Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Event related potentials indexing the influence of emotion on cognitive processing in veterans with comorbid post-traumatic stress disorder and traumatic brain injury.

OBJECTIVE: Emotion regulation and cognitive executive control are significantly impaired in both post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). These illnesses are increasingly common in veterans and their co-occurrence may exacerbate symptoms and recovery. The current study sought to investigate neural correlates of these impairments via event-related potentials (ERPs) and examined the association of PTSD symptom severity and impulsivity with these correlates. METHODS: Electroencephalographic data from seventy-nine veterans with PTSD and TBI and 17 control participants were recorded during a visual emotional oddball task and analyzed for the N2 and P3b ERPs. RESULTS: Results revealed that veterans showed a reduced P3b ERP in response to both target images and standard images. However, for standard images that followed a negative emotional distractor, the veterans showed a heightened N2 amplitude while the controls did not. In addition, impulsivity predicted modulation of the P3b across stimulus conditions, with a greater P3b amplitude associated with an increase in impulsivity. CONCLUSIONS: These findings suggest that veterans showed hyper-responsivity to background information and reduced ERPs to task-relevant information. SIGNIFICANCE: These findings may reflect heightened internal states that create neural noise and a reduced ability to modulate relevant responses.

Implementation of the Addendum Guidelines for Peanut Allergy Prevention by US allergists, a survey conducted by the NIAID, in collaboration with the AAAAI.

BACKGROUND: In 2017, the Addendum Guidelines for the Prevention of Peanut Allergy were published with recommendations on early introduction of peanut-containing foods based on infants' clinical history. OBJECTIVE: We sought to conduct a nationwide US survey to assess Guidelines implementation among allergists and immunologists who manage infants for food allergy. METHODS: Survey invitations were delivered to 3281 nonretired, US members of the American Academy of Asthma, Allergy & Immunology, board certified in allergy and immunology. The survey assessed awareness and implementation of the Guidelines and barriers to implementation. Descriptive statistics were generated. RESULTS: Twenty-nine percent (946 of 3281) of surveyed allergists/immunologists responded, and 87.1% (825 of 946) of responders met eligibility criteria. Among eligible responders, 97.1% were aware of the Guidelines. Of these, 64.5% reported full implementation of the Guidelines as published, 34.4% reported partial implementation, and 1.1% reported using none of the Guidelines. Barriers to Guidelines use included parental (47.6%) and self (21.8%) concerns about allergic reactions, lack of referrals (33.6%), parents uninterested in early feeding (28.2%), and lack of clinic time (20.9%). The 2 most common deviations from the Guidelines were considering additional factors not specified in the Guidelines such as family history (50.2%) and conducting skin prick testing in non-high-risk children (43.9%). Of respondents using the Guidelines, 45.7% indicated they needed more education or training. CONCLUSIONS: Essentially all allergists/immunologists who responded to the survey reported full or partial Guidelines implementation. Parental concerns and lack of referrals are major identifiable barriers. Improved Guidelines messaging to parents and referring physicians is warranted.

Assessment of Pediatrician Awareness and Implementation of the Addendum Guidelines for the Prevention of Peanut Allergy in the United States.

