Systematic Review and Network Meta-Analysis: Efficacy and Safety of Antipsychotics vs Antiepileptics or Lithium for Acute Mania in Children and Adolescents.

OBJECTIVE: To compare second-generation antipsychotics (SGAs) and mood stabilizers (MSs) in youth with a bipolar disorder type-1 (BD-I) manic/mixed episode. METHOD: Systematic PubMed/Embase/PsycInfo literature search until 12/31/2023 for randomized trials of SGAs or MSs in patients aged ≤18 years with BD-I manic/mixed episode. Network meta-analysis comparing treatments regarding mania symptoms and mania response (co-primary outcomes), and secondary efficacy and tolerability outcomes. RESULTS: Eighteen studies (n=2844, mean age=11.74, females=48.0%, mean study duration=5.4 weeks) comparing six SGAs (aripiprazole, asenapine, olanzapine, quetiapine, risperidone, ziprasidone) and four MSs (lithium, oxcarbazepine, topiramate, valproate) were meta-analyzed. All six SGAs outperformed placebo in reducing manic symptomatology, including risperidone (SMD=-1.18,95%CI=-0.92;-1.45, CINeMA= moderate confidence), olanzapine (SMD=-0.77,95%CI=-0.36;-1.18, low confidence), aripiprazole (SMD=-0.67,95%CI=-0.33;-1.01, moderate confidence), quetiapine (SMD=-0.60,95%CI=-0.32,-0.87, high confidence), asenapine (SMD=-0.54,95%CI=-0.19; -0.89, moderate confidence), and ziprasidone (SMD=-0.43,95%CI=-0.17-0.70, low confidence), while no mood stabilizer outperformed placebo. Concerning mania response, risperidone (RR=2.58,95%CI=1.88;3.54, low confidence), olanzapine (RR=2.42,95%CI=1.33-3.54, very low confidence), aripiprazole (RR=2.05,95%CI=1.44-2.92, low confidence), quetiapine (RR=1.89,95%CI=1.45-2.47, moderate confidence), asenapine (RR=1.81,95%CI=1.28-2.55, very low confidence) and lithium (RR=1.35,95%CI=1.00;1.83, p-value=0.049, very low confidence) outperformed placebo, without superiority of other MSs versus placebo. Individually, risperidone was more efficacious in reducing manic symptomatology than all other comparators, except olanzapine and topiramate, yet with low/very low confidence, and was associated with increased prolactin and glucose. Pooled together, SGAs outperformed both placebo and MSs for mania symptoms reduction (SMD=-0.68,95%CI=-0.86;-0.51 and SMD=-0.61,95%CI=-0.82;-0.40, moderate confidence), and mania response (RR=1.85,95%CI=1.53;2.24 and RR=1.65,95%CI=1.33-2.04, moderate confidence) without differences between MSs and placebo. There were no significant treatment-placebo differences for all-cause discontinuation, while lithium, ziprasidone and oxcarbazepine were associated with more adverse event-related drop-outs than placebo. Most SGAs were associated with more sedation, weight gain, and metabolic issues versus placebo and MSs. CONCLUSION: SGAs are more efficacious than placebo and MSs in treating acute mania symptoms, however, their use must be carefully weighed against important side effects.

Development of a Symptom-Focused Model to Guide the Prescribing of Antipsychotics in Children and Adolescents: Results of the First Phase of the Safer Use of Antipsychotics in Youth (SUAY) Clinical Trial.

OBJECTIVE: To develop a new approach to prescribing guidelines as part of a pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY; ClinicalTrials.gov Identifier: NCT03448575), which supports prescribers in delivering high-quality mental health care to youths. METHOD: A nominal group technique was used to identify first- to nth-line treatments for target symptoms and potential diagnoses. The panel included US pediatricians, child and adolescent psychiatrists, and psychopharmacology experts. Meeting materials included information about Medicaid review programs, systematic reviews, prescribing guidelines, and a description of the pragmatic trial. Afterward, a series of 4 webinar discussions were held to achieve consensus on recommendations. RESULTS: The panel unanimously agreed that the guideline should focus on target symptoms rather than diagnoses. Guidance included recommendations for first- to nth-line treatment of target mental health symptoms, environmental factors to be addressed, possible underlying diagnoses that should first be considered and ruled out, and general considerations for pharmacological and therapeutic treatments. CONCLUSION: Prescribing guidelines are often ignored because they do not incorporate the real-world availability of first-line psychosocial treatments, comorbid conditions, and clinical complexity. Our approach addresses some of these concerns. If the approach proves successful in our ongoing pragmatic trial, Safer Use of Antipsychotics in Youth (SUAY), it may serve as a model to state Medicaid programs and health systems to support clinicians in delivering high-quality mental health care to youths. CLINICAL TRIAL REGISTRATION INFORMATION: Safer Use of Antipsychotics in Youth; http://clinicaltrials.gov/; NCT03448575.

