Evaluating Mineral Biomarkers as Mediators and Moderators of Behavioural Improvements in a Randomized Controlled Trial of Multinutrients for Children with ADHD.

Essential minerals are cofactors for synthesis of neurotransmitters supporting cognition and mood. An 8-week fully-blind RCT of multinutrients for ADHD demonstrated three times as many children (age 6-12) had significantly improved behavior ("treatment responders") on multinutrients (54%) compared to placebo (18%). The aim of this secondary study was to evaluate changes in fasted plasma and urinary mineral concentrations following the intervention, and their role as mediators and moderators of treatment response. Fourteen essential or trace minerals were measured in plasma and/or urine at baseline and week 8 from 86 participants (49 multinutrient, 37 placebo). Two-sample t-tests/Mann-Whitney U-tests compared 8-week change between treatment and placebo groups, which were also evaluated as potential mediators. Baseline levels were evaluated as potential moderators, using logistic regression models with clinical treatment response as the outcome. After 8 weeks, plasma boron, chromium (in females only), lithium, molybdenum, selenium, and vanadium, and urinary iodine, lithium, and selenium increased more with multinutrients than placebo, while plasma phosphorus decreased. These changes did not mediate treatment response. However, baseline urinary lithium trended toward moderation: participants with lower baseline urinary lithium were more likely to respond to multinutrients (p=0.058). Additionally, participants with higher baseline iron were more likely to be treatment responders regardless of treatment group (p=0.036.) These results show that multinutrient treatment response among children with ADHD is independent of their baseline plasma mineral levels, while baseline urinary lithium levels show potential as a non-invasive biomarker of treatment response requiring further study.

Treatment response to supplemental nutrients for ADHD is independent of diet quality: the MADDY Study RCT.

OBJECTIVES: The 8-week Micronutrients for ADHD in Youth (MADDY) randomized controlled trial (N = 126, age 6-12) of broad-spectrum multinutrients for ADHD with emotional dysregulation found 3 times as many responders with multinutrients (54%) compared to placebo (18%) by Clinical Global Impression-Improvement (CGI-I). Our primary aim for this analysis tests the hypothesis that those with poor overall diet quality at baseline benefit more. The second aim is to explore whether specific components of diet quality moderate treatment response. METHODS: 124 children (69 multinutrients, 55 placebo) had diet quality assessed using the Healthy Eating Index-2015 (HEI-2015). For each potential moderator, the outcome CGI-I at week 8 (RCT-end), was modeled two ways: (1) as a dichotomous variable: responder/non-responder, with responders defined by a rating of 1 or 2 'very much' or 'much improved,' all else equals non-responder using logistic regression, and (2) as a dimensional improvement outcome from 1 = very much improved to 7 = very much worse, using linear regression. RESULTS: HEI-2015 total score did not moderate treatment response [odds ratio = 1.00 (95% CI: 0.90,1.10), p = 0.984] or improvement [ß = -0.01 (95% CI: -0.06,0.04), p = 0.648]. However, total vegetable intake moderated level of improvement in exploratory analysis [ß = -0.48 (95% CI: -0.82, -0.13), p = 0.007]: those with higher baseline vegetable intake showed greater benefit from multinutrients compared to placebo. CONCLUSIONS: Multinutrients may benefit children with ADHD and irritability regardless of overall diet quality. The finding that higher baseline vegetable intake may improve response to multinutrients deserves further exploration, including dietary effect on gut microbiota and absorption of multinutrients and parental factors.

The stability and persistence of symptoms in childhood-onset ADHD.

