Neural and Cognitive Predictors of Stimulant Treatment Efficacy in Medication-Naïve ADHD Adults: A Pilot Diffusion Tensor Imaging Study.

OBJECTIVE: Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response rate. This study aimed to identify neural and cognitive markers predictive of longitudinal improvement in response to stimulant treatment in drug-naïve adults with ADHD. METHOD: We used diffusion tensor imaging (DTI) and executive function measures with 36 drug-naïve adult ADHD patients in a prospective study design. RESULTS: Structural connectivity (measured by fractional anisotropy, FA) in striatal regions correlated with ADHD clinical symptom improvement following stimulant treatment (amphetamine or methylphenidate) in better medication responders. A significant positive correlation was also found between working memory performance and stimulant-related symptom improvement. Higher pre-treatment working memory scores correlated with greater response. CONCLUSION: These findings provide evidence of pre-treatment neural and behavioral markers predictive of longitudinal treatment response to stimulant medications in adults with ADHD.

ADHD in Adults: Does Age at Diagnosis Matter?

OBJECTIVE: To provide additional information about clinical features associated with adult ADHD in patients diagnosed in childhood compared to those first diagnosed in adulthood. METHOD: We stratified a sample of adults with ADHD into patients diagnosed in childhood versus adulthood and compared demographic and clinical characteristics. RESULTS: We found similar clinical features in adults diagnosed in childhood and adults diagnosed in adulthood. Among those diagnosed in adulthood, 95% reported symptom onset in youth. Our results do not support the hypothesis that ADHD diagnosed in adulthood is due to misinterpreting symptoms of other disorders as ADHD. They also suggest incorporating behavioral signs of executive dysfunction into diagnostic criteria for ADHD in adults may increase diagnostic sensitivity. CONCLUSION: These results support the validity of ADHD diagnoses in adulthood, as these adults show similar clinical profiles to those diagnosed in youth. Our results also suggest that if adult-onset ADHD exists, it is rare.

Growth Trajectories in Stimulant Treated Children and Adolescents: A Qualitative Review of the Literature from Comprehensive Datasets and Registries.

Objective: Attention-deficit/hyperactivity disorder (ADHD) treatment with stimulant products has been shown to be safe and effective; however, there are remaining concerns about their possible adverse effects on growth trajectories. We conducted a systematic review of the extant literature derived from ecologically valid databases and registries to assess the body of knowledge about the effects of stimulants on growth trajectories in naturalistic samples. Methods: Using PubMed and PsycINFO, we searched for articles published before February 8, 2023 that focused on growth findings associated with stimulant treatment in pediatric ADHD from comprehensive datasets derived from naturalistic population studies. Results: Of the 1070 articles initially identified, 12 met all inclusion criteria. Sample sizes ranged from 157 to 163,820 youths. Seven of 10 articles examining height found significant decreases in height associated with chronic stimulant treatment that normalized over time in 2 studies. Three articles found no significant association between stimulant treatment and height. No clear associations were identified between cumulative duration and dose of stimulant treatment and adult height. All articles examining weight and six of eight articles examining body mass index (BMI) found significant initial decreases that tended to normalize then increase over time. Longer duration of stimulant medication use was predominantly associated with significant weight and BMI reductions. The effects of stimulant dose on weight and BMI were mostly weak and clinically insignificant. Most studies found no significant association between age at start of stimulant treatment and change in height, weight, or BMI. Most studies did not find significant sex effects in relation to growth parameters. Conclusions: This review of ecologically informative samples revealed that the effects of stimulant treatment on growth trajectories are mainly small and transient. These effects seem to be clinically insignificant for most youth with ADHD who receive stimulant treatment from childhood onto adolescence and adulthood.

Further Evidence of an Association Between a Positive Child Behavior Checklist-Bipolar Profile and a Diagnosis of Pediatric Bipolar Disorder: A Meta-Analysis.