A Randomized Comparison of Two Psychosocial Interventions on Family Functioning in Adolescents with Bipolar Disorder.

Impairments in family functioning are associated with more severe depressive and manic symptoms, earlier recurrences, and more suicidal behaviors in early-onset bipolar disorder. This study examined whether family-focused treatment for adolescents (FFT-A) with BD I or II disorder led to greater increases in family cohesion and adaptability and decreases in conflict over 2 years compared to a briefer psychoeducational treatment (enhanced care, EC). Participants were 144 adolescents (mean age: 15.6 ± 1.4 years) with BD I or II with a mood episode in the previous 3 months. Adolescents and parents were randomized to either FFT-A (21 sessions) or EC (three sessions). Patients received guideline-based pharmacotherapy throughout the 2-year study. Trajectories of adolescent- and parent-rated family cohesion, adaptability, and conflict were analyzed over 2 years. FFT-A had greater effects on adolescent-rated family cohesion compared to EC over 2 years. Participants in FFT-A and EC reported similar improvements in family conflict across the 2 years. In the FFT-A group, low-conflict families had greater adolescent-rated family cohesion throughout the study compared to high-conflict families. High-conflict families in both treatment groups tended to show larger reductions in conflict over 2 years than low-conflict families. Family psychoeducation and skills training may improve family cohesion in the early stages of BD. Measuring levels of family conflict at the start of treatment may inform treatment responsiveness among those receiving FFT-A.

Los problemas en el funcionamiento familiar están asociados con síntomas depresivos y maníacos más graves, recidivas en periodos más breves y más conductas suicidas en el trastorno bipolar de inicio precoz. Este estudio analizó si el "Tratamiento centrado en la familia para adolescentes" (Family-Focused Treatment for Adolescents, FFT-A) con trastorno bipolar tipo I y tipo II condujo a mayores aumentos en la cohesión familiar y en la adaptabilidad y a disminuciones en el conflicto durante dos años en comparación con un tratamiento psicoeducativo más breve (atención optimizada; Enhanced Care: EC). Los participantes fueron 144 adolescentes (edad promedio: 15.6±1.4 años) con trastorno bipolar tipo I o tipo II con un episodio de alteración del humor en los tres meses previos. Los adolescentes y los padres fueron asignados aleatoriamente al FFT-A (21 sesiones) o a la EC (3 sesiones). Los pacientes recibieron farmacoterapia pautada durante todo el estudio de dos años. Las trayectorias de la cohesión familiar evaluada por los adolescentes y los padres, la adaptabilidad y el conflicto se analizaron durante dos años. El FFT-A tuvo mayores efectos en la cohesión familiar evaluada por los adolescentes en comparación con la EC durante dos años. Los participantes del FFT-A y de la EC informaron mejoras similares en el conflicto familiar durante los dos años. Las familias con un alto nivel de conflicto en el FFT-A tuvieron una menor cohesión evaluada por los adolescentes y una menor adaptabilidad durante dos años en comparación con las familias con un bajo nivel de conflicto en el FFT-A. Las familias con un alto nivel de conflicto en ambos grupos de tratamiento tendieron a mostrar reducciones más grandes en el conflicto durante dos años que las familias con un bajo nivel de conflicto. La psicoeducación familiar y la capacitación en habilidades pueden mejorar la cohesión familiar en las etapas iniciales del trastorno bipolar. La medición de los niveles de conflicto familiar al comienzo del tratamiento puede respaldar la capacidad de respuesta al tratamiento entre aquellos que reciben el FFT-A.