The course of childhood-onset attention deficit hyperactivity disorder (ADHD) varies across individuals; some will experience persistent symptoms while others' symptoms fluctuate or remit. We describe the longitudinal course of ADHD symptoms and associated clinical characteristics in adolescents with childhood-onset ADHD. Participants (aged 6-12 at baseline) from the Longitudinal Assessment of Manic Symptoms (LAMS) study who met DSM criteria for ADHD prior to age 12 were evaluated annually with the Kiddie Schedule for Affective Disorders and Schizophrenia for eight years. At each timepoint, participants were categorized as meeting ADHD criteria, subthreshold criteria, or not having ADHD. Stability of course was defined by whether participants experienced consistent ADHD symptoms, fluctuating symptoms, or remission. The persistence of the symptoms was defined by symptom status at the final two follow-ups (stable ADHD, stable remission, stable partial remission, unstable). Of 685 baseline participants, 431 had childhood-onset ADHD and at least two follow-ups. Half had a consistent course of ADHD, nearly 40% had a remitting course, and the remaining participants had a fluctuating course. More than half of participants met criteria for ADHD at the end of their participation; about 30% demonstrated stable full remission, 15% had unstable symptoms, and one had stable partial remission. Participants with a persistent course and stable ADHD outcome reported the highest number of symptoms and were most impaired. This work builds on earlier studies that describe fluctuating symptoms in young people with childhood-onset ADHD. Results emphasize the importance of ongoing monitoring and detailed assessment of factors likely to influence course and outcome to help young people with childhood-onset ADHD.

Challenging the Diagnostic Value of Theta/Beta Ratio: Insights From an EEG Subtyping Meta-Analytical Approach in ADHD.

The frequently reported high theta/beta ratio (TBR) in the electroencephalograms (EEGs) of children with attention-deficit/hyperactivity disorder (ADHD) has been suggested to include at least two distinct neurophysiological subgroups, a subgroup with high TBR and one with slow alpha peak frequency, overlapping the theta range. We combined three large ADHD cohorts recorded under standardized procedures and used a meta-analytical approach to leverage the large sample size (N = 417; age range: 6-18 years), classify these EEG subtypes and investigate their behavioral correlates to clarify their brain-behavior relationships. To control for the fact that slow alpha might contribute to theta power, three distinct EEG subgroups (non-slow-alpha TBR (NSAT) subgroup, slow alpha peak frequency (SAF) subgroup, not applicable (NA) subgroup) were determined, based on a halfway cut-off in age- and sex-normalized theta and alpha, informed by previous literature. For the meta-analysis, Cohen's d was calculated to assess the differences between EEG subgroups for baseline effects, using means and standard deviations of baseline inattention and hyperactivity-impulsivity scores. Non-significant, small Grand Mean effect sizes (-0.212 < d < 0.218) were obtained when comparing baseline behavioral scores between the EEG subgroups. This study could not confirm any association of EEG subtype with behavioral traits. This confirms previous findings suggesting that TBR has no diagnostic value for ADHD. TBR could, however, serve as an aid to stratify patients between neurofeedback protocols based on baseline TBR. A free online tool was made available for clinicians to calculate age- and sex-corrected TBR decile scores (Brainmarker-IV) for stratification of neurofeedback protocols.

Cognitive-attentional mechanisms of cooperation-with implications for attention-deficit hyperactivity disorder and cognitive neuroscience.

People's cooperativeness depends on many factors, such as their motives, cognition, experiences, and the situation they are in. To date, it is unclear how these factors interact and shape the decision to cooperate. We present a computational account of cooperation that not only provides insights for the design of effective incentive structures but also redefines neglected social-cognitive characteristics associated with attention-deficit hyperactivity disorder (ADHD). Leveraging game theory, we demonstrate that the source and magnitude of conflict between different motives affected the speed and frequency of cooperation. Integrating eye-tracking to measure motivation-based information processing during decision-making shows that participants' visual fixations on the gains of cooperation rather than its costs and risks predicted their cooperativeness on a trial-by-trial basis. Using Bayesian hierarchical modeling, we find that a situation's prosociality and participants' past experience each bias the decision-making process distinctively. ADHD characteristics explain individual differences in responsiveness across contexts, highlighting the clinical importance of experimentally studying reactivity in social interactions. We demonstrate how the use of eye-tracking and computational modeling can be used to experimentally investigate social-cognitive characteristics in clinical populations. We also discuss possible underlying neural mechanisms to be investigated in future studies.

Fruit and vegetable intake is inversely associated with severity of inattention in a pediatric population with ADHD symptoms: the MADDY Study.