Importance: The 2017 Addendum Guidelines for the Prevention of Peanut Allergy in the United States recommend that pediatricians assess infant peanut allergy risk and introduce peanut in the diet at age 4 to 6 months. Early introduction has the potential to prevent peanut allergy development. Objectives: To measure the rates of guideline awareness and implementation and to identify barriers to and factors associated with implementation among US pediatricians. Design, Setting, and Participants: This population-based study survey used a 29-item electronic survey instrument that was administered to pediatricians practicing across the United States from June 1, 2018, to December 1, 2018. Invitations to complete a survey were emailed to all pediatricians in the American Academy of Pediatrics vendor database. Eligible participants were nonretired US-based pediatricians providing general care to infants aged 12 months or younger. Main Outcomes and Measures: The primary outcome was the prevalence of guideline implementation, which was measured by 1 survey item about awareness followed by a second item about implementation. Secondary outcomes included identification of guidelines-focused services provided by pediatricians, knowledge of the guidelines (measured with 3 clinical scenarios), barriers to guideline implementation, need for training, and facilitators of guideline implementation. Results: A total of 1781 pediatricians were eligible to participate and completed the entire survey. Most respondents self-identified as white (1287 [72.5%]) and female (1210 [67.4%]) individuals. Overall, 1725 (93.4%; 95% CI, 92.2%-94.5%) pediatricians reported being aware of the guidelines. Of those pediatricians who had knowledge of the guidelines, 497 (28.9%; 95% CI, 26.8%-31.1%) reported full implementation and 1105 (64.3%; 95% CI, 62.0%-66.6%) reported partial implementation. Common barriers to implementation included parental concerns about allergic reactions (reported by 575 respondents [36.6%; 95% CI, 34.3%-39.1%]), uncertainty in understanding and correctly applying the guidelines (reported by 521 respondents [33.2%; 95% CI, 30.9%-35.6%]), and conducting in-office supervised feedings (reported by 509 respondents [32.4%; 95% CI, 30.1%-34.8%]). Many pediatricians (1175 [68.4%; 95% CI, 66.1%-70.5%]) reported a need for further training on the guidelines. Conclusions and Relevance: This survey found that most pediatrician respondents appeared to know of the 2017 guidelines, but less than one-third of respondents reported full implementation. Results of this study may inform future efforts to eliminate barriers to guideline implementation and adherence, thereby reducing the incidence of peanut allergy in infants.

Nasal allergen challenge and environmental exposure chamber challenge: A randomized trial comparing clinical and biological responses to cat allergen.

BACKGROUND: The direct-instillation nasal allergen challenge (NAC) and the environmental exposure chamber (EEC) are 2 methods of conducting controlled allergen provocations. The clinical and biological comparability of these methods has not been thoroughly investigated. OBJECTIVE: We sought to compare clinical and immunologic responses to cat allergen in NAC versus EEC. METHODS: Twenty-four participants were randomized to receive either NAC followed by a 2-day challenge in an EEC or a 2-day challenge in an EEC followed by NAC. Challenges were separated by 28-day washout periods. We measured total nasal symptom scores, peak nasal inspiratory flow, nasal (0-8 hours) and serum cytokines, serum antibodies, peripheral blood antigen-specific T lymphocytes, and gene expression in nasal scrapings. The primary outcome was the total nasal symptom score area under the curve for the first 3 hours after allergen exposure in NAC or after initiation of exposure in EEC. RESULTS: Both challenges increased IL-5 and IL-13 in nasal fluids and serum and resulted in altered nasal cell expression of gene modules related to mucosal biology and transcriptional regulation. Changes in gene modules, more so than cytokine measurements, showed significant associations with total nasal symptom score and peak nasal inspiratory flow. Overall, EEC exposure generated larger responses and more early terminations compared with NAC. Although the 2 challenges did not correlate in symptom magnitude or temporality, striking correlations were observed in cytokine levels. CONCLUSIONS: Although clinical outcomes of NAC and EEC were temporally different and nonequivalent in magnitude, immunologic responses were similar. Selection of a particular allergen challenge method should depend on considerations of study objectives and cost.

The transgenerational effects of oocyte mitochondrial supplementation.

Many women suffer from either failed fertilisation or their embryos arrest early during development. Autologous mitochondrial supplementation has been proposed as an assisted reproductive technology to overcome these problems. However, its safety remains to be tested in an animal model to determine if there are transgenerational effects. We have supplemented oocytes with autologous populations of mitochondria to generate founders. We mated the female founders and their offspring to produce three generations. We assessed litter size, the ovarian reserve, and weight gain and conducted a full histopathological analysis from each of the three generations. Across the generations, we observed significant increases in litter size and in the number of primordial follicles in the ovary matched by changes in global gene expression patterns for these early-stage oocytes. However, full histopathological analysis revealed that cardiac structure was compromised in first and second generation offspring, which could seriously affect the health of the offspring. Furthermore, the offspring were prone to increased weight gain during early life. Mitochondrial supplementation appears to perturb the regulation of the chromosomal genome resulting in transgenerational phenotypic gains and losses. These data highlight the need for caution when using autologous mitochondrial supplementation to treat female factor infertility.