Classifying Mood Symptom Trajectories in Adolescents With Bipolar Disorder.

OBJECTIVE: The Course and Outcome of Bipolar Youth study found that children and adolescents with bipolar spectrum disorders followed 1 of 4 distinct mood trajectories over 8 years of follow-up, with as many as 25% of participants showing a predominantly euthymic course. We evaluated whether similar patterns of illness course are observed in adolescents with bipolar I and II disorder who participated in a 2-year clinical trial. METHOD: A total of 144 adolescents with bipolar I or II disorder, identified shortly after a mood episode, were assessed over a 2-year period. Participants were randomly assigned to one of 2 psychosocial family treatments during the first 9 months of the study, and pharmacotherapy was provided throughout the 2 years. Using latent class growth analyses, we classified participants into distinct courses of illness based on mood ratings collected over the 2 years. We examined demographic and illness variables as predictors of these course classifications. RESULTS: Latent class growth analyses indicated four mood trajectories: "predominantly euthymic" (29.9% of sample), "ill with significantly improving course" (11.1%), "moderately euthymic" (26.4%), and "ill with moderately improving course" (32.6%). Adolescents in these classes were euthymic 77.7%, 53.6%, 44.1%, and 18.6% of the weeks of follow-up, respectively. Psychosocial treatment condition and baseline medication exposure were not associated with trajectories. However, youth with more severe baseline depressive symptoms, suicidality, lower quality of life scores, and minority race/ethnicity had more symptomatic courses of illness over time. CONCLUSION: A substantial proportion (25%-30%) of youth with bipolar I or II disorder maintain euthymic states over extended periods of follow-up. Identifying youth who are more and less likely to remain stable over time may help guide psychosocial and pharmacological treatments after an illness episode. CLINICAL TRIAL REGISTRATION INFORMATION: Effectiveness of Family-Focused Treatment Plus Pharmacotherapy for Bipolar Disorder in Adolescents; https://clinicaltrials.gov/; NCT00332098.

Clinical, cortical thickness and neural activity predictors of future affective lability in youth at risk for bipolar disorder: initial discovery and independent sample replication.

We aimed to identify markers of future affective lability in youth at bipolar disorder risk from the Pittsburgh Bipolar Offspring Study (BIOS) (n = 41, age = 14, SD = 2.30), and validate these predictors in an independent sample from the Longitudinal Assessment of Manic Symptoms study (LAMS) (n = 55, age = 13.7, SD = 1.9). We included factors of mixed/mania, irritability, and anxiety/depression (29 months post MRI scan) in regularized regression models. Clinical and demographic variables, along with neural activity during reward and emotion processing and gray matter structure in all cortical regions at baseline, were used to predict future affective lability factor scores, using regularized regression. Future affective lability factor scores were predicted in both samples by unique combinations of baseline neural structure, function, and clinical characteristics. Lower bilateral parietal cortical thickness, greater left ventrolateral prefrontal cortex thickness, lower right transverse temporal cortex thickness, greater self-reported depression, mania severity, and age at scan predicted greater future mixed/mania factor score. Lower bilateral parietal cortical thickness, greater right entorhinal cortical thickness, greater right fusiform gyral activity during emotional face processing, diagnosis of major depressive disorder, and greater self-reported depression severity predicted greater irritability factor score. Greater self-reported depression severity predicted greater anxiety/depression factor score. Elucidating unique clinical and neural predictors of future-specific affective lability factors is a step toward identifying objective markers of bipolar disorder risk, to provide neural targets to better guide and monitor early interventions in bipolar disorder at-risk youth.

Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

Comorbid disorders as moderators of response to family interventions among adolescents with bipolar disorder.

