Co-Occurring Psychopathology Moderates Social Skills Improvement in a Randomized Controlled Trial of a Collaborative School-Home Intervention for Children with ADHD.

OBJECTIVE: Children with ADHD often exhibit marked impairment in their social skills, but evidence-based psychosocial interventions for ADHD have shown limited efficacy in remediating these deficits. Co-occurring psychopathology exacerbates social deficits in children with ADHD and is a plausible moderator of treatment response. To identify factors contributing to variable social skills treatment response, we examined co-occurring externalizing, depression, and anxiety symptoms as moderators of social skills outcomes in a randomized controlled trial of the Collaborative Life Skills (CLS) program, an evidence-based collaborative school-home ADHD intervention. METHOD: Participants were 159 children with ADHD (M age = 8.35 years, 28.3% female) at 27 schools in an urban public school district. Twenty-three schools were randomly assigned to CLS or usual services, with an additional four schools assigned to Spanish-adapted CLS or usual services. Multi-informant measures of co-occurring psychopathology and social skills were collected at baseline and post-treatment. RESULTS: Parent-rated externalizing and depression symptoms moderated treatment effects on social skills, whereby higher symptomatology in each domain was unrelated to social skills improvement in the CLS group but predicted worsening social skills in response to usual services. In contrast, teacher-rated anxiety moderated treatment effects on social skills, whereby higher anxiety predicted greater social skills improvement in response to CLS but was unrelated to social skills outcomes following usual services. CONCLUSIONS: Findings reflect novel evidence that child psychopathology domains exhibit unique moderating effects on social skills treatment response in children with ADHD. We discuss implications for optimizing evidence-based interventions to target social impairment in this population.

Refractory and Super-Refractory Status Epilepticus in Nerve Agent-Poisoned Rats Following Application of Standard Clinical Treatment Guidelines.

Nerve agents (NAs) induce a severe cholinergic crisis that can lead to status epilepticus (SE). Current guidelines for treatment of NA-induced SE only include prehospital benzodiazepines, which may not fully resolve this life-threatening condition. This study examined the efficacy of general clinical protocols for treatment of SE in the specific context of NA poisoning in adult male rats. Treatment with both intramuscular and intravenous benzodiazepines was entirely insufficient to control SE. Second line intervention with valproate (VPA) initially terminated SE in 35% of rats, but seizures always returned. Phenobarbital (PHB) was more effective, with SE terminating in 56% of rats and 19% of rats remaining seizure-free for at least 24 h. The majority of rats demonstrated refractory SE (RSE) and required treatment with a continuous third-line anesthetic. Both ketamine (KET) and propofol (PRO) led to high levels of mortality, and nearly all rats on these therapies had breakthrough seizure activity, demonstrating super-refractory SE (SRSE). For the small subset of rats in which SE was fully resolved, significant improvements over controls were observed in recovery metrics, behavioral assays, and brain pathology. Together these data suggest that NA-induced SE is particularly severe, but aggressive treatment in the intensive care setting can lead to positive functional outcomes for casualties.

Prenatal maternal C-reactive protein prospectively predicts child executive functioning at ages 4-6 years.

This prospective longitudinal study evaluated multiple maternal biomarkers from the preconception and prenatal periods as time-sensitive predictors of child executive functioning (EF) in 100 mother-child dyads. Maternal glycated hemoglobin (HbA1C ), C-reactive protein (CRP), and blood pressure (BP) were assayed before pregnancy and during the second and third trimesters. Subsequently, children were followed from birth and assessed for EF (i.e. cognitive flexibility, response inhibition) at ages 4-6 years. Perinatal data were also extracted from neonatal records. Higher maternal CRP, but not maternal HbA1C or BP, uniquely predicted poorer child cognitive flexibility, even with control of maternal HbA1C and BP, relevant demographic factors, and multiple prenatal/perinatal covariates (i.e. preconception maternal body mass index, maternal depression, maternal age at birth, child birth weight, child birth order, child gestational age, and child birth/neonatal complications). Predictions from maternal CRP were specific to the third trimester, and third trimester maternal CRP robustly predicted child cognitive flexibility independently of preconception and second trimester CRP. Child response inhibition was unrelated to maternal biomarkers from all time points. These findings provide novel, prospective evidence that maternal inflammation uniquely predicts child cognitive flexibility deficits, and that these associations depend on the timing of exposure before or during pregnancy.

The nature and nurture of social development: The role of 5-HTTLPR and gene-parenting interactions.