OBJECTIVES: Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder with a U.S. pediatric prevalence of 8-10%. It presents with inattention and hyperactivity/impulsivity; frequently associated with emotional dysregulation (ED) symptoms common in Oppositional Defiant Disorder and Disruptive Mood Dysregulation Disorder. The etiology of ADHD is multi-factorial; symptom severity is associated with diet. This study examines the association of diet quality with ADHD and ED symptoms within a pediatric research cohort. METHODS: Baseline data were analyzed for 134 children aged 6-12 years with symptoms of ADHD and ED enrolled in an RCT of multinutrient supplementation. Diet quality was based on Healthy Eating Index-2015 (HEI-2015). ADHD and ED symptoms were assessed using Child and Adolescent Symptom Inventory-5 and Strengths and Difficulties Questionnaire. Linear regression models, adjusting for covariates when necessary, determined association. RESULTS: The mean HEI Total Score of 63.4 (SD = 8.8) was not significantly associated with any outcome symptoms. However, after adjusting for covariates, HEI component scores for total fruit intake (ß = -0.158, p = .037) and total vegetable intake (ß = -0.118, p = .004) were negatively associated with inattention. CONCLUSIONS: The lack of association with total diet quality could be explained by the relatively good baseline diet quality and mild symptom severity in this sample, along with measurement error from dietary intake estimates and relatively small sample size. These findings suggest that dietary intake may impact inattention in children with ADHD and ED: those eating less fruits and vegetables were likely to have more severe symptoms of inattention. Causality is not established by this cross-sectional analysis.

Micronutrients for ADHD in youth (MADDY) study: comparison of results from RCT and open label extension.

BACKGROUND: The Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youth (MADDY) study evaluated the efficacy and safety of a multinutrient formula for children with ADHD and emotional dysregulation. The post-RCT open-label extension (OLE) compared the effect of treatment duration (8 weeks vs 16 weeks) on ADHD symptoms, height velocity, and adverse events (AEs). METHODS: Children aged 6-12 years randomized to multinutrients vs. placebo for 8 weeks (RCT), received an 8-week OLE for a total of 16 weeks. Assessments included the Clinical Global Impression-Improvement (CGI-I), Child and Adolescent Symptom Inventory-5 (CASI-5), Pediatric Adverse Events Rating Scale (PAERS), and anthropometric measures (height and weight). RESULTS: Of the 126 in the RCT, 103 (81%) continued in the OLE. For those initially assigned to placebo, CGI-I responders increased from 23% in the RCT to 64% in the OLE; those who took multinutrients for 16 weeks increased from 53% (RCT) to 66% responders (OLE). Both groups improved on the CASI-5 composite score and subscales from week 8 to week 16 (all p-values < 0.01). The group taking 16 weeks of multinutrients had marginally greater height growth (2.3 cm) than those with 8 weeks (1.8 cm) (p = 0.07). No difference in AEs between groups was found. CONCLUSION: The response rate to multinutrients by blinded clinician ratings at 8 weeks was maintained to 16 weeks; the response rate in the group initially assigned to placebo improved significantly with 8 weeks of multinutrients and almost caught up with 16 weeks. Longer time on multinutrients did not result in greater AEs, confirming an acceptable safety profile.

For Which Children with ADHD is TBR Neurofeedback Effective? Comorbidity as a Moderator.

We examined psychiatric comorbidities moderation of a 2-site double-blind randomized clinical trial of theta/beta-ratio (TBR) neurofeedback (NF) for attention deficit hyperactivity disorder (ADHD). Seven-to-ten-year-olds with ADHD received either NF (n = 84) or Control (n = 58) for 38 treatments. Outcome was change in parent-/teacher-rated inattention from baseline to end-of-treatment (acute effect), and 13-month-follow-up. Seventy percent had at least one comorbidity: oppositional defiant disorder (ODD) (50%), specific phobias (27%), generalized anxiety (23%), separation anxiety (16%). Comorbidities were grouped into anxiety alone (20%), ODD alone (23%), neither (30%), or both (27%). Comorbidity (p = 0.043) moderated acute effect; those with anxiety-alone responded better to Control than to TBR NF (d = - 0.79, CI - 1.55- - 0.04), and the other groups showed a slightly better response to TBR NF than to Control (d = 0.22 ~ 0.31, CI - 0.3-0.98). At 13-months, ODD-alone group responded better to NF than Control (d = 0.74, CI 0.05-1.43). TBR NF is not indicated for ADHD with comorbid anxiety but may benefit ADHD with ODD.Clinical Trials Identifier: NCT02251743, date of registration: 09/17/2014.

EEG Connectivity in ADHD Compared to a Normative Database: A Cohort Analysis of 120 Subjects from the ICAN Study.