BACKGROUND: While family interventions have shown efficacy in improving mood symptoms and family functioning in pediatric bipolar disorder, few studies have examined the effects of comorbid psychiatric conditions on patients' symptomatic or functional responses to treatment. METHODS: 145 adolescents with bipolar I or II disorder were randomly assigned to family-focused therapy (FFT-A) or a brief psychoeducational therapy (enhanced care; EC) and followed over 2 years. Participants received pharmacotherapy for the study's duration. We examined whether comorbid anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and disruptive behavior disorders (DBDs; i.e., oppositional defiant and conduct disorder) predicted the proportion of weeks that participants experienced mood symptoms during follow-up, and whether comorbid disorders moderated the effects of treatment assignment on mood symptoms and family conflict. RESULTS: Comorbid anxiety was associated with a greater proportion of weeks with depressive symptoms, more severe (hypo)manic symptoms during follow-up, and greater family conflict over the 2-year study. Comorbid ADHD was associated with a greater proportion of weeks with (hypo)manic symptoms, more severe (hypo)manic symptoms, and greater family conflict. Additionally, youth with comorbid ADHD who received FFT-A had more favorable trajectories of (hypo)manic symptoms and family functioning than youth with comorbid ADHD who received EC. Comorbid DBDs were consistently associated with more severe depressive symptoms and greater family conflict throughout the study. LIMITATIONS: Randomization to treatments was not stratified on comorbid disorders. The longitudinal trajectories of anxiety, attentional, and disruptive behavior symptoms were not examined. CONCLUSIONS: The course of bipolar disorder in adolescents is strongly affected by comorbid disorders. Future research should examine whether adolescents with more complex presentations of bipolar disorder should be treated with different or more intensive psychosocial protocols than adolescents without these presentations.

Diagnostic Accuracy of the CASI-4R Psychosis Subscale for Children Evaluated in Pediatric Outpatient Clinics.

Diagnostic accuracy of the Diagnostic and Statistical Manual of Mental Disorders-oriented Child and Adolescent Symptom Inventory (CASI-4R) Psychotic Symptoms scale was tested using receiver operating characteristic analyses to identify clinically significant psychotic symptoms. Participants were new outpatients (N = 700), ages 6.0 to 12.9 years (M = 9.7, SD = 1.8) at 9 child outpatient mental health clinics, who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) Study baseline assessment. Because LAMS undersampled participants with low mania scores by design, present analyses weighted low scorers to produce unbiased estimates. Psychotic symptoms, operationally defined as a score of 3 or more for hallucinations or 4 or more for delusions based on the Schedule for Affective Disorders and Schizophrenia (K-SADS) psychosis items, occurred in 7% of youth. K-SADS diagnoses for those identified with psychotic symptoms above threshold included major depressive disorder, bipolar spectrum disorder, attention deficit/hyperactivity disorder, posttraumatic stress disorder, psychotic disorders, and autism spectrum disorder. The optimal psychosis screening cut score (maximizing sensitivity and specificity) was 2.75+ (corresponding diagnostic likelihood ratio [DiLR] = 4.29) for the parent version and 3.50+ (DiLR = 5.67) for the teacher version. The Area under the Curve for parent and teacher report was .83 and .74 (both p < .001). Parent report performed significantly better than teacher report for identifying psychotic symptoms above threshold (p = .03). The CASI-4R Psychosis subscale (J) appears clinically useful for identifying psychotic symptoms in children because of its brevity and accuracy.

Decreased functional connectivity in the fronto-parietal network in children with mood disorders compared to children with dyslexia during rest: An fMRI study.

Background: The DSM-5 separates the diagnostic criteria for mood and behavioral disorders. Both types of disorders share neurocognitive deficits of executive function and reading difficulties in childhood. Children with dyslexia also have executive function deficits, revealing a role of executive function circuitry in reading. The aim of the current study is to determine whether there is a significant relationship of functional connectivity within the fronto-parietal and cingulo-opercular cognitive control networks to reading measures for children with mood disorders, behavioral disorders, dyslexia, and healthy controls (HC). Method: Behavioral reading measures of phonological awareness, decoding, and orthography were collected. Resting state fMRI data were collected, preprocessed, and then analyzed for functional connectivity. Differences in the reading measures were tested for significance among the groups. Global efficiency (GE) measures were also tested for correlation with reading measures in 40 children with various disorders and 17 HCs. Results: Significant differences were found between the four groups on all reading measures. Relative to HCs and children with mood disorders or behavior disorders, children with dyslexia as a primary diagnosis scored significantly lower on all three reading measures. Children with mood disorders scored significantly lower than controls on a test of phonological awareness. Phonological awareness deficits correlated with reduced resting state functional connectivity MRI (rsfcMRI) in the cingulo-opercular network for children with dyslexia. A significant difference was also found in fronto-parietal global efficiency in children with mood disorders relative to the other three groups. We also found a significant difference in cingulo-opercular global efficiency in children with mood disorders relative to the Dyslexia and Control groups. However, none of these differences correlate significantly with reading measures. Conclusions/significance: Reading difficulties involve abnormalities in different cognitive control networks in children with dyslexia compared to children with mood disorders. Findings of the current study suggest increased functional connectivity of one cognitive control network may compensate for reduced functional connectivity in the other network in children with mood disorders. These findings provide guidance to clinical professionals for design of interventions tailored for children suffering from reading difficulties originating from different pathologies.

