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.

Stimulant Treatment and Potential Adverse Outcomes in Pediatric Populations With Bipolar Disorder: A Systematic Review of the Literature.

OBJECTIVE: To explore outcomes of stimulant treatment for ADHD in pediatric populations with particular attention to bipolar disorder (BPD). METHOD: We conducted a literature search of PubMed articles published prior to August 25, 2022 that focused on BPD, mania, and psychosis prior to, or as result of, stimulant treatment. We excluded studies: (1) unrelated to stimulants, (2) general stimulant research, (3) articles older than 40 years, (4) study protocols, or (5) case reports. RESULTS: A total of 11 articles met all inclusion/exclusion criteria. Some reports found stimulant treatment safe and well-tolerated in children with comorbid BPD and ADHD. Others found evidence of treatment-emergent mania (TEM), discontinuation, and other adverse events with stimulant treatment. CONCLUSION: Poor outcomes associated with stimulant treatment in pediatric populations with BPD necessitate work to identify patients at risk of serious stimulant-related adverse events. Our results were limited by automated search filters and a pediatric, primarily male sample.

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.

Solriamfetol for Attention-Deficit/Hyperactivity Disorder in Adults: A Double-Blind Placebo-Controlled Pilot Study.

Objective: Some individuals with attention-deficit/hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. This study examined whether solriamfetol could have a favorable pattern of effects and tolerability as a treatment for ADHD in adults.Methods: Sixty adults with DSM-5 ADHD participated from August 2021 through January 2023 in a remotely conducted, randomized, double-blind, placebo-controlled, 6-week dose-optimization trial of 75 mg or 150 mg of solriamfetol. Measures included the Adult ADHD Investigator Symptom Rating Scale (AISRS), which was our primary outcome measure, as well as the Clinical Global Impressions scale (CGI), vital signs, the Global Assessment of Functioning (GAF), the Behavior Rating Inventory of Executive Function-Adult Form (BRIEF-A), the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and a modified Adult ADHD Self-Report Scale (MASRS).Results: Solriamfetol was well tolerated, with no significant effect on mean heart rate (+3.7 vs +2.2 bpm, P = .5609), systolic blood pressure (+2.4 vs +1.5 mm Hg, P = .6474), or diastolic blood pressure (+1.1 vs +1.5 mm Hg, P = .8117). There was no statistically significant treatment effect on occurrence of adverse events. Compared to individuals on placebo, individuals on solriamfetol treatment experienced adverse events at a rate of at least 10 percentage points higher in the categories of decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic. Compared to individuals on placebo, by study endpoint, a greater proportion of individuals in the treatment group met the a priori-defined treatment response (CGI score indicating much or very much improved and AISRS score reduced ≥ 25%: 45% vs 6.9%, P = .0020); those treated with solriamfetol also had greater improvement in total AISRS scores by week 3 through week 6 (P = .0012; week 6 effect size = 1.09). Significantly more solriamfetol-treated adults than placebo-treated adults had 0.5-standard deviation improvement in T-score on the BRIEF-A Global Executive Composite (P = .0173); those treated with solriamfetol also had greater mean change in GAF score (-4.8 vs -0.3, P = .0006) and greater mean MASRS total score change (P = .0047; effect size = 1.23). Mean ESS score improved more with solriamfetol than with placebo (P = .0056), but this difference did not predict AISRS response (P = .3735). There was no significant association between solriamfetol and change in PSQI scores.Conclusions: Solriamfetol may be a novel and effective treatment for the management of ADHD in adults. Further replication in larger trials is indicated.Trial Registration: ClinicalTrials.gov identifier: NCT04839562.

Diagnosing major depressive disorder and substance use disorder using the electronic health record: A preliminary validation study.

Background: One mechanism to examine if major depressive disorder (MDD) is related to the development of substance use disorder (SUD) is by leveraging naturalistic data available in the electronic health record (EHR). Rules for data extraction and variable construction linked to psychometrics validating their use are needed to extract data accurately. Objective: We propose and validate a methodologic framework for using EHR variables to identify patients with MDD and non-nicotine SUD. Methods: Proxy diagnoses and index dates of MDD and/or SUD were established using billing codes, problem lists, patient-reported outcome measures, and prescriptions. Manual chart reviews were conducted for the 1-year period surrounding each index date to determine (1) if proxy diagnoses were supported by chart notes and (2) if the index dates accurately captured disorder onset. Results: The results demonstrated 100% positive predictive value for proxy diagnoses of MDD. The proxy diagnoses for SUD exhibited strong agreement (Cohen's kappa of 0.84) compared to manual chart review and 92% sensitivity, specificity, positive predictive value, and negative predictive value. Sixteen percent of patients showed inaccurate SUD index dates generated by EHR extraction with discrepancies of over 6 months compared to SUD onset identified through chart review. Conclusions: Our methodology was very effective in identifying patients with MDD with or without SUD and moderately effective in identifying SUD onset date. These findings support the use of EHR data to make proxy diagnoses of MDD with or without SUD.