Social skills are traditionally viewed as acquired through social environments including parenting. However, biopsychosocial models highlight the importance of genetic influences and gene-environment interactions (G×Es) in child development. Extant G×E investigations often fail to account for developmental changes in the phenotype or rigorously assess the social environment using observational measures. The present study prospectively assessed 110 children (44.5% female) and their parents to explore biologically plausible independent and interactive associations of the serotonin transporter-linked polymorphic region (5-HTTLPR) and observed positive and negative parenting in prediction of (a) initial levels of social skills at school entry (age 6 years) and (b) developmental changes in social skills across the early school years (ages 6-9 years). Overall, the SS (vs. SL/LL) 5-HTTLPR genotype inversely predicted social skills across all domains, although parenting behavior moderated these associations wherein putative G×E effects differed by developmental timing and social skills domain. Positive parenting positively predicted concurrent (age 6) overall social skills for children with SL/LL genotypes, but not the SS genotype. However, for the SS group only, age 6 positive parenting positively predicted prospective growth in social responsibility, although negative parenting positively predicted growth in social cooperation. Findings suggest that 5-HTTLPR may signal differential sensitivities to parenting styles and patterns of social development, which may help to inform targeted intervention approaches to enhance person-environment fit. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Patterns of Sensitivity to Parenting and Peer Environments: Early Temperament and Adolescent Externalizing Behavior.

Although parenting behavior and friendship quality predict adolescent externalizing behaviors (EBs), individual differences in temperament may differentially affect susceptibility to these factors over time. In a multi-method and multi-informant study of 141 children followed prospectively from toddlerhood to adolescence, we tested the independent and interactive associations of age 3 reactive temperament (e.g., negative emotionality) and age 13 observed parenting (i.e., positive and negative behavior) and friendship (i.e., conflict and warmth), with multi-informant ratings of age 15 aggression and rule-breaking behavior. Negative parenting predicted growth in parent-rated EB, but only for adolescents with early reactive temperament. Temperament did not affect sensitivity to positive parenting or friendship. Results are discussed in the context of differential susceptibility theory and intervention implications for adolescents.

Fluid Reasoning Mediates the Association of Birth Weight With ADHD Symptoms in Youth From Multiplex Families With ADHD.

OBJECTIVE: We tested mediation of birth weight and ADHD symptoms by multiple biologically plausible neurocognitive functions and evaluated familiality of observed indirect effects. METHOD: 647 youth from 284 multiplex families with ADHD completed the Arithmetic, Digit Span, Vocabulary, and Block Design subtests of the Wechsler Intelligence Scale for Children (WISC). Multiple mediation tested WISC subtests as mediators of birth weight and multi-informant ADHD symptoms. Familiality of indirect effects was estimated via moderated mediation comparing conditional indirect effects across siblings concordant and discordant for ADHD. RESULTS: Controlling for IQ and demographic factors, Arithmetic uniquely mediated birth weight and ADHD symptoms. Conditional indirect effects through Arithmetic did not differ across ADHD concordant and discordant siblings. CONCLUSION: These cross-sectional findings support previous prospective longitudinal research implicating Arithmetic (i.e., fluid reasoning) as a preliminary causal mediator of birth weight and ADHD symptoms, and suggest that this pathway is independent of genetic influences on ADHD.

Pathways from Birth Weight to ADHD Symptoms through Fluid Reasoning in Youth with or without Intellectual Disability.

Although individual differences in fluid reasoning reliably mediate predictions of attention-deficit/hyperactivity disorder (ADHD) symptoms from birth weight in youth with typical cognitive development (TD), it is unknown if this indirect effect operates similarly in the development of ADHD symptoms secondary to intellectual disability (ID). Thus, we evaluated mediation by fluid reasoning in a longitudinal sample of 163 youth (45% female) with (n = 52) or without (n = 111) ID who were followed prospectively from age 5 to age 13. At age 9, youth completed the Arithmetic subtest of the Wechsler Intelligence Scale for Children, a measure of fluid reasoning. At ages 9 and 13, mothers and teachers separately rated youth ADHD symptoms and mothers completed a diagnostic interview. Mediation was tested via path analysis with bootstrapped confidence intervals, and moderated mediation estimated whether indirect effects differed between ID and TD youth or based on youth IQ. Controlling for demographic factors and age 9 ADHD symptoms, age 9 Arithmetic mediated birth weight and multi-method/informant age 13 ADHD symptoms, such that birth weight positively predicted Arithmetic, which negatively predicted ADHD symptoms. Neither ID status nor IQ moderated the observed indirect effect through Arithmetic, suggesting that it was similar for ID and TD youth as well as across the range of youth IQs. These findings support previous evidence that fluid reasoning, as measured by Arithmetic, may causally mediate birth weight and ADHD symptoms, and suggest that this pathway operates similarly with respect to the development of ADHD symptoms in youth with ID.