This study explores how EEG connectivity measures in children with ADHD ages 7-10 (n = 140) differ from an age-matched nonclinical database. We differentiated connectivity in networks, Brodmann area pairs, and frequencies. Subjects were in the International Collaborative ADHD Neurofeedback study, which explored neurofeedback for ADHD. Inclusion criteria were mainly rigorously diagnosed ADHD and a theta/beta power ratio (TBR) ≤ 4.5. Using statistical and machine learning algorithms, connectivity values were extracted in coherence, phase, and lag coherence at all Brodmann, subcortical, and cerebellar areas within the main networks in all EEG frequencies and then compared with a normative database. There is a higher rate of dysregulation (more than ± 1.97SD), in some cases as much as 75%, of the Brodmann pairs observed in coherence and phase between BAs 7, 10, and 11 with secondary connections from these areas to BAs 21, 30, 35, 37, 39, and 40 in the ADHD children as compared to the normative database. Left and right Brodmann areas 10 and 11 are highly disconnected to each other. The most dysregulated Brodmann Areas in ADHD are 7, 10, and 11, relevant to ADHD executive-function deficits and provide important considerations when developing interventions for ADHD children.

Paths to postsecondary education enrollment among adolescents with and without childhood attention-deficit/hyperactivity disorder (ADHD): A longitudinal analysis of symptom and academic trajectories.

We examined developmental trajectories of attention-deficit/hyperactivity disorder (ADHD) symptoms, standardized achievement, and school performance for adolescents with and without ADHD who did and did not enroll in postsecondary education (PSE; N = 749; 79% boys; 63% White, 17% non-Hispanic Black, 10% Hispanic, and 10% other ethnicities). In a multisite study (recruitment based in New York, North Carolina, Pennsylvania, California, and Quebec), participants were originally enrolled between 1994 and 1998 at ages 7 to 9.9 and followed up through 2012 (Mage = 25 at final follow-up). Adolescents who eventually enrolled in PSE had less severe symptoms, but differences were modest and trajectories were similar over time. For all adolescents, standardized achievement trajectories declined up to two thirds of a standard deviation from ages 9 to 17. By the end of high school, the average GPA of adolescents with ADHD was three quarters of a point higher for those who eventually enrolled in PSE compared to those who did not. Overall, school performance mattered more than academic achievement for understanding eventual enrollment of adolescents with ADHD.

Parents' priorities and preferences for treatment of children with ADHD: Qualitative inquiry in the MADDY study.

BACKGROUND: Parents' lived experiences of having a child with ADHD may shape their decision making regarding ADHD treatment options for their child. The aim of this study was to explore parents' experiences of living with a child with ADHD in the family and how their experiences influence their perspectives on treatment preferences and priorities. METHODS: A phenomenological qualitative design was used. Semistructured interviews were conducted with parents of children with ADHD who were enrolled in a multisite randomized controlled trial. Interviews were transcribed verbatim, and transcripts at each site were double coded. Initial codes were derived directly from the text. Qualitative data were analysed with an inductive approach. RESULTS: Twenty-three parents were interviewed: eight from Alberta, Canada; eight from Portland, Oregon, USA; and seven from Columbus, Ohio, USA. Among the parents, 69% were married, 86% completed college education and 52% reported household income over $80,000. Among the children, the mean age was 9.6 years (SD = 1.8 years), 78% were boys and 48% were never medicated for their ADHD. Two major themes emerged from the analysis. Theme 1 was 'impact of ADHD on families within and outside the home' with the following subthemes: 'reconfiguring the home life', 'trial-and-error of accommodations at school' and 'responding to social pressures to fit in'. Theme 2 was 'enabling appropriate and accessible treatments for families' with the following subthemes: 'finding the "right fit" with professionals and treatments' and 'factors influencing inequitable access to treatments'. CONCLUSIONS: Parents described shared experiences and identified similar barriers, preferences and priorities for ADHD treatments regardless of demographic differences by site. Families desired access to family-centred, multimodal approaches to ADHD treatment. Further research is needed to identify the specific structural changes to healthcare, services and policies that will better support this approach.

Predictors of Hospitalization in a Cohort of Children with Elevated Symptoms of Mania.