Mood instability as a predictor of clinical and functional outcomes in adolescents with bipolar I and bipolar II disorder.

BACKGROUND: Traditional assessment and treatment of bipolar disorder (BD) often overlooks an important feature of the illness, mood instability (MI). MI - the presence of intense, rapidly shifting emotional states - is associated with a number of poor prognostic outcomes. This study examined whether MI among adolescents with BD was cross-sectionally related to bipolar subtype (I vs. II) and prognostically associated with symptoms and functioning over 3 months. METHODS: Participants included 145 adolescents (mean age: 15.6 years ±â€¯1.4) with BD I or II with a mood episode in the previous 3 months. Depression and (hypo)mania instability were computed using the root mean square successive difference (rMSSD) score, reflecting both the size and temporal order of changes in weekly depression and (hypo)mania scores (over 12 weeks) from the Adolescent Longitudinal Interval Follow-Up Evaluation. RESULTS: Greater depression instability was associated with BD II, whereas greater (hypo)mania instability was associated with BD I. Baseline MI, particularly depression, predicted more instability, a higher percentage of weeks in a clinical mood state, and poorer global functioning over 3 months, even when covarying concurrent mood severity scores. LIMITATIONS: The clinical measure of symptoms used retrospective reports of clinically significant symptoms only. We were unable to standardize medication use or adherence. CONCLUSIONS: MI differs by diagnostic subtype, is relatively stable over time, and predicts clinical and functional outcomes. Targeting MI should be considered a clinical focus to augment traditional methods of assessing and treating BD during adolescence to enhance clinical and functional outcomes.

Diagnostic Efficiency of the Child and Adolescent Symptom Inventory (CASI-4R) Depression Subscale for Identifying Youth Mood Disorders.

This study examined the diagnostic and clinical utility of the Child and Adolescent Symptom Inventory-4 R (CASI-4 R) Depressive and Dysthymia subscale for detecting mood disorders in youth (ages 6-12; M = 9.37) visiting outpatient mental health clinics. Secondary analyses (N = 700) utilized baseline data from the Longitudinal Assessment of Manic Symptoms study. Semistructured interviews with youth participants and their parents/caregivers determined psychiatric diagnoses. Caregivers and teachers completed the CASI-4 R. CASI-4 R depressive symptom severity and symptom count scores each predicted mood disorder diagnoses. Both caregiver scores (symptom severity and symptom count) of the CASI-4 R subscale significantly identified youth mood disorders (areas under the curve [AUCs] = .78-.79, ps < .001). The symptom severity version showed a small but significant advantage. Teacher symptom severity report did not significantly predict mood disorder diagnosis (AUC = .56, p > .05), whereas the teacher symptom count report corresponded to a small effect size (AUC = .61, p < .05). The CASI-4 R Depression scale showed strong incrememental validity even controlling for the other CASI-4 R scales. Caregiver subscale cutoff scores were calculated to assist in ruling in (diagnostic likelihood ratio [DLR] = 3.73) or ruling out (DLR = 0.18) presence of a mood disorder. The CASI-4 R Depressive subscale caregiver report can help identify youth mood disorders, and using DLRs may help improve diagnostic accuracy.

Diagnostic Efficiency of Caregiver Report on the SCARED for Identifying Youth Anxiety Disorders in Outpatient Settings.