Parental Serotonin Transporter Polymorphism (5-HTTLPR) Moderates Associations of Stress and Child Behavior With Parenting Behavior.

The serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with caregiving in nonhuman animals and with affective and cognitive correlates of human parenting, yet its association with human parenting is largely unknown. Using a well-characterized sample of parents and offspring, we evaluated the association of parental 5-HTTLPR with observed positive and negative parenting behavior, as well as its biologically plausible moderation of child-related stress and disruptive child behavior as predictors of parenting. One hundred and sixty-two parents (86% mothers) and their 6- to 9-year-old children with and without attention-deficit/hyperactivity disorder were ascertained using multiple methods including structured interviews, rating scales, and observed parent-child interaction, yielding strong measures of key constructs. Controlling for multiple youth-level (e.g., sex, 5-HTTLPR genotype, disruptive behavior) and parent-level (e.g., demographics, depression, attention-deficit/hyperactivity disorder) factors, parents with an S allele exhibited significantly less observed positive parenting than those with the LL genotype. Significant Gene × Environment interactions were also observed: Child-related stress was negatively associated with observed parental negativity among SS/SL genotype parents but not LL genotype parents; next, observed disruptive child behavior was positively associated with parental negativity for both genotypes, but the effect was strongest in SS/SL parents. These preliminary findings suggest that parental 5-HTTLPR is uniquely associated with positive and negative parenting behavior, with more specific patterns according to child-related stress and disruptive child behavior. We consider implications for future research evaluating genetic influences on parenting as well as considerations for designing and delivering parenting-based interventions.

Neurocognitive Functioning Mediates the Prospective Association of Birth Weight With Youth ADHD Symptoms.

Although birth weight is a potential causal risk factor for attention-deficit/hyperactivity disorder (ADHD) symptoms, both the specificity of this association and its mediating pathways are largely unknown. We carefully assessed youth with and without ADHD (i.e., Wave 1), and followed them prospectively for 2 years (i.e., Wave 2). We (a) tested the association of birth weight with Wave 2 ADHD symptoms, and (b) evaluated biologically plausible neurocognitive functions from Wave 1 as temporally ordered mediators of birth weight and Wave 2 ADHD symptoms in a multiple mediation framework. At Wave 1, 222 ethnically diverse youth (30% female; ages 5-10) completed the Digit Span, Vocabulary, Symbol Search, and Arithmetic subtests of the Wechsler Intelligence Scale for Children-IV. At both Wave 1 and Wave 2 (ages 7-13), multiple informants (i.e., parents, teachers) rated youth ADHD symptoms and co-occurring psychopathology using multiple methods (i.e., structured interview, rating scale). Controlling for demographic factors, gestational age, and co-occurring externalizing and internalizing psychopathology, birth weight inversely predicted Wave 2 ADHD symptoms across multiple methods and informants. Additionally, controlling for Wave 1 ADHD symptoms and relevant covariates, Wave 1 Arithmetic uniquely mediated the association of birth weight with multi-method/informant Wave 2 ADHD symptoms. These findings suggest that birth weight is a relatively specific risk factor for youth ADHD symptoms and they implicate individual differences in fluid reasoning as a preliminary causal mediator of this association. We discuss implications for future research evaluating causal mechanisms underlying risk factors for ADHD.

COMT and DAT1 polymorphisms moderate the indirect effect of parenting behavior on youth ADHD symptoms through neurocognitive functioning.

Although gene × environment interactions contribute to youth attention-deficit/hyperactivity disorder (ADHD) symptoms, the pathways mediating these influences are unknown. We tested genetic moderation of indirect effects from parenting behavior to youth ADHD symptoms through multiple neurocognitive factors. Two hundred and twenty-nine youth with and without ADHD were assessed at baseline (Wave 1; ages 5-10) and at a 2-year follow-up (Wave 2; ages 7-13). At Wave 1, youth completed a neurocognitive battery including measures of response inhibition, visuospatial working memory, and fluid reasoning, and a standardized parent-child interaction task yielding observational measures of positive and negative parenting. At Wave 2, youth psychopathology was rated by parents and teachers using multiple methods (i.e., structured interview, rating scale). We employed moderated multiple mediation and compared conditional indirect effects across youth genotypes at two biologically plausible genetic loci. Controlling for parent ADHD symptoms as well as youth demographic factors and co-occurring externalizing symptoms, these genetic factors moderated the indirect effect from Wave 1 parenting to multi-method/informant Wave 2 ADHD symptoms through Wave 1 neurocognitive functioning. This preliminary study is the first to identify genetic moderation of mediated effects underlying ADHD symptoms and suggests that specific gene × parenting interactions may underlie neurocognitive functioning deficits and subsequent ADHD.