Cognitive Rehabilitation With Mobile Technology and Social Support for Veterans With TBI and PTSD: A Randomized Clinical Trial.

OBJECTIVE: To investigate effects of cognitive rehabilitation with mobile technology and social support on veterans with traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). PARTICIPANTS: There were 112 dyads, comprised by a veteran and a family member or friend (224 participants in total). DESIGN: Dyads were randomized to the following: (1) a novel intervention, Cognitive Applications for Life Management (CALM), involving goal management training plus mobile devices for cueing and training attentional control; or (2) Brain Health Training, involving psychoeducation plus mobile devices to train visual memory. MAIN MEASURES: Executive dysfunction (disinhibition, impulsivity) and emotional dysregulation (anger, maladaptive interpersonal behaviors) collected prior to randomization and following intervention completion at 6 months. RESULTS: The clinical trial yielded negative findings regarding executive dysfunction but positive findings on measures of emotion dysregulation. Veterans randomized to CALM reported a 25% decrease in anger over 6 months compared with 8% reduction in the control (B = -5.27, P = .008). Family/friends reported that veterans randomized to CALM engaged in 26% fewer maladaptive interpersonal behaviors (eg, aggression) over 6 months compared with 6% reduction in the control (B = -2.08, P = .016). An unanticipated result was clinically meaningful change in reduced PTSD symptoms among veterans randomized to CALM (P < .001). CONCLUSION: This preliminary study demonstrated effectiveness of CALM for reducing emotional dysregulation in veterans with TBI and PTSD.

Neuropsychological correlates of self-reported impulsivity and informant-reported maladaptive behaviour among veterans with posttraumatic stress disorder and traumatic brain injury history.

OBJECTIVE: Frontal lobe deficits resulting from traumatic brain injury (TBI) and/or posttraumatic stress disorder (PTSD) have been linked to impulsive behaviour. We sought to examine whether neuropsychological performance predicted self-reported impulsivity and informant-reported maladaptive behaviour. METHOD: We administered the Delis-Kaplan Executive Function System (D-KEFS) to 116 Iraq/Afghanistan-era veterans diagnosed with a history of TBI and PTSD. RESULTS: Poorer performance on D-KEFS Stroop Task (both colour and word, separately) and Trail making (letter sequencing and motor speed) tasks and higher PTSD symptom severity were associated with higher self-reported impulsivity. Trail making letter sequencing performance was negatively associated with informant-reported maladaptive behaviour. Regression analyses revealed PTSD symptom severity and Trail making letter sequencing best predicted self-reported impulsivity, even when accounting for age, sex, and education. Only Trail making letter sequencing predicted informant-reported maladaptive behaviour when accounting for other variables in the model. CONCLUSIONS: Attention and processing speed impairments and PTSD symptom severity appear to be important predictors of impulsivity and problematic behaviour among veterans. Findings have implications for theoretical models of aggression and violence and inform the assessment and treatment of individuals with TBI and PTSD.

Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns.

Mitochondrial DNA copy number is strictly regulated during development as naive cells differentiate into mature cells to ensure that specific cell types have sufficient copies of mitochondrial DNA to perform their specialised functions. Mitochondrial DNA haplotypes are defined as specific regions of mitochondrial DNA that cluster with other mitochondrial sequences to show the phylogenetic origins of maternal lineages. Mitochondrial DNA haplotypes are associated with a range of phenotypes and disease. To understand how mitochondrial DNA haplotypes induce these characteristics, we used four embryonic stem cell lines that have the same set of chromosomes but possess different mitochondrial DNA haplotypes. We show that mitochondrial DNA haplotypes influence changes in chromosomal gene expression and affinity for nuclear-encoded mitochondrial DNA replication factors to modulate mitochondrial DNA copy number, two events that act synchronously during differentiation. Global DNA methylation analysis showed that each haplotype induces distinct DNA methylation patterns, which, when modulated by DNA demethylation agents, resulted in skewed gene expression patterns that highlight the effectiveness of the new DNA methylation patterns established by each haplotype. The haplotypes differentially regulate α-ketoglutarate, a metabolite from the TCA cycle that modulates the TET family of proteins, which catalyse the transition from 5-methylcytosine, indicative of DNA methylation, to 5-hydroxymethylcytosine, indicative of DNA demethylation. Our outcomes show that mitochondrial DNA haplotypes differentially modulate chromosomal gene expression patterns of naive and differentiating cells by establishing mitochondrial DNA haplotype-specific DNA methylation patterns.

Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial.

BACKGROUND: Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated hormone-free interval are superior to placebo. However, results of such trials are mixed, and no existing studies have directly compared continuous and intermittent dosing schedules of the same oral contraceptive. The present study compared placebo, intermittent dosing of oral contraceptives, and continuous dosing of contraceptives for the treatment of PMD. METHODS: Fifty-five women with prospectively confirmed PMD completed a three-arm, RCT in which they were randomized to 3 months of placebo (n = 22), intermittent drospirenone/ethinyl estradiol dosed on a 21-7 schedule (n = 17), or continuous drospirenone/estradiol (n = 16) following a baseline assessment month. RESULTS: All three groups demonstrated similar, robust reductions in premenstrual symptoms over time. A marked placebo response was observed. CONCLUSIONS: The study fails to replicate a uniquely beneficial effect of continuous COC on PMD. Additional work is needed to understand the psychosocial context bolstering the placebo response in women with PMD.

A 12-week randomized controlled trial of twice-daily intranasal oxytocin for social cognitive deficits in people with schizophrenia.

Social cognition is impaired in people with schizophrenia and these deficits are strongly correlated with social functioning. Oxytocin is a hypothalamic peptide that contributes to maternal infant bonding and has diverse pro-social effects in adults. This study tested the hypothesis that 12weeks of intranasal oxytocin will improve social cognitive function in outpatients with schizophrenia and schizoaffective disorder. Sixty-eight eligible participants were randomized to oxytocin (24IU twice daily) or placebo. Social cognitive function was assessed using the Emotion Recognition-40, Brüne Theory of Mind, Reading the Mind in the Eyes test, Trustworthiness task and Ambiguous Intentions Hostility Questionnaire at baseline, 6weeks and 12weeks. In addition, social function was assessed using the Specific Levels of Functioning Scale and a role-play test, and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Fifty-five participants completed the 12-week trial. The study found no evidence for a differential advantage of oxytocin over placebo on social cognition. Among secondary outcomes, there was a modest advantage for oxytocin over placebo on a component of social functioning, although there was also evidence that the placebo group outperformed the oxytocin group on the role-play task. No between-group differences emerged on measures of psychopathology in pre-specified comparisons, but oxytocin showed significant within-group reduction in PANSS negative symptoms and significant between-group improvement in negative symptoms in the schizophrenia subgroup. Further testing is needed to clarify whether oxytocin has therapeutic potential for social cognitive deficits and/or negative symptoms in people with schizophrenia.

Toward the Reliable Diagnosis of DSM-5 Premenstrual Dysphoric Disorder: The Carolina Premenstrual Assessment Scoring System (C-PASS).

OBJECTIVE: Despite evidence for the validity of premenstrual dysphoric disorder (PMDD) and the inclusion of the disorder in DSM-5, variable diagnostic practices compromise the construct validity of the diagnosis and threaten the clarity of efforts to understand and treat its underlying pathophysiology. In an effort to hasten and streamline the translation of the DSM-5 criteria for PMDD into terms compatible with existing research practices, the authors present the development and initial validation of the Carolina Premenstrual Assessment Scoring System (C-PASS). The C-PASS (available as a worksheet, Excel macro, and SAS macro) is a standardized scoring system for making DSM-5 PMDD diagnoses using two or more months of daily symptom ratings with the Daily Record of Severity of Problems (DRSP). METHOD: Two hundred women recruited for retrospectively reported premenstrual emotional symptoms provided two to four months of daily symptom ratings on the DRSP. Diagnoses made by expert clinician and by the C-PASS were compared. RESULTS: Agreement of C-PASS diagnosis with expert clinical diagnosis was excellent; overall correct classification by the C-PASS was estimated at 98%. Consistent with previous evidence, retrospective reports of premenstrual symptom increases were a poor predictor of prospective C-PASS diagnosis. CONCLUSIONS: The C-PASS is a reliable and valid companion protocol to the DRSP that standardizes and streamlines the complex, multilevel diagnosis of DSM-5 PMDD. Consistent use of this robust diagnostic method would result in more clearly defined, homogeneous samples of women with PMDD, thereby improving the clarity of studies seeking to characterize and treat the underlying pathophysiology of the disorder.