This study investigated the diagnostic and clinical utility of the parent-rated Screen for Child Anxiety Related Emotional Disorders (SCARED-P) for detecting youth anxiety disorders. Youth ages 6 to 12 years, 11 months were recruited from 9 outpatient mental health clinics (N = 707). Consensus diagnoses were based on semistructured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children) with youth and caregivers; 31% were diagnosed with at least one anxiety disorder. Caregivers completed the SCARED-P to describe youth anxiety levels. SCARED-P scores were not considered during the consensus diagnoses. Areas under the curve (AUCs) from receiver operating characteristic analyses and diagnostic likelihood ratios (DLRs) quantified performance of the SCARED-P total score and subscale scores (generalized anxiety disorder and separation anxiety disorder). SCARED-P total scores had variable efficiency (AUCs = .69-.88), and Generalized Anxiety Disorder and Separation Anxiety subscale scores were excellent (AUCs = .86-.89) for identifying specific anxiety disorders. Optimal subscale cutoff scores were computed to help rule in (DLRs = 2.7-5.4) or rule out (DLRs < 1.0) anxiety disorders among youth. Results suggest that the Generalized Anxiety Disorder and Separation Anxiety SCARED-P subscales accurately identify their respective matched diagnoses. DLRs may aid clinicians in screening for youth anxiety disorders and improve accuracy of diagnosis.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research.

OBJECTIVES: Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS: An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS: Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS: As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Using machine learning and surface reconstruction to accurately differentiate different trajectories of mood and energy dysregulation in youth.

Difficulty regulating positive mood and energy is a feature that cuts across different pediatric psychiatric disorders. Yet, little is known regarding the neural mechanisms underlying different developmental trajectories of positive mood and energy regulation in youth. Recent studies indicate that machine learning techniques can help elucidate the role of neuroimaging measures in classifying individual subjects by specific symptom trajectory. Cortical thickness measures were extracted in sixty-eight anatomical regions covering the entire brain in 115 participants from the Longitudinal Assessment of Manic Symptoms (LAMS) study and 31 healthy comparison youth (12.5 y/o;-Male/Female = 15/16;-IQ = 104;-Right/Left handedness = 24/5). Using a combination of trajectories analyses, surface reconstruction, and machine learning techniques, the present study aims to identify the extent to which measures of cortical thickness can accurately distinguish youth with higher (n = 18) from those with lower (n = 34) trajectories of manic-like behaviors in a large sample of LAMS youth (n = 115; 13.6 y/o; M/F = 68/47, IQ = 100.1, R/L = 108/7). Machine learning analyses revealed that widespread cortical thickening in portions of the left dorsolateral prefrontal cortex, right inferior and middle temporal gyrus, bilateral precuneus, and bilateral paracentral gyri and cortical thinning in portions of the right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, and right parahippocampal gyrus accurately differentiate (Area Under Curve = 0.89;p = 0.03) youth with different (higher vs lower) trajectories of positive mood and energy dysregulation over a period up to 5years, as measured by the Parent General Behavior Inventory-10 Item Mania Scale. Our findings suggest that specific patterns of cortical thickness may reflect transdiagnostic neural mechanisms associated with different temporal trajectories of positive mood and energy dysregulation in youth. This approach has potential to identify patterns of neural markers of future clinical course.

Enhancing quality of life among adolescents with bipolar disorder: A randomized trial of two psychosocial interventions.

BACKGROUND: Adolescents with bipolar disorder (BD) report lower quality of life (QoL) than adolescents with other psychiatric disorders. This study compared the efficacy of family-focused therapy for adolescents (FFT-A) plus pharmacotherapy to brief psychoeducation (enhanced care, or EC) plus pharmacotherapy on self-rated QoL in adolescents with BD over 2 years. METHODS: Participants were 141 adolescents (mean age: 15.6±1.4yr) with BD I or II who had a mood episode in the previous 3 months. Adolescents and parents were randomly assigned to (1) FFT-A, given in 21 sessions in 9 months of psychoeducation, communication enhancement training, and problem-solving skills training, or (2) EC, given in 3 family psychoeducation sessions. Study psychiatrists provided patient participants with protocol-based pharmacotherapy for the duration of the study. QoL was assessed with The KINDLRQuestionnaire (Ravens-Sieberer and Bullinger, 1998) during active treatment (baseline to 9 months) and during a post-treatment follow-up (9-24 months). RESULTS: The two treatment groups did not differ in overall QoL scores over 24 months. However, adolescents in FFT-A had greater improvements in quality of family relationships and physical well-being than participants in EC. For quality of friendships, the trajectory during active treatment favored EC, whereas the trajectory during post-treatment favored FFT-A. LIMITATIONS: We were unable to standardize medication use or adherence over time. Quality of life was based on self-report rather than on observable functioning. CONCLUSIONS: A short course of family psychoeducation and skills training may enhance relational functioning and health in adolescents with BD. The effects of different psychosocial interventions on peer relationships deserves further study.