Background: Previous research has found that a unique profile of the Child Behavior Checklist comprising of aggregate elevations of the Attention, Anxiety/Depression and Aggression scales (A-A-A profile, CBCL-Bipolar (BP) profile, CBCL-Dysregulation profile (DP); henceforth CBCL-BP/DP profile) is associated with a clinical diagnosis of pediatric bipolar (BP) disorder. Objective: The main aim of the study is to evaluate the strength of the association between the CBCL-BP/DP profile and the clinical diagnosis of pediatric BP disorder through a meta-analysis. Methods: A literature search was performed to identify studies that examined the association between a positive CBCL-BP/DP profile and a clinical diagnosis of pediatric BP disorder. The meta-analyses first examined studies assessing the rates of a positive CBCL-BP/DP profile in youth with BP disorder versus those with 1) ADHD, anxiety/depression, or disruptive behavior disorders (DBDs), and 2) non-bipolar controls. The second analysis evaluated studies examining the rates of pediatric BP disorder in youth with and without a positive CBCL-BP/DP profile. Results: Eighteen articles met our inclusion and exclusion criteria, and fifteen articles had adequate data for meta-analysis. Results showed that BP youth were at significantly increased odds of having a positive CBCL-BP/DP profile compared to those with other psychiatric disorders (i.e., ADHD, anxiety/depression, or DBDs) (pooled OR=4.34, 95% CI=2.82, 8.27; p<0.001) and healthy control groups (pooled OR=34.77, 95% CI=2.87, 420.95; p=0.005). Further, meta-analysis results showed that youth with a positive CBCL-BP/DP profile were at significantly increased odds of having a BP disorder diagnosis compared to those without (pooled OR=4.25, 95% CI=2.12, 8.52; p<0.001). Conclusion: Our systematic review and meta-analysis of the extant literature provides strong support for the association between the CBCL-BP/DP profile and pediatric BP disorder.

Examining the clinical correlates of conduct disorder in youth with bipolar disorder.

BACKGROUND: Conduct Disorder (CD) is highly comorbid with Bipolar Disorder (BP) and this comorbidity is associated with high morbidity and dysfunction. We sought to better understand the clinical characteristics and familiality of comorbid BP + CD by examining children with BP with and without co-morbid CD. METHODS: 357 subjects with BP were derived from two independent datasets of youth with and without BP. All subjects were evaluated with structured diagnostic interviews, the Child Behavior Checklist (CBCL), and neuropsychological testing. We stratified the sample of subjects with BP by the presence or absence of CD and compared the two groups on measures of psychopathology, school functioning, and neurocognitive functioning. First-degree relatives of subjects with BP +/- CD were compared on rates of psychopathology in relatives. RESULTS: Subjects with BP + CD compared to BP without CD had significantly more impaired scores on the CBCL Aggressive Behavior (p < 0.001), Attention Problems (p = 0.002), Rule-Breaking Behavior (p < 0.001), Social Problems (p < 0.001), Withdrawn/Depressed clinical scales (p = 0.005), the Externalizing Problems (p < 0.001), and Total Problems composite scales(p < 0.001). Subjects with BP + CD had significantly higher rates of oppositional defiant disorder (ODD) (p = 0.002), any SUD (p < 0.001), and cigarette smoking (p = 0.001). First-degree relatives of subjects with BP + CD had significantly higher rates of CD/ODD/ASPD and cigarette smoking compared to first-degree relatives of subjects without CD. LIMITATIONS: The generalization of our findings was limited due to a largely homogeneous sample and no CD only comparison group. CONCLUSIONS: Given the deleterious outcomes associated with comorbid BP + CD, further efforts in identification and treatment are necessary.

Growth Trajectories in Stimulant-Treated Children Ages 6 to 12: An Electronic Medical Record Analysis.

OBJECTIVE: The aim of this study was to evaluate growth trajectories in stimulant-exposed and stimulant-unexposed children using electronic medical record data from a large health care organization attending to moderating effects of the magnitude of exposure to stimulants, sex, and race. METHODS: Weight, height, body mass index (BMI), prescription, and sociodemographic information were extracted from the electronic medical records of a large health care organization. Included were children who were 6 to 12 years at the time they were receiving stimulants with a concurrent growth assessment (index assessment) plus 1 to 4 years of additional growth assessments thereafter. Non-attention-deficit/hyperactivity disorder (ADHD) children who were unexposed to stimulants were age and sex matched to those exposed. Stimulant exposure was examined as the total number of months with stimulant prescriptions, percentage of follow-up time exposed to stimulants, and cumulative stimulant dose. RESULTS: Our sample consisted of 323 children exposed to stimulants with available growth data and 1615 unexposed children. Small but significant decreases in height trajectories were found over time in exposed children compared with those unexposed. Weight and BMI trajectories decreased in the first year of follow-up with stabilization and increased thereafter. Growth trajectory effects were largest in girls (height, weight, and BMI), White children (weight), and children with more total stimulant exposure (weight). CONCLUSION: This comprehensive analysis of an ecologically informative sample attending to key covariates of the magnitude of exposure to stimulants, sex, and race extends previous findings, showing that effects on growth trajectories are small and do not appear to pose a significant clinical concern for most children with ADHD treated with stimulants from childhood onto adolescent years.