Describe hospitalization rates in children with elevated symptoms of mania and determine predictors of psychiatric hospitalizations during the 96 month follow-up. Eligible 6-12.9 year olds and their parents visiting 9 outpatient mental health clinics were invited to be screened with the Parent General Behavior Inventory 10-item Mania Scale. Of 605 children with elevated symptoms of mania eligible for follow-up, 538 (88.9%) had ≥ 1 of 16 possible follow-up interviews and are examined herein. Multivariate Cox regression indicated only four factors predicted hospitalizations: parental mental health problems (HR 1.80; 95% CI 1.21, 2.69); hospitalization prior to study entry (HR 3.03; 95% CI 1.80, 4.43); continuous outpatient mental health service use (HR 3.73; 95% CI 2.40, 5.50); and low parental assessment of how well treatment matched child's needs (HR 3.97; 95% CI 2.50, 6.31). Parental perspectives on mental health services should be gathered routinely, as they can signal treatment failures.

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.

Development of bipolar disorder and other comorbidity among youth with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine development of bipolar spectrum disorders (BPSD) and other disorders in prospectively followed children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In the Longitudinal Assessment of Manic Symptoms (LAMS) study, 531 of 685 children age 6-12 (most selected for scores > 12 on General Behavior Inventory 10-item Mania scale) had ADHD, 112 with BPSD, and 419 without. With annual assessments for 8 years, retention averaged 6.2 years. Chi-square analyses compared rate of new BPSD and other comorbidity between those with versus without baseline ADHD and between retained versus resolved ADHD diagnosis. Cox regression tested factors influencing speed of BPSD onset. RESULTS: Of 419 with baseline ADHD but not BPSD, 52 (12.4%) developed BPSD, compared with 16 of 110 (14.5%) without either baseline diagnosis. Those who developed BPSD had more nonmood comorbidity over the follow-up than those who did not develop BPSD (p = .0001). Of 170 who still had ADHD at eight-year follow-up (and not baseline BPSD), 26 (15.3%) had developed BPSD, compared with 16 of 186 (8.6%) who had ADHD without BPSD at baseline but lost the ADHD diagnosis (χ2  = 3.82, p = .051). There was no statistical difference in whether ADHD persisted or not across new BPSD subtypes (χ2  = 1.62, p = .446). Of those who developed BPSD, speed of onset was not significantly related to baseline ADHD (p = .566), baseline anxiety (p = .121), baseline depression (p = .185), baseline disruptive behavior disorder (p = .184), age (B = -.11 p = .092), maternal mania (p = .389), or paternal mania (B = .73, p = .056). Those who started with both diagnoses had more severe symptoms/impairment than those with later developed BPSD and reported having ADHD first. CONCLUSIONS: In a cohort selected for symptoms of mania at age 6-12, baseline ADHD was not a significant prospective risk factor for developing BPSD. However, persistence of ADHD may marginally mediate risk of BPSD, and early comorbidity of both diagnoses increases severity/impairment.

Associations between Parental Psychopathology and Sexual Behavior in an Outpatient Psychiatric Sample.

Early age of sexual debut is associated with an increase in negative outcomes, including higher incidence of nonconsensual sexual experiences, higher rates of sexually transmitted infections, and risky sexual practices. Little research has examined the role of parental psychopathology as a predictor of adolescent sexual activity, however. The current study aims to close this gap by examining the relationship between parental psychopathology and sexual activity in a longitudinal sample of youth. Participants were 685 adolescents from the Longitudinal Assessment of Manic Symptoms study, the majority of whom were male (67%) and White (65%). Analyses considering likelihood of sexual initiation included the full sample, whereas analyses considering predictors of the age of sexual debut included the 162 participants who reported ever having sexual intercourse (62% male, 51% White) via the Youth Risk Behavior Surveillance-High School version. Cox regression analyses suggested that maternal generalized anxiety disorder predicted decreased likelihood of initiating sex during the 8-year follow-up period, whereas paternal conduct disorder predicted increased likelihood of initiating sex. Multivariate linear regressions also showed that maternal conduct disorder predicted earlier age of sexual debut among those who had initiated, whereas paternal antisocial personality disorder predicted later age of sexual debut. These associations were observed in both male and female adolescents. Furthermore, these effects were largely not explained by the established relationship between youth psychopathology and sexual behavior. Results have implications for interventions aimed at decreasing sexual risk taking in vulnerable youth.