Longitudinal relationships among activity in attention redirection neural circuitry and symptom severity in youth.

BACKGROUND: Changes in neural circuitry function may be associated with longitudinal changes in psychiatric symptom severity. Identification of these relationships may aid in elucidating the neural basis of psychiatric symptom evolution over time. We aimed to distinguish these relationships using data from the Longitudinal Assessment of Manic Symptoms (LAMS) cohort. METHODS: Forty-one youth completed two study visits (mean=21.3 months). Elastic-net regression (Multiple response Gaussian family) identified emotional regulation neural circuitry that changed in association with changes in depression, mania, anxiety, affect lability, and positive mood and energy dysregulation, accounting for clinical and demographic variables. RESULTS: Non-zero coefficients between change in the above symptom measures and change in activity over the inter-scan interval were identified in right amygdala and left ventrolateral prefrontal cortex. Differing patterns of neural activity change were associated with changes in each of the above symptoms over time. Specifically, from Scan1 to Scan2, worsening affective lability and depression severity were associated with increased right amygdala and left ventrolateral prefrontal cortical activity. Worsening anxiety and positive mood and energy dysregulation were associated with decreased right amygdala and increased left ventrolateral prefrontal cortical activity. Worsening mania was associated with increased right amygdala and decreased left ventrolateral prefrontal cortical activity. These changes in neural activity between scans accounted for 13.6% of the variance; that is 25% of the total explained variance (39.6%) in these measures. CONCLUSIONS: Distinct neural mechanisms underlie changes in different mood and anxiety symptoms overtime.

Comparing the CASI-4R and the PGBI-10 M for Differentiating Bipolar Spectrum Disorders from Other Outpatient Diagnoses in Youth.

We compared 2 rating scales with different manic symptom items on diagnostic accuracy for detecting pediatric bipolar spectrum disorder (BPSDs) in outpatient mental health clinics. Participants were 681 parents/guardians of eligible children (465 male, mean age = 9.34) who completed the Parent General Behavior Inventory-10-item Mania (PGBI-10 M) and mania subscale of the Child and Adolescent Symptom Inventory-Revised (CASI-4R). Diagnoses were based on KSADS interviews with parent and youth. Receiver operating characteristic (ROC) analyses and diagnostic likelihood ratios (DLRs) determined discriminative validity and provided clinical utility, respectively. Logistic regressions tested for incremental validity in the CASI-4R mania subscale and PGBI-10 M in predicting youth BPSD status above and beyond demographic and common diagnostic comorbidities. Both CASI-4R and PGBI-10 M scales significantly distinguished BPSD (N = 160) from other disorders (CASI-4R: Area under curve (AUC) = .80, p < 0.0005; PGBI-10 M: AUC = 0.79, p < 0.0005) even though scale items differed. Both scales performed equally well in differentiating BPSDs (Venkatraman test p > 0.05). Diagnostic likelihood ratios indicated low scores on either scale (CASI: 0-5; PGBI-10 M: 0-6) cut BPSD odds to 1/5 of those with high scores (CASI DLR- = 0.17; PGBI-10 M DLR- = 0.18). High scores on either scale (CASI: 14+; PGBI-10 M: 20+) increased BPSD odds about fourfold (CASI DLR+ = 4.53; PGBI-10 M DLR+ = 3.97). Logistic regressions indicated the CASI-4R mania subscale and PGBI-10 M each provided incremental validity in predicting youth BPSD status. The CASI-4R is at least as valid as the PGBI-10 M to help identify BPSDs, and can be considered as part of an assessment battery to screen for pediatric BPSDs.