The Heritability of ADHD in Children of ADHD Parents: A Post-hoc Analysis of Longitudinal Data.

OBJECTIVE: A growing literature suggests attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder. We evaluated children at risk for ADHD by virtue of having parents with ADHD and compared them with children of parents without ADHD to assess the degree of heritability of ADHD. METHOD: The sample for this study was derived from three longitudinal studies that tracked families with various disorders, including ADHD. Children were stratified based on presence of parental ADHD, and clinical assessments were taken to evaluate presence of ADHD and related psychiatric and functional outcomes in children. RESULTS: Children with parental ADHD had significantly more full or subthreshold psychiatric disorders (including ADHD) as well as functional impairments compared to children without parental ADHD. CONCLUSION: Our findings suggest that offspring of parents with ADHD are at significant risk for ADHD and its associated psychiatric, cognitive, and educational impairments. These findings aid in identifying early manifestations of ADHD in young children at risk.

Decreased risk for substance use disorders in individuals with high-functioning autism spectrum disorder.

The objective of this study was to evaluate the risk for developing a substance use disorder (SUD, alcohol or drug abuse or dependence) in individuals with high-functioning autism spectrum disorder (ASD). Subjects with high-functioning ASD were derived from consecutive referrals to a specialized ambulatory program for ASD at a major academic center from 2007 to 2016. Age-matched controls and attention-deficit hyperactivity disorder (ADHD) comparison subjects were derived from three independent studies of children and adults with and without ADHD using identical assessment methodology. Cox proportional hazard models were used to analyze the prevalence of SUD (alcohol or drug use disorder). Age of onset of SUD was analyzed with linear regression models. Our sample included 230 controls, 219 subjects with ADHD, and 230 subjects with ASD. The mean age for the ASD subjects was 20.0 ± 10.3 years. Among ASD subjects, 69% had a lifetime prevalence of ADHD, and the ASD subjects had significantly higher rates of other psychiatric psychopathology compared to ADHD and control subjects (p < 0.001) ASD subjects were at significantly decreased risk for developing a SUD compared to ADHD (hazard ratio (HR) = 0.22, p < 0.001) and control subjects (HR = 0.62, p = 0.04). The age of onset of a SUD was significantly older in ASD subjects, mean age 21.7 years, when compared to ADHD and control subjects (both p < 0.005). Individuals with ASD are at decreased risk to develop a SUD, and when they do, the onset is significantly later than ADHD and controls.

Attention-Deficit/Hyperactivity Disorder Is Associated With Increased Rates of Childhood Infectious Diseases: A Population-Based Case-Control Study.

