using a voxel-based, t-image approach. 3. The authors found relative rCBF increases in the depressed group as compared to normals in the right mesial temporal cortex, the right superior-anterior temporal lobe, and the left infero-lateral temporal lobe. We found rCBF decreases in the depressed group as compared to normals in the left parietal lobe, the anterior thalamus and the right caudate. 4. Adolescents with MDD show rCBF abnormalities similar to those found in adult MDD rCBF studies. Further controlled studies with larger numbers of MDD subjects and normal age- and gender-matched controls are necessary before any definitive conclusions can be made from these findings.

Fluoxetine in child and adolescent depression: acute and maintenance treatment.

The objective was to present naturalistic 1-year follow-up information of 96 child and adolescent outpatients with major depressive disorder who had been randomized in an 8-week double-blind, placebo-controlled trial of fluoxetine. Subjects were children and adolescents, ages 8-18 years, who were entered in a randomized clinical trial of fluoxetine. Following the acute treatment trial, treatment was not controlled. At 6 months and 1 year, the subjects and parents were interviewed using the Kiddie Longitudinal Interval Follow-up Evaluation (K-LIFE) for course of depression. Eighty-seven of the 96 subjects were followed for 1 year. Of these, 74 (85%) recovered from the depressive episode during that time (47 on fluoxetine, 22 on no medication, and 5 on other antidepressants or lithium). Twenty-nine of the subjects (39%) who recovered had a recurrence of depression during the 1-year follow-up, with 55% of these occurring within 6 months. Results of this study are similar to adult studies, with respect to response and recovery of depressive episodes. Most patients (85%) recover from the episode within 1 year, but approximately 40% have a recurrence within 12 months, which is a higher recurrence rate than in adults. Recovery was associated with younger age, lower severity of depressive symptoms, higher family functioning, and fewer comorbid diagnoses. Recurrence, which occurs both on and off medication, was difficult to predict, as there was little clinical data associated with recurrence in this population.

Mood stabilizers and anticonvulsants.

This article provides pediatricians and other clinicians who treat children and adolescents with a working knowledge of mood stabilizers and their potential uses in children and adolescents with mood and behavior disorders. Mood stabilizers are ubiquitous agents that are often effective in the treatment of children and adolescents with bipolar disorders or conduct disorders and mentally retarded patients with aggressive behavior. The authors' also discuss mechanisms of action, pharmacokinetics, dosing, drug interactions, and potential uses. Following these medication details, specific information concerning the diagnosis and treatment of several child and adolescent mood and behavior disorders, and in which treatment with mood stabilizers may be helpful, is presented.

A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression.

BACKGROUND: Depression is a major cause of morbidity and mortality in children and adolescents. To date, randomized, controlled, double-blind trials of antidepressants (largely tricyclic agents) have yet to reveal that any antidepressant is more effective than placebo. This article is of a randomized, double-blind, placebo-controlled trial of fluoxetine in children and adolescents with depression. METHODS: Ninety-six child and adolescent outpatients (aged 7-17 years) with nonpsychotic major depressive disorder were randomized (stratified for age and sex) to 20 mg of fluoxetine or placebo and seen weekly for 8 consecutive weeks. Randomization was preceded by 3 evaluation visits that included structured diagnostic interviews during 2 weeks, followed 1 week later by a 1-week, single-blind placebo run-in. Primary outcome measurements were the global improvement of the Clinical Global Impressions scale and the Children's Depression Rating Scale--Revised, a measure of the severity depressive symptoms. RESULTS: Of the 96 patients, 48 were randomized to fluoxetine treatment and 48 to placebo. Using the intent to treat sample, 27 (56%) of those receiving fluoxetine and 16 (33%) receiving placebo were rated "much" or "very much" improved on the Clinical Global Impressions scale at study exit (chi 2 = 5.1, df = 1, P = .02). Significant differences were also noted in weekly ratings of the Children's Depression Rating Scale--Revised after 5 weeks of treatment (using last observation carried forward). Equivalent response rates were found for patients aged 12 years and younger (n = 48) and those aged 13 years and older (n = 48). However, complete symptom remission (Children's Depression Rating Scale--Revised < or = 28) occurred in only 31% of the fluoxetine-treated patients and 23% of the placebo patients. CONCLUSION: Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent outpatients with severe, persistent depression. Complete remission of symptoms was rare.

Plasma GABA in children and adolescents with mood, behavior, and comorbid mood and behavior disorders: a preliminary study.

Plasma GABA concentrations (pGABA) were measured in 115 inpatients (aged 7-17) with child psychiatric disorders. Group mean pGABAs were compared for 38 patients with mood disorders only (MOOD), 29 with behavior disorders only (BEH), 48 with comorbid mood and behavior disorders (MOOD + BEH), and 14 normal controls (CON, aged 14-17). The BEH group was characterized by (a) high mean pGABAs (157 vs. 133 pmol/ml), (b) lower mean pGABAs in BEH subjects who had been receiving pharmacotherapy with SSRIs or other medications (p < 0.026), and (c) decreased pGABA with increasing age (p = 0.019). These features were not found in controls or in groups of patients with mood disorders (MOOD or MOOD + BEH). Elevated mean pGABA in the BEH group appeared specifically in patients with comorbid CD and ADHD, not in patients with ADHD or CD alone (p = 0.004). No patient in BEH (or CON) had pGABA below 100 pmol/ml, but low pGABAs were found in 15% of MOOD patients (who had no behavior disorder) and in 16% of MOOD + BEH patients. Pharmacotherapy did not change pGABAs in the MOOD or the MOOD + BEH groups. No pGABA differences were found among the anxiety disorders, either alone or with mood or behavior comorbidity. The finding that plasma GABA levels are elevated in nonmedicated behavior disorders that present in the absence of mood disorders, and appear to lower following medication treatments, merits increased attention to the pharmacological study of nonaffective behavior disorders.

The effects of extended evaluation on depressive symptoms in children and adolescents.

A sample of 137 child and adolescent outpatients with major depressive disorder were examined to identify baseline clinical characteristics that predicted symptom severity at the end of a 3-week evaluation period and to determine whether change in symptom severity between week 1 and week 2 predicted symptom severity at week three. Subjects underwent three consecutive weekly evaluations prior to being considered for entry into a double-blind, placebo-controlled treatment trial of fluoxetine. Results indicated that the combination of age, social functioning, family history, Children's Depressive Rating Scale-Revised (CDRS-R) (Poznanski et al. (1985) Psychopharmacol. Bull. 21, 979-989) total score at visit one, and percent change in symptom severity between visit one and visit two were predictors of symptom severity at visit three. These findings suggest that (1) subjects should not be excluded from randomized controlled clinical treatment trials based solely on improvement of symptom severity between visits and (2) an extended evaluation period is warranted, especially for adolescents whose symptom severity tends to fluctuate from week to week.

Cognitive-behavior therapy for late-life insomnia.

Twenty-four older adults with persistent psychophysiological insomnia were randomly assigned to an immediate or a delayed cognitive-behavioral intervention in a waiting-list control group design. Cognitive-behavior therapy consisted of an 8-week group intervention aimed at changing maladaptive sleep habits and altering dysfunctional beliefs and attitudes about sleeplessness. Treatment was effective in reducing sleep latency, wake after sleep onset, and early morning awakening, and in increasing sleep efficiency. The magnitude of changes obtained on polysomnographic measures was smaller but in the same direction as that obtained on daily sleep diaries. Sleep improvements obtained by the immediate-treatment group were replicated with the delayed treatment condition. Therapeutic gains were well maintained at 3- and 12-month follow-ups. Clinical validation of outcome was obtained through collateral ratings from the patients and their significant others. The findings indicate that late-life insomnia can be effectively treated with nonpharmacological interventions.

Patients' acceptance of psychological and pharmacological therapies for insomnia.

This study evaluated the acceptance of psychological and pharmacological therapies among chronic insomniacs and noncomplaining good sleepers. After reading a brief written description of two treatment methods commonly used for persistent insomnia (i.e. cognitive-behavior therapy and pharmacotherapy), the subjects rated in a counter-balanced order several dimensions of these two treatment modalities. The results showed that the psychological intervention was rated as more acceptable and more suitable than the pharmacological one among both insomniacs and their noncomplaining significant others. Behavior therapy was also expected to be more effective on a long-term basis and to produce fewer side effects as well as more benefits on daytime functioning. The clinical implications and relevance of treatment acceptance in the management of insomnia are discussed.

Electroencephalographic sleep and mood during cocaine withdrawal.

We report on nine patients between the ages of 21 and 39 years who were admitted to an inpatient substance abuse treatment unit for cocaine treatment. The patients' sleep was studied in the laboratory for 4 nights during the first week, and 2 nights during the second and third weeks of their hospitalization. Daily mood ratings, cocaine craving scores and sleep logs were also recorded on each patient. During the first week of withdrawal, these patients had a markedly shortened REM latency, an increased REM sleep percentage, a very high REM density and a long total sleep period time. During the third week, REM latencies were very short and total percentage of REM sleep was increased. By week three of withdrawal the sleep continuity pattern was similar to that found in chronic insomnia, with a long sleep latency, an abnormally increased total time awake after sleep onset and a poor sleep efficiency. The subjects' ratings of cocaine craving, total POMS scores and depression fell precipitously after the first week of withdrawal and were at sub-clinical levels by week three of withdrawal.