Prenatal programming of postnatal plasticity for externalizing behavior: Testing an integrated developmental model of genetic and temperamental sensitivity to the environment.

Although both gene- and temperament-environment interactions contribute to the development of youth externalizing problems, it is unclear how these factors jointly affect environmental sensitivity over time. In a 7-year longitudinal study of 232 children (aged 5-10) with and without ADHD, we employed moderated mediation to test a developmentally sensitive mechanistic model of genetic and temperamental sensitivity to prenatal and postnatal environmental factors. Birth weight, a global measure of the prenatal environment, moderated predictions of child negative emotionality from a composite of dopaminergic polymorphisms (i.e., DRD4 and DAT1), such that birth weight inversely predicted negative emotionality only for children with genetic plasticity. Negative emotionality, in turn, predicted externalizing behavior 4-5 years later, beyond genetic and postnatal parenting effects. Finally, birth weight moderated the indirect effect of dopaminergic genotypes on externalizing problems through negative emotionality, partially supporting a prenatal programming model. We discuss theoretical and empirical implications for models of environmental sensitivity.

Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

IMPORTANCE: Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition. OBJECTIVE: To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD. DESIGN, SETTING, AND PARTICIPANTS: Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements. INTERVENTIONS: Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg). MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale-Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression-Severity and -Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. RESULTS: Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms. CONCLUSIONS AND RELEVANCE: This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00749203.

Patterns of symptom onset and remission in episodes of hopelessness depression.

BACKGROUND: Hopelessness depression (HD) is a subtype of depression postulated by the Hopelessness Theory of Depression to present as a constellation of symptoms occurring when an individual with a specific cognitive vulnerability (negative inferential style) experiences negative life events. In the current study, the course of HD episodes was evaluated prospectively and analyzed to explore patterns of symptom onset and remission. METHODS: In 169 HD episodes reported by 65 participants, survival analyses were conducted on the time to onset or remission for 29 individual symptoms. Survival analyses yielded probability density graphs for risk of onset and risk of offset that indicated whether the symptom tended to appear or remit early, late, or unpredictably during the episode. RESULTS: The symptom of hopelessness often appeared earliest in HD episodes, followed by self-blame, brooding/worry, decreased self-esteem, dependency, and decreased appetite. Hopelessness, decreased self-esteem, self-blame, brooding/worry, dependency, and increased appetite were typically the latest symptoms to remit. CONCLUSIONS: The current study provided evidence for patterns of symptom onset and remission in HD episodes. Hopelessness and other symptoms predicted to appear according to the Hopelessness Theory were generally the earliest to appear, latest to remit, and appeared to form the core syndrome of these HD episodes. Identifying patterns of symptom onset and remission may provide a tool for subtyping depression episodes. Clinically, these results point to the utility of attending to patterns of symptom onset and remission in patients presenting with HD episodes, particularly for treatment planning and monitoring.

Coping and PTSD symptoms in Pakistani earthquake survivors: purpose in life, religious coping and social support.

BACKGROUND: High rates of posttraumatic stress disorder (PTSD) and depressive symptoms have been observed in earthquake survivors from less developed areas of the world. This study, conducted three years after the 2005 Pakistan earthquake, aimed to identify potentially protective psychosocial factors associated with lower PTSD and depressive symptom levels. METHODS: Adult earthquake survivors (N=200) were recruited from affected areas in Northwestern Pakistan and completed self-report questionnaires measuring PTSD and depressive symptoms, positive and negative affect, and four psychosocial variables (purpose in life, positive and negative religious coping, and social support). RESULTS: Sixty five percent of participants met criteria for probable PTSD. Purpose in life was associated with lower symptom levels and higher positive emotions. A form of negative religious coping (feeling punished by God for one's sins or lack of spirituality) was associated with higher symptom levels and negative emotions. Higher perceived social support was associated with higher positive emotions. Other significant relationships were also identified. LIMITATIONS: Limitations include the recruitment of a sample of convenience, a modest sample size, and the cross-sectional nature of the study. CONCLUSIONS: Findings suggest that some psychosocial factors may be protective across cultures, and that the use of negative religious coping is associated with poorer mental health outcomes in earthquake survivors. This study can inform preventive and treatment interventions for earthquake survivors in Pakistan and other less industrialized countries as they develop mental health care services.