OBJECTIVE: Infectious diseases (IDs) pose a heavy burden on children. An association between pediatric attention-deficit/hyperactivity disorder (ADHD) and specific IDs has been documented. Our objective was to test the possibility that ADHD is associated with increased likelihood for pediatric IDs at large. METHOD: A population-based case-control study was conducted using Electronic Medical Records (EMRs) of a national Health Maintenance Organization, Leumit Health Services (LHS). ICD-9/10 criteria were used for all diagnoses. The study population consisted of all children and adolescents (aged 5-18 years), members of LHS between January 1, 2006-June 30, 2021. Case patients met International Classification of Diseases (ICD-9/10) criteria for ADHD. Controls included randomly selected persons without ADHD (2:1 ratio), matched individually by demographic indices. The EMRs retrieved 3 exposure categories: pediatric ID, anti-infective medications use, and number of physician visits. The study was approved by the review board of Shamir Medical Center and the Research Committee of LHS. RESULTS: Cases patients comprised 18,756 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Matched controls comprised 37,512 participants, with a mean age of 8.3 ± 2.6 years and a male/female ratio of 63%:37%. Demographic variables were similar between the groups. The rates of all IDs were significantly higher in participants with ADHD than in controls and were not restricted to a single body system, including acute respiratory infection (OR = 1.4, 95% CI = 1.3-1.4, p < .001), acute gastroenteritis (OR = 1.3,95% CI 1.3-1.4, p < .001), salmonellosis (OR = 2.8, 95% CI = 2.3-3.5, p < .001), and urinary tract infection (OR = 1.3, 95% CI = 1.2-1.4, p < .001). All anti-infective agents were prescribed significantly more often to children with ADHD. There were significantly higher rates of physician visits for participants with ADHD. CONCLUSION: Study findings suggest an association between ID and pediatric ADHD Health care providers should be aware of this potential association. CLINICAL TRIAL REGISTRATION INFORMATION: The Health and Economic Impact of Treated and Untreated ADHD; https://www.shamir.org/; 005-18-LEU.

Toward Operationalizing Executive Function Deficits in Adults With ADHD Using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A).

Objective: Although group findings document that executive function deficits (EFDs) contribute to the morbidity associated with adult attention-deficit/hyperactivity disorder (ADHD), it is unclear whether easy-to-use assessment methods can aid in the identification of EFDs at the individual level. The aim of the present study was to assess whether the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), a well-standardized, self-report instrument that assesses behavioral concomitants of EFDs, can serve that purpose.Methods: 1,090 consecutively referred 18- to 55-year-old adults of both sexes who were clinically referred for the evaluation and treatment of ADHD between June 2016 and December 2021 completed a battery of scales assessing several non-overlapping domains of functioning. Because the BRIEF Global Executive Composite (GEC) offers a single point summary of all other BRIEF-A scales, we used receiver operator characteristic (ROC) curves to identify the optimal cutoff on the BRIEF-A GEC to categorize patients as having executive dysfunction.Results: We averaged the optimal BRIEF-A GEC cut-points from the ROC curve analyses to categorize patients with (N = 480; 44%) and without (N = 610; 56%) EFDs (BRIEF-A GEC score ≥ 70 or < 70, respectively). Adults with ADHD with EFDs had significantly more severe ADHD symptoms (ADHD Self-Report Scale scores ≥ 24: 94% vs 41%, P < .001); higher levels of psychopathology (Adult Self Report Total Problems T-scores ≥ 64: 75% vs 19%, P < .001), emotional dysregulation (69% vs 23%, P < .001), mind wandering (84% vs 48%, P < .001), and symptoms of autism (Social Responsiveness Scale T-scores ≥ 66: 24% vs 3%, P < .001); and worse quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire mean scores: 44.4 ± 8.2 vs 51.9 ± 8.5, P = .001) compared to those without EFDs. There were no major differences in outcomes by age, sex, or race.Conclusions: The BRIEF-A helped identify a sizeable minority of adults with ADHD with behavioral concomitants of EFDs that added substantial morbidity and disability beyond that expected by having ADHD alone.

A Randomized, Double-Blind, Controlled Clinical Trial of Omega-3 Fatty Acids and Inositol as Monotherapies and in Combination for the Treatment of Pediatric Bipolar Spectrum Disorder in Children Age 5-12.

Objectives: The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (FAs) and inositol alone and in combination for the treatment of pediatric bipolar (BP) spectrum disorder in young children. Methods: Participants were male and female children ages 5-12 meeting DSM-IV diagnostic criteria for a BP spectrum disorder and displaying mixed, manic, or hypomanic symptoms without psychotic features at the time of evaluation. Results: Participants concomitantly taking psychotropic medication were excluded from efficacy analyses. There were significant reductions in YMRS and HDRS mean scores in the inositol and combination treatment groups (all p < 0.05) and in CDRS mean scores in the combination treatment group (p < 0.001), with the largest changes seen in the combination group. Those receiving the combination treatment had the highest rates of antimanic and antidepressant response. The odds ratios for the combination group compared to the omega-3 FAs and inositol groups were clinically meaningful (ORs ≥2) for 50% improvement on the YMRS, normalization of the YMRS (score <12) (vs. inositol group only), 50% improvement on the HDRS, 50% improvement on CDRS (vs. omega-3 FAs group only), and CGI-I Mania, CGI-I MDD, and CGI-I Anxiety scores <2. Conclusion: The antimanic and antidepressant effects of the combination treatment of omega-3 FAs and inositol were consistently superior to either treatment used alone. This combination may offer a safe and effective alternative or augmenting treatment for youth with BP spectrum disorder, but more work is needed to confirm the statistical significance of this finding.