Maternal personality traits moderate treatment response in the Multimodal Treatment Study of attention-deficit/hyperactivity disorder.

Some mothers of children with attention-deficit/hyperactivity disorder (ADHD) present with maladaptive personality profiles (high neuroticism, low conscientiousness). The moderating effect of maternal personality traits on treatment outcomes for childhood ADHD has not been examined. We evaluate whether maternal neuroticism and conscientiousness moderated response in the Multimodal Treatment Study of Children with ADHD. This is one of the first studies of this type. In a randomized controlled trial (RCT), 579 children aged 7-10 (M = 8.5); 19.7% female; 60.8% White with combined-type ADHD were randomly assigned to systematic medication management (MedMgt) alone, comprehensive multicomponent behavioral treatment (Beh), their combination (Comb), or community comparison treatment-as-usual (CC). Latent class analysis and linear mixed effects models included 437 children whose biological mothers completed the NEO Five-Factor Inventory at baseline. A 3-class solution demonstrated best fit for the NEO: MN&MC = moderate neuroticism and conscientiousness (n = 284); HN&LC = high neuroticism, low conscientiousness (n = 83); LN&HC = low neuroticism, high conscientiousness (n = 70). Per parent-reported symptoms, children of mothers with HN&LC, but not LN&HC, had a significantly better response to Beh than to CC; children of mothers with MN&MC and LN&HC, but not HN&LC, responded better to Comb&MedMgt than to Beh&CC. Per teacher-reported symptoms, children of mothers with HN&LC, but not LN&HC, responded significantly better to Comb than to MedMgt. Children of mothers with high neuroticism and low conscientiousness benefited more from behavioral treatments (Beh vs. CC; Comb vs. MedMgt) than other children. Evaluation of maternal personality may aid in treatment selection for children with ADHD, though additional research on this topic is needed.

Different Spectral Analysis Methods for the Theta/Beta Ratio Calculate Different Ratios But Do Not Distinguish ADHD from Controls.

There has been ongoing research on the ratio of theta to beta power (Theta/Beta Ratio, TBR) as an EEG-based test in the diagnosis of ADHD. Earlier studies reported significant TBR differences between patients with ADHD and controls. However, a recent meta-analysis revealed a marked decline of effect size for the difference in TBR between ADHD and controls for studies published in the past decade. Here, we test if differences in EEG processing explain the heterogeneity of findings. We analyzed EEG data from two multi-center clinical studies. Five different EEG signal processing algorithms were applied to calculate the TBR. Differences between resulting TBRs were subsequently assessed for clinical usability in the iSPOT-A dataset. Although there were significant differences in the resulting TBRs, none distinguished between children with and without ADHD, and no consistent associations with ADHD symptoms arose. Different methods for EEG signal processing result in significantly different TBRs. However, none of the methods significantly distinguished between ADHD and healthy controls in our sample. The secular effect size decline for the TBR is most likely explained by factors other than differences in EEG signal processing, e.g. fewer hours of sleep in participants and differences in inclusion criteria for healthy controls.

Cigarette Smoking Progression Among Young Adults Diagnosed With ADHD in Childhood: A 16-year Longitudinal Study of Children With and Without ADHD.

