A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder.

Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12-17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism.

The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F 1,20 = 9.853; P = 0.0052; ηp 2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

Sibling-Controlled Study of Parental Bonding, Coping, and Urgent Health-Care Use in Families With Children With Nonepileptic Seizures.

Objectives: Pediatric psychogenic nonepileptic seizures (PNES) is a functional somatic symptom condition with significant health-care service burden. While both family and individual factors play an important role in the development and maintenance of PNES, little is known about what predicts urgent health-care use in families with children who have PNES. The aim of the current study was to explore whether child coping and parental bonding styles influence the decision to seek urgent medical care in these families. Methods: Data were analyzed from youth of age 8-18 years, 47 with PNES, and their 25 sibling controls. Parents provided the number of youth emergency room visits and hospitalizations in the preceding year. Youth completed a questionnaire about their coping styles and a measure about their mothers' and fathers' bonding styles. Using a mixed model with family as a random effect, we regressed urgent health-care use on participant type (youth with PNES or sibling), parental bonding style, and youth coping style, controlling for number of child prescription medications. Results: Higher urgent health-care use was associated with having PNES, coping via monitoring, and perceiving one's father to be rejecting and overprotective. Lower urgent health-care use was associated with coping via venting and with perceiving one's mother to be caring and overprotective. Conclusions: This study provides preliminary empirical support for family-based clinical efforts to reduce child urgent health-care use by enhancing effective child coping skills and improving parental response to child impairment and distress in families with youth with PNES.

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism.

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

Risk factors for learning problems in youth with psychogenic non-epileptic seizures.

OBJECTIVES: This study examined the risk factors for learning problems (LP) in pediatric psychogenic non-epileptic seizures (PNES) and their specificity by comparing psychopathology, medical, cognitive/linguistic/achievement, bullying history, and parent education variables between subjects with PNES with and without LP and between subjects with PNES and siblings with LP. METHODS: 55 subjects with PNES and 35 siblings, aged 8-18years, underwent cognitive, linguistic, and achievement testing, and completed somatization and anxiety sensitivity questionnaires. A semi-structured psychiatric interview about the child was administered to each subject and parent. Child self-report and/or parent report provided information on the presence/absence of LP. Parents also provided each subject's medical, psychiatric, family, and bullying history information. RESULTS: Sixty percent (33/55) of the PNES and 49% (17/35) of the sibling subjects had LP. A multivariable logistic regression demonstrated that bullying and impaired formulation of a sentence using a stimulus picture and stimulus word were significantly associated with increased likelihood of LP in the PNES youth. In terms of the specificity of the LP risk factors, a similar analysis comparing LP in the youth with PNES and sibling groups identified anxiety disorder diagnoses and bullying as the significant risk factors associated with LP in the PNES youth. CONCLUSIONS: These findings emphasize the need to assess youth with PNES for LP, particularly if they have experienced bullying, have linguistic deficits, and meet criteria for anxiety disorder diagnoses.

Risk factors for comorbid psychopathology in youth with psychogenic nonepileptic seizures.

PURPOSE: To examine the risk factors for internalizing (anxiety, depression) and posttraumatic stress (PTSD) disorders, somatization, and anxiety sensitivity (AS) in youth with psychogenic non-epileptic seizures (PNES). METHODS: 55 probands with PNES and 35 siblings, aged 8-18 years, underwent a psychiatric interview, cognitive and language testing, and completed somatization and AS questionnaires. Parents provided the subjects' medical, psychiatric, family, and adversity history information. RESULTS: The risk factors for the probands' internalizing disorders (girls, older age of PNES onset), somatization (older age, epilepsy), and anxiety sensitivity (girls, adversities) differed from their siblings. The risk factors in the siblings, however, were similar to the general pediatric population. Proband depression was unrelated to the study's risk variables while PTSD was significantly associated with female gender and lower Full Scale IQ. CONCLUSIONS: Knowledge about the specificity of the risk factors for comorbid psychopathology in youth with PNES might facilitate their early identification and treatment.

A multisite controlled study of risk factors in pediatric psychogenic nonepileptic seizures.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) in youth are symptoms of a difficult to diagnose and treat conversion disorder. PNES is associated with high medical and psychiatric morbidity, but specific PNES risk factors in the pediatric population are not known. We examined if youth with PNES have a distinct biopsychosocial risk factor profile compared to their siblings and if the interrelationships between these risk factors differentiate the PNES probands from the sibling group. METHODS: This multisite study included 55 youth with a confirmed diagnosis of PNES (age range 8.6-18.4 years) and their 35 sibling controls (age range 8.6-18.1 years). A video EEG and psychiatric assessment confirmed the PNES diagnosis. Parents reported on each child's past and present medical/epilepsy, psychiatric, family, and educational history. Each child underwent a structured psychiatric interview, standardized cognitive and academic achievement testing, and completed self-report coping, daily stress, adversities, and parental bonding questionnaires. RESULTS: Compared to their siblings, the PNES probands had significantly more lifetime comorbid medical, neurological (including epilepsy), and psychiatric problems; used more medications and intensive medical services; had more higher anxiety sensitivity, practiced solitary emotional coping, and experienced more lifetime adversities. A principal components analysis of these variables identified a somatopsychiatric, adversity, epilepsy, and cognitive component. The somatopsychiatric and adversity components differentiated the probands from the siblings, and were highly significant predictors of PNES with odds ratios of 15.1 (95% CI [3.4, 67.3], and 9.5 (95% CI [2.0, 45.7]), respectively. The epilepsy and cognitive components did not differentiate between the PNES and sibling groups. SIGNIFICANCE: These findings highlight the complex biopsychosocial and distinct vulnerability profile of pediatric PNES. They also underscore the need for screening the interrelated risk factors included in the somatopsychiatric and adversity components and subsequent mental health referral for confirmation of the diagnosis and treatment of youth with PNES.