Can machine learning identify childhood characteristics that predict future development of bipolar disorder a decade later?

Early identification of bipolar disorder may provide appropriate support and treatment, however there is no current evidence for statistically predicting whether a child will develop bipolar disorder. Machine learning methods offer an opportunity for developing empirically-based predictors of bipolar disorder. This study examined whether bipolar disorder can be predicted using clinical data and machine learning algorithms. 492 children, ages 6-18 at baseline, were recruited from longitudinal case-control family studies. Participants were assessed at baseline, then followed-up after 10 years. In addition to sociodemographic data, children were assessed with psychometric scales, structured diagnostic interviews, and cognitive and social functioning assessments. Using the Balanced Random Forest algorithm, we examined whether the diagnostic outcome of full or subsyndromal bipolar disorder could be predicted from baseline data. 45 children (10%) developed bipolar disorder at follow-up. The model predicted subsequent bipolar disorder with 75% sensitivity, 76% specificity, and an Area Under the Receiver Operating Characteristics of 75%. Predictors best differentiating between children who did or did not develop bipolar disorder were the Child Behavioral Checklist Externalizing and Internalizing behaviors, the Child Behavioral Checklist Total t-score, problematic school functions indexed through the Child Behavioral Checklist School Competence scale, and the Child Behavioral Checklist Anxiety/Depression and Aggression scales. Our study provides the first quantitative model to predict bipolar disorder. Longitudinal prediction may help clinicians assess children with emergent psychopathology for future risk of bipolar disorder, an area of clinical and scientific importance. Machine learning algorithms could be implemented to alert clinicians to risk for bipolar disorder.

Examining the impact of ADHD polygenic risk scores on ADHD and associated outcomes: A systematic review and meta-analysis.

Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis. Because of the strong genetic basis of ADHD, the use of polygenic risk scores (PRS) could potentially aid in the early identification of ADHD and associated outcomes. Therefore, a systematic search of the literature on the association between ADHD and PRS in pediatric populations was conducted. All articles were screened for a priori inclusion and exclusion criteria, and, after careful review, 33 studies were included in our systematic review and 16 studies with extractable data were included in our meta-analysis. The results of the review were categorized into three common themes: the associations between ADHD-PRS with 1) the diagnosis of ADHD and ADHD symptoms 2) comorbid psychopathology and 3) cognitive and educational outcomes. Higher ADHD-PRS were associated with increased odds of having a diagnosis (OR = 1.37; p<0.001) and more symptoms of ADHD (ß = 0.06; p<0.001). While ADHD-PRS were associated with a persistent diagnostic trajectory over time in the systematic review, the meta-analysis did not confirm these findings (OR = 1.09; p = 0.62). Findings showed that ADHD-PRS were associated with increased odds for comorbid psychopathology such as anxiety/depression (OR = 1.16; p<0.001) and irritability/emotional dysregulation (OR = 1.14; p<0.001). Finally, while the systematic review showed that ADHD-PRS were associated with a variety of negative cognitive outcomes, the meta-analysis showed no significant association (ß = 0.08; p = 0.07). Our review of the available literature suggests that ADHD-PRS, together with risk factors, may contribute to the early identification of children with suspected ADHD and associated disorders.

Long term outcomes of pediatric Bipolar-I disorder: A prospective follow-up analysis attending to full syndomatic, subsyndromal and functional types of remission.