INTRODUCTION: Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for smoking cigarettes, but there is little longitudinal research on the array of smoking characteristics known to be prognostic of long-term smoking outcomes into adulthood. These variables were studied into early adulthood in a multisite sample diagnosed with ADHD combined type at ages 7-9.9 and followed prospectively alongside an age- and sex-matched local normative comparison group (LNCG). METHODS: Cigarette smoking quantity, quit attempts, dependence, and other characteristics were assessed in the longitudinal Multimodal Treatment Study of Children with ADHD (MTA) eight times to a mean age of 24.9 years: ADHD n = 469; LNCG n = 240. RESULTS: In adulthood, the ADHD group had higher rates of daily cigarette smoking, one or more quit attempts, shorter time to first cigarette of the day, and more severe withdrawal than the LNCG. The ADHD group did not appear to have better smoking cessation rates despite a higher proportion quitting at least once. Smoking quantity and nicotine dependence did not differ between groups. The ADHD group reported younger daily smoking onset and faster progression from smoking initiation to daily smoking across assessments. Finally, ADHD symptom severity in later adolescence and adulthood was associated with higher risk for daily smoking across assessments in the ADHD sample. CONCLUSIONS: This study shows that ADHD-related smoking risk begins at a young age, progresses rapidly, and becomes resistant to cessation attempts by adulthood. Prevention efforts should acknowledge the speed of uptake; treatments should target the higher relapse risk in this vulnerable population. IMPLICATIONS: Although childhood ADHD predicts later smoking, longitudinal studies of this population have yet to fully characterize smoking behaviors into adulthood that are known to be prognostic of long-term smoking outcome. The current study demonstrates earlier and faster progression to daily smoking among those with a childhood ADHD diagnosis, as well as greater risk for failed quit attempts. Prevention efforts should address speed of smoking uptake, while treatments are needed that address smoking relapse risk. The current study also demonstrates ADHD symptom severity over development increases daily smoking risk, implicating the need for continuous ADHD symptom management.

Not All Masks Are Created Equal: Masking Success in Clinical Trials of Children and Adolescents.

The current study assessed the success of masking omega-3 (Ω3) and psychotherapy in clinical trials of youth with depression or bipolar spectrum disorder. Participants were youth ages 7-14 with DSM-IV-TR diagnosed depressive (n = 72) or bipolar spectrum (n = 23) disorders. Inclusion diagnoses were depressive disorder, cyclothymic disorder, or bipolar disorder not otherwise specified. Exclusion diagnoses included bipolar I or II disorder, chronic medical condition or autism. Youth participated in 2 × 2 randomized controlled trials, in which they received Ω3 or placebo (PBO) and psychoeducational psychotherapy (PEP) or active monitoring (AM). Participants and study staff (including independent interviewers) were masked to Ω3/PBO allocation. Besides the masked independent interviewers, one coprincipal investigator (Co-PI) was fully masked to both conditions and completed all consensus conference ratings postrandomization. At the endpoint assessment or last completed interview, interviewers and the masked Co-PI guessed whether each child was assigned to Ω3 or PBO and to PEP or AM. Masking failure was calculated using the degree of correct guesses above chance level using binomial tests across all participants for Ω3 versus PBO and PEP versus AM. For all guessers, Ω3 allocation was guessed correctly approximately half the time (50%-52.5%). Rates of correct guessing were higher for PEP, but only the interviewer guesses were correct significantly more often (58.5%-68.7%) than chance. Reporting of masking success should be an essential element of RCTs. Psychotherapy is generally more difficult to mask, but with attentive masking procedures reasonable masking can be achieved.

Predicting Therapeutic Effects of Psychodiagnostic Assessment Among Children and Adolescents Participating in Randomized Controlled Trials.

This study explored predictors of improvement after completing a psychodiagnostic screening assessment but before randomization among youth who participated in two pilot randomized controlled trials of omega-3 supplementation and Individual-Family Psychoeducational Psychotherapy (PEP). Ninety-five youth (56.8% male, 61.1% White) ages 7-14 with mood disorders completed screening and baseline assessments (including Clinical Global Impressions-Improvement [CGI-I], Children's Depression Rating Scale-Revised, Young Mania Rating Scale), then were randomized into a 12-week trial of omega-3, PEP, their combination, or placebo. Between screening and randomization, 35.8% minimally improved (CGI-I = 3), 12.6% much improved (CGI-I < 3), totaling 48.4% improved. Caregiver postsecondary education (p = .018), absence of attention-deficit/hyperactivity disorder (p = .027), and lower screen depression severity (p = .034) were associated with CGI-I. Caregiver postsecondary education (p = .020) and absence of a disruptive behavior diagnosis (p = .038) were associated with depression severity improvement. Prerandomization improvement moderated treatment outcomes: Among youth who improved prerandomization, those who received PEP (alone or with omega-3) had more favorable placebo-controlled depression trajectories due to a lack of placebo response. This open-label trial of psychodiagnostic assessment provides suggestive evidence that psychodiagnostic assessment is beneficial, especially for those with depression and without externalizing disorders. Prerandomization improvement is associated with better placebo-controlled treatment response. Future research should test alternative hypotheses for change and determine if less intensive (shorter and/or automated) assessments would provide comparable results.