Amygdala-prefrontal cortical functional connectivity during implicit emotion processing differentiates youth with bipolar spectrum from youth with externalizing disorders.

OBJECTIVE: Both bipolar spectrum disorders (BPSD) and attention deficit hyperactivity disorder (ADHD) present with emotion-regulation deficits, but require different clinical management. We examined how the neurobiological underpinnings of emotion regulation might differentiate youth with BPSD versus ADHD (and healthy controls, HCs), specifically assessing functional connectivity (FxC) of amygdala-prefrontal circuitry during an implicit emotion processing task. METHODS: We scanned a subset of the Longitudinal Assessment of Manic Symptoms (LAMS) sample, a clinically recruited cohort with elevated behavioral and emotional dysregulation, and age/sex-ratio matched HCs. Our sample consisted of 22 youth with BPSD, 30 youth with ADHD/no BPSD, and 26 HCs. We used generalized psychophysiological interaction (gPPI) to calculate group differences to emerging emotional faces vs. morphing shapes in FxC between bilateral amygdala and ventral prefrontal cortex/anterior cingulate cortex. RESULTS: FxC between amygdala and left ventrolateral prefrontal cortex (VLPFC) in response to emotions vs. shapes differed by group (p=.05): while BPSD showed positive FxC (emotions>shapes), HC and ADHD showed inverse FxC (emotions

Diagnosis, Phenomenology, Differential Diagnosis, and Comorbidity of Pediatric Bipolar Disorder.

Diagnosing a pediatric patient with bipolar disorder can pose a challenge for clinicians. Children typically do not present with the full criteria for a mood episode and may have symptoms of other disorders such as attention-deficit/hyperactivity disorder, oppositional defiant disorder, anxiety disorders, and other mood disorders, which may complicate the diagnostic process. By diligently interviewing parents and children about behaviors, thoroughly reviewing family histories, and systematically ruling out other disorders, clinicians can provide an accurate diagnosis for their pediatric patients.

Disruptive Mood Dysregulation Disorder and Bipolar Disorder Not Otherwise Specified: Fraternal or Identical Twins?

OBJECTIVE: The purpose of this study was to examine similarities and differences between disruptive mood dysregulation disorder (DMDD) and bipolar disorder not otherwise specified (BP-NOS) in baseline sociodemographic and clinical characteristics and 36 month course of irritability in children 6-12.9 years of age. METHODS: A total of 140 children with DMDD and 77 children with BP-NOS from the Longitudinal Assessment of Manic Symptoms cohort were assessed at baseline, then reassessed every 6 months for 36 months. RESULTS: Groups were similar on most sociodemographic and baseline clinical variables other than most unfiltered (i.e., interviewer-rated regardless of occurrence during a mood episode) Young Mania Rating Scale (YMRS) and parent-reported General Behavior Inventory-10 Item Mania (PGBI-10M) items. Children with DMDD received lower scores on every item (including irritability) except impaired insight; differences were significant except for sexual interest and disruptive-aggressive behavior. Children with DMDD received lower scores on eight of 10 PGBI-10M items, the other two items rated irritability. Youth with DMDD were significantly less likely to have a biological parent with a bipolar diagnosis than were youth with BP-NOS. Children with DMDD were more likely to be male and older than children with BP-NOS, both small effect sizes, but had nearly double the rate of disruptive behavior disorders (large effect). Caregiver ratings of irritability based on the Child and Adolescent Symptom Inventory-4R (CASI-4R) were comparable at baseline; the DMDD group had a small but significantly steeper decline in scores over 36 months relative to the BP-NOS group (b = -0.24, SE = 0.12, 95% CI -0.48 to -0.0004). Trajectories for both groups were fairly stable, in the midrange of possible scores. CONCLUSIONS: In a sample selected for elevated symptoms of mania, twice as many children were diagnosed with DMDD than with BP-NOS. Children with DMDD and BP-NOS are similar on most characteristics other than manic symptoms, per se, and parental history of bipolar disorder. Chronic irritability is common in both groups. Comprehensive evaluations are needed to diagnose appropriately. Clinicians should not assume that chronic irritability leads exclusively to a DMDD diagnosis.