Histories of abuse predict stronger within-person covariation of ovarian steroids and mood symptoms in women with menstrually related mood disorder.

OBJECTIVE: Individual differences in sensitivity to cyclical changes in ovarian steroids estradiol (E2) and progesterone (P4) have been implicated in the pathophysiology of menstrually related mood disorder (MRMD). However, no prospective studies have investigated psychosocial risk factors for sensitivity to hormone effects on mood in MRMD. Using a repeated measures approach and multilevel models, we tested the hypothesis that a history of abuse provides a context in which within-person elevations of E2 and P4 prospectively predict daily symptoms. METHOD: 66 women with prospectively-confirmed MRMD recruited for a trial of oral contraceptives provided 1 month of baseline hormone and mood data prior to randomization. Lifetime physical and sexual abuse experiences were assessed. Across one cycle, women completed daily measures of symptoms and provided blood samples on 5 days across the menstrual cycle. Current E2 and P4 were centered within person (CWP) such that higher values represented cyclical elevations in hormones. RESULTS: Rates of physical (27%) and sexual (29%) abuse were high, consistent with previous work documenting a link between trauma and MRMD. In women with a history of physical abuse, cyclical increases in P4 predicted greater mood and interpersonal symptoms on the three days following that sample. In women with a history of sexual abuse, cyclical increases in E2 predicted greater anxiety symptoms on the three days following that sample. CONCLUSIONS: Results inform further inquiry into the role of severe life stressors and stress response systems in MRMD. We discuss areas for future research on the psychosocial and physiological pathways through which abuse may influence the link between hormones and symptoms.

Recommendations for choosing an analysis method that controls Type I error for unbalanced cluster sample designs with Gaussian outcomes.

We used theoretical and simulation-based approaches to study Type I error rates for one-stage and two-stage analytic methods for cluster-randomized designs. The one-stage approach uses the observed data as outcomes and accounts for within-cluster correlation using a general linear mixed model. The two-stage model uses the cluster specific means as the outcomes in a general linear univariate model. We demonstrate analytically that both one-stage and two-stage models achieve exact Type I error rates when cluster sizes are equal. With unbalanced data, an exact size α test does not exist, and Type I error inflation may occur. Via simulation, we compare the Type I error rates for four one-stage and six two-stage hypothesis testing approaches for unbalanced data. With unbalanced data, the two-stage model, weighted by the inverse of the estimated theoretical variance of the cluster means, and with variance constrained to be positive, provided the best Type I error control for studies having at least six clusters per arm. The one-stage model with Kenward-Roger degrees of freedom and unconstrained variance performed well for studies having at least 14 clusters per arm. The popular analytic method of using a one-stage model with denominator degrees of freedom appropriate for balanced data performed poorly for small sample sizes and low intracluster correlation. Because small sample sizes and low intracluster correlation are common features of cluster-randomized trials, the Kenward-Roger method is the preferred one-stage approach.

Power calculation for overall hypothesis testing with high-dimensional commensurate outcomes.

The complexity of system biology means that any metabolic, genetic, or proteomic pathway typically includes so many components (e.g., molecules) that statistical methods specialized for overall testing of high-dimensional and commensurate outcomes are required. While many overall tests have been proposed, very few have power and sample size methods. We develop accurate power and sample size methods and software to facilitate study planning for high-dimensional pathway analysis. With an account of any complex correlation structure between high-dimensional outcomes, the new methods allow power calculation even when the sample size is less than the number of variables. We derive the exact (finite-sample) and approximate non-null distributions of the 'univariate' approach to repeated measures test statistic, as well as power-equivalent scenarios useful to generalize our numerical evaluations. Extensive simulations of group comparisons support the accuracy of the approximations even when the ratio of number of variables to sample size is large. We derive a minimum set of constants and parameters sufficient and practical for power calculation. Using the new methods and specifying the minimum set to determine power for a study of metabolic consequences of vitamin B6 deficiency helps illustrate the practical value of the new results. Free software implementing the power and sample size methods applies to a wide range of designs, including one group pre-intervention and post-intervention comparisons, multiple parallel group comparisons with one-way or factorial designs, and the adjustment and evaluation of covariate effects.

Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods.

BACKGROUND: Youth with serious mental illness may experience improved psychiatric stability with second generation antipsychotic (SGA) medication treatment, but unfortunately may also experience unhealthy weight gain adverse events. Research on weight loss strategies for youth who require ongoing antipsychotic treatment is quite limited. The purpose of this paper is to present the design, methods, and rationale of the Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) study, a federally funded, randomized trial comparing two pharmacologic strategies against a control condition to manage SGA-related weight gain. METHODS: The design and methodology considerations of the IMPACT trial are described and embedded in a description of health risks associated with antipsychotic-related weight gain and the limitations of currently available research. RESULTS: The IMPACT study is a 4-site, six month, randomized, open-label, clinical trial of overweight/obese youth ages 8-19 years with pediatric schizophrenia-spectrum and bipolar-spectrum disorders, psychotic or non-psychotic major depressive disorder, or irritability associated with autistic disorder. Youth who have experienced clinically significant weight gain during antipsychotic treatment in the past 3 years are randomized to either (1) switch antipsychotic plus healthy lifestyle education (HLE); (2) add metformin plus HLE; or (3) HLE with no medication change. The primary aim is to compare weight change (body mass index z-scores) for each pharmacologic intervention with the control condition. Key secondary assessments include percentage body fat, insulin resistance, lipid profile, psychiatric symptom stability (monitored independently by the pharmacotherapist and a blinded evaluator), and all-cause and specific cause discontinuation. This study is ongoing, and the targeted sample size is 132 youth. CONCLUSION: Antipsychotic-related weight gain is an important public health issue for youth requiring ongoing antipsychotic treatment to maintain psychiatric stability. The IMPACT study provides a model for pediatric research on adverse event management using state-of-the art methods. The results of this study will provide needed data on risks and benefits of two pharmacologic interventions that are already being used in pediatric clinical settings but that have not yet been compared directly in randomized trials. TRIAL REGISTRATION: Clinical Trials.gov NCT00806234.

Neurocognitive outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders study.

OBJECTIVE: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). METHOD: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. RESULTS: Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. CONCLUSIONS: Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703.

A history of depression in women is associated with an altered GABAergic neuroactive steroid profile.

The 3α,5α- and 3α,5ß-reduced metabolites of progesterone, deoxycorticosterone, and dehydroepiandrosterone (DHEA) have potent effects on neurotransmission mediated by GABA(A) receptors, and dysregulation of these receptors has been implicated in depression. Using gas chromatography-mass spectrometry, we compared neuroactive steroid concentrations in women with a history of depressive disorders, but who were in full remission at the time of testing (n=11) to never depressed women (n=17) both before and after a challenge with oral micronized progesterone (300 mg). Serum concentrations of the following were obtained: four progesterone-derived GABAergic neuroactive steroids, the precursor pregnenolone, androstenedione-derived neuroactive steroids, and the precursor DHEA. As an index of conversion of progesterone to neuroactive steroids, we also examined ratios of neuroactive steroids to progesterone following the oral progesterone challenge. Results indicated that both before and after oral progesterone, women with histories of depression showed lower concentrations of all GABAergic neuroactive steroids than never depressed women. Those with a history of depression also had lower cortisol concentrations. Because serum neuroactive steroids are mainly synthesized in the adrenals, we hypothesize that histories of depression may be associated with persistent adrenal suppression. Following the progesterone challenge, ratios of the progesterone-derived neuroactive steroids to plasma progesterone concentrations were elevated in women with depression histories, suggesting there may be an adaptive shift in the metabolism of progesterone that compensates for lower circulating neuroactive steroid concentrations.

Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study.

OBJECTIVE: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. METHOD: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. RESULTS: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. CONCLUSIONS: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.