OBJECTIVE: To examine patterns of remission of pediatric bipolar I (BP-I) disorder attending to syndromatic, symptomatic, and functional outcomes from childhood to adolescent and young adult years. METHODS: We analyzed data from a six-year prospective follow-up study of youths aged 6-17 years with BP-I disorder. Subjects were comprehensively assessed at baseline and subsequently at four, five, and six years thereafter. Assessments included structured diagnostic interviews and measures of psychosocial and educational functioning. Patterns of remission were calculated attending to whether syndromatic, symptomatic, and functional remission were achieved. RESULTS: Kaplan-Meier failure functions revealed that the probability of functional recovery from pediatric BP-I disorder was very low. Of the 88 youths assessed, only 6% (N = 5) of the sample were euthymic with normal functioning during the year prior to their last follow-up assessment (average follow-up time = 5.8 ± 1.8 years). CONCLUSIONS: These results provide compelling evidence of the high level of persistence of pediatric BP-I disorder. Symptomatic and functional remission were uncommon and most subjects continued to demonstrate high morbidity into late adolescence and early adulthood.

Can pediatric bipolar disorder be successfully treated when comorbid with conduct disorder? A secondary analysis of clinical trials of risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

BACKGROUND: Pediatric bipolar disorder (BP) is frequently comorbid with conduct disorder (CD) and its presence adds to the morbidity of BP. While there are no known pharmacological treatments for CD, pediatric BP is responsive to treatment with medications initially indicated for the treatment of psychosis, several of which have Food and Drug Administration (FDA) approval for the treatment of pediatric mania. AIMS: The main aim of this secondary analysis was to examine whether pediatric BP comorbid with CD responds similarly to treatment with such selected medications. Considering the well-documented morbidity of CD, this finding could have important clinical and public health significance. METHODS: We conducted a secondary analysis of six prospective 8-week open-label trials of selected medications (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) using identical methodology in youth with BP with and without comorbid CD. Results: Of 165 youths with BP, 54% (N = 89) met criteria for comorbid CD. The antimanic effects observed did not significantly differ between BP youths with and without comorbid CD, as measured either by a reduction in Young Mania Rating Scale (YMRS) ⩾ 30% or Clinical Global Impression (CGI)-Improvement ⩽ 2 (p = 0.23), or by the more stringent definition of a reduction in YMRS ⩾ 50% (p = 0.61). CONCLUSION: Pediatric BP can be effectively treated with the abovementioned medications in the context of comorbid CD. Based on previous research showing that remission of BP is associated with remission of CD, if confirmed, these findings raise the possibility that antimanic treatment of youth with BP comorbid with CD could have secondary benefits in mitigating the morbidity associated with CD. This is a pilot scale finding, the results of which are promising and should be confirmed by larger and long-term follow-up studies.

Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania.

BACKGROUND: Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder. METHODS: We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression. RESULTS: This study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint. CONCLUSIONS: These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.

Disentangling the heterogeneity of emotional dysregulation in referred youth using the Child Behavior Checklist attending to age and sex effects.

PURPOSE: To assess the utility of the Child Behavior Checklist (CBCL) to identify meaningful subtypes of emotional dysregulation in an outpatient pediatric psychiatry clinic. METHODS: The sample consisted of 417 newly referred youth 6-18 years of age. Parents completed the CBCL and rating scales measuring executive function deficits, social functioning, and quality of life. Patients were stratified into subtypes of emotional dysregulation and compared on clinical correlates based on the A-A-A profile consisting of the CBCL Anxious/Depressed, Aggressive Behavior, and Attention Problems (A-A-A) scales. RESULTS: 67% of youth had emotional dysregulation (CBCL A-A-A T-score ≥ 180) and of these, 39% had a positive CBCL-Bipolar (BP) profile (A-A-A T-score ≥ 210), 24% had depression without the BP profile (CBCL Anxious/Depressed and/or Withdrawn/Depressed T-scores ≥70 and A-A-A T-score ≥ 180 and ã€ˆ210), and 37% had emotional impulsivity (A-A-A T-score ≥ 180 and <210) with normal CBCL Anxious/Depressed and Withdrawn/Depressed T-scores. Patients with the CBCL-BP profile were significantly more impaired on all measures of social and executive functioning compared to the other two groups. LIMITATIONS: Since our findings relied on the CBCL, other instruments may have led to different results. Because we included youth from a single clinic, largely Caucasian and referred, our findings may not generalize to other ethnic groups or settings. CONCLUSIONS: The CBCL can aid in the identification of subtypes of emotional dysregulation affecting youth seeking mental health services.

Identifying Pediatric Mood Disorders From Transdiagnostic Polygenic Risk Scores: A Study of Children and Adolescents.

Objective: Mood disorders often co-occur with attention-deficit/hyperactive disorder (ADHD), disruptive behavior disorders (DBDs), and aggression. We aimed to determine if polygenic risk scores (PRSs) based on external genome-wide association studies (GWASs) of these disorders could improve genetic identification of mood disorders.Methods: We combined 6 independent family studies that had genetic data and diagnoses for mood disorders that were made using different editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). We identified mood disorders, either concurrently or in the future, in participants between 6 and 17 years of age using PRSs calculated using summary statistics of GWASs for ADHD, ADHD with DBD, major depressive disorder (MDD), bipolar disorder (BPD), and aggression to compute PRSs.Results: In our sample of 485 youths, 356 (73%) developed a subthreshold or full mood disorder and 129 (27%) did not. The cross-validated mean areas under the receiver operating characteristic curve (AUCs) for the 7 models identifying participants with any mood disorder ranged from 0.552 in the base model of age and sex to 0.648 in the base model + all 5 PRSs. When included in the base model individually, the ADHD PRS (OR = 1.65, P < .001), Aggression PRS (OR = 1.27, P = .02), and MDD PRS (OR = 1.23, P = .047) were significantly associated with the development of any mood disorder.Conclusions: Using PRSs for ADHD, MDD, BPD, DBDs, and aggression, we could modestly identify the presence of mood disorders. These findings extend evidence for transdiagnostic genetic components of psychiatric illness and demonstrate that PRSs calculated using traditional diagnostic boundaries can be useful within a transdiagnostic framework.

Nicotine and the developing brain: Insights from preclinical models.

Use of tobacco products during pregnancy is associated with increased risk for neurodevelopmental disorders in the offspring. Preclinical models of developmental nicotine exposure have offered valuable insights into the neurobiology of nicotine's effects on the developing brain and demonstrated lasting effects of developmental nicotine exposure on brain structure, neurotransmitter signaling and behavior. These models have facilitated discovery of novel compounds as candidate treatments for attention deficit hyperactivity disorder, a neurodevelopmental disorder associated with prenatal nicotine exposure. Using these models the significance of heritability of behavioral phenotypes from the nicotine-exposed pregnant female or adult male to multiple generations of descendants has been demonstrated. Finally, research using the preclinical models has demonstrated synergistic interactions between developmental nicotine exposure and repetitive mild traumatic brain injury that contribute to "worse" outcomes from the injury in individuals with attention deficit hyperactivity disorder associated with developmental nicotine exposure.

Review: Adult Outcome as Seen Through Controlled Prospective Follow-up Studies of Children With Attention-Deficit/Hyperactivity Disorder Followed Into Adulthood.

OBJECTIVE: To describe adult outcome of people with attention-deficit/hyperactivity disorder (ADHD) diagnosed in childhood and its several key predictors via a review of 7 North American controlled prospective follow-up studies: Montreal, New York, Milwaukee, Pittsburgh, Massachusetts General Hospital (MGH), Berkeley, and 7-site Multimodal Treatment Study of Children With ADHD (MTA). METHOD: All studies were prospective and followed children with a diagnosis of ADHD and an age- and gender-matched control group at regular intervals from childhood (6-12 years of age) through adolescence into adulthood (20-40 years of age), evaluating symptom and syndrome persistence, functional outcomes, and predictors of these outcomes. RESULTS: The rates of ADHD syndrome persistence ranged from 5.7% to 77%, likely owing to varying diagnostic criteria and the source of information (self-report vs informant report) across the studies. However, all studies observed high rates of symptomatic persistence ranging from 60% to 86%. The 7 studies were largely consistent in finding that relative to control groups, research participants with childhood-diagnosed ADHD had significant impairments in the areas of educational functioning, occupational functioning, mental health, and physical health as well as higher rates of substance misuse, antisocial behavior, and unsafe driving. The most consistently observed predictors of functional outcomes included ADHD persistence and comorbidity, especially with disruptive behavior disorders. CONCLUSION: Childhood ADHD has high rates of symptomatic persistence, which is associated with negative functional outcomes. Characteristics that predict these negative outcomes, such as comorbid disruptive behavior disorders, may be important targets for intervention.