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.

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.

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.

Substance Use Disorders and Psychiatric Illness Among Transitional Age Youth Experiencing Homelessness.

Objective: Transitional age youth experiencing homelessness (TAY-EH) bear a high burden of substance use disorders (SUDs) and psychopathology. However, limited data exist on the co-occurrence and interactions between these diagnoses in this marginalized group. This study sought to identify rates of single and co-occurring SUDs and psychiatric diagnoses among a sample of TAY-EH and to investigate associations between psychopathology and prevalence and severity of SUDs in this group. Method: TAY-EH accessing a low-threshold social service agency in a large metropolitan area completed psychosocial and diagnostic interviews to assess for SUDs and psychopathology. Analyses examined rates of single and co-occurring disorders and associations between burden of psychopathology and presence and severity of SUDs. Results: The assessment was completed by 140 TAY-EH; the majority were youth of color (54% Black/African American, 16% Latinx), and 57% identified as male. Rates of single and co-occurring psychiatric disorders and specific SUDs (cannabis use disorder [CUD] and alcohol use disorder [AUD]) were notably high. An increasing number of psychiatric diagnoses was significantly associated with elevated CUD/AUD prevalence and severity. Mood, anxiety, attention-deficit/hyperactivity, and antisocial personality disorders were significantly associated with elevated CUD/AUD prevalence and severity, as was suicidality (all p < .05). Conclusion: This study reveals a complex overlay of SUDs and psychopathology facing TAY-EH, with a significant association between co-occurring psychopathology and severity of CUD/AUD. To the authors' knowledge, this is the first study to examine associations between specific psychopathology and severity of SUDs among TAY-EH. Further research into the mechanistic and temporal links between these conditions is needed to inform tailored treatment interventions.

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.

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.

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.

Are adolescents and young adults in substance use disorder treatment as engaged in the research recruitment process as those in general behavioral health treatment?

BACKGROUND AND OBJECTIVE: While prior research suggests that individuals with substance use disorders (SUD) are generally more difficult to engage in research, little is known about the research engagement of adolescents and young adults (AYA) in SUD treatment as it compares to peers seen in general behavioral health settings. This study aimed to systematically compare engagement in virtual research recruitment between AYA in SUD treatment and AYA in behavioral health (BH) treatment. METHODS: Study staff contacted patients ages 16-30 at three outpatient clinics to recruit them for a naturalistic longitudinal online study. Staff documented whether patients answered the phone, expressed interest in the study, answered questions regarding eligibility, and enrolled in the study. RESULTS: Overall, 18% (n = 117) of those contacted by phone enrolled in the study. The rate of AYA reached did not significantly differ between those in SUD treatment (51%) and those in BH treatment (55%). Among those who were reached, those in SUD and BH treatment did not significantly differ (all p > 0.05) in rates of being interested in the study (SUD: 58%; BH: 49%), completing the phone screen (SUD: 46%; BH: 41%) or enrolling in the study (SUD: 33%; BH: 35%). CONCLUSIONS: Overall, we found that engaging AYA in SUD treatment in virtual naturalistic longitudinal research was no more difficult than engaging AYA seen in general behavioral health settings. Future research should examine generalizability of engagement in naturalistic research to other study designs and explore the continuity of this effect into study retention and completion.

Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

To examine current clinical research on the use of transcranial magnetic stimulation (TMS) in the treatment of pediatric and young adult autism spectrum disorder in intellectually capable persons (IC-ASD). We searched peer-reviewed international literature to identify clinical trials investigating TMS as a treatment for behavioral and cognitive symptoms of IC-ASD. We identified sixteen studies and were able to conduct a meta-analysis on twelve of these studies. Seven were open-label or used neurotypical controls for baseline cognitive data, and nine were controlled trials. In the latter, waitlist control groups were often used over sham TMS. Only one study conducted a randomized, parallel, double-blind, and sham controlled trial. Favorable safety data was reported in low frequency repetitive TMS, high frequency repetitive TMS, and intermittent theta burst studies. Compared to TMS research of other neuropsychiatric conditions, significantly lower total TMS pulses were delivered in treatment and neuronavigation was not regularly utilized. Quantitatively, our multivariate meta-analysis results report improvement in cognitive outcomes (pooled Hedges' g = 0.735, 95% CI = 0.242, 1.228; p = 0.009) and primarily Criterion B symptomology of IC-ASD (pooled Hedges' g = 0.435, 95% CI = 0.359, 0.511; p < 0.001) with low frequency repetitive TMS to the dorsolateral prefrontal cortex. The results of our systematic review and meta-analysis data indicate that TMS may offer a promising and safe treatment option for pediatric and young adult patients with IC-ASD. However, future work should include use of neuronavigation software, theta burst protocols, targeting of various brain regions, and robust study design before clinical recommendations can be made.

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.