John S March’s research while affiliated with Duke University Medical Center and other places

Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75–80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.

Background: Obsessive-compulsive disorder (OCD) is often a life-long disorder with high psychosocial impairment. Serotonin reuptake inhibitors (SRIs) are the only FDA approved drugs, and approximately 50% of patients are non-responders when using a criterion of 25% to 35% improvement with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). About 30% are non-responders to combined first-line therapies (SRIs and exposure and response prevention). Previous research (one open, one randomized clinical trial) has demonstrated that Kundalini Yoga (KY) meditation can lead to an improvement in symptoms of obsessive-compulsive severity. We expand here with a larger trial. Design: This trial compared two parallel run groups [KY vs. Relaxation Response meditation (RR)]. Patients were randomly allocated based on gender and Y-BOCS scores. They were told two different (unnamed) types of meditation would be compared, and informed if one showed greater benefits, the groups would merge for 12 months using the more effective intervention. Raters were blind in Phase One (0–4.5 months) to patient assignments, but not in Phase Two. Main Outcome Measures: Primary outcome variable, clinician-administered Y-BOCS. Secondary scales: Dimensional Yale-Brown Obsessive Compulsive Scale (clinician-administered), Profile of Mood Scales, Beck Anxiety Inventory, Beck Depression Inventory, Clinical Global Impression, Short Form 36 Health Survey. Results: Phase One: Baseline Y-BOCS scores: KY mean = 26.46 (SD 5.124; N = 24), RR mean = 26.79 (SD = 4.578; N = 24). An intent-to-treat analysis with the last observation carried forward for dropouts showed statistically greater improvement with KY compared to RR on the Y-BOCS, and statistically greater improvement on five of six secondary measures. For completers, the Y-BOCS showed 40.4% improvement for KY (N = 16), 17.9% for RR (N = 11); 31.3% in KY were judged to be in remission compared to 9.1% in RR. KY completers showed greater improvement on five of six secondary measures. At the end of Phase Two (12 months), patients, drawn from the initial groups, who elected to receive KY continued to show improvement in their Y-BOCS scores. Conclusion: KY shows promise as an add-on option for OCD patients unresponsive to first line therapies. Future studies will establish KY’s relative efficacy compared to Exposure and Response Prevention and/or medications, and the most effective treatment schedule. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01833442.

Objective: This sequential multiple assignment randomized trial (SMART) tested the effect of beginning treatment of childhood OCD with fluoxetine (FLX) or group cognitive-behavioral therapy (GCBT) accounting for treatment failures over time. Methods: A two-stage, 28-week SMART was conducted with 83 children and adolescents with OCD. Participants were randomly allocated to GCBT or FLX for 14 weeks. Responders to the initial treatment remained in the same regimen for additional 14 weeks. Non-responders, defined by less than 50% reduction in baseline Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, were re-randomized to either switch to or add the other treatment. Assessments were performed at baseline, 7, 14, 21, and 28 weeks. Results: Among the 43 children randomized to FLX who completed the first stage, 15 (41.7%) responded to treatment and 21 non-responders were randomized to switch to (N = 9) or add GCBT (N = 12). Among the 40 children randomized to GCBT who completed the first stage, 18 (51.4%) responded to treatment and 17 non-responders were randomized to switch to (N = 9) or add FLX (N = 8). Primary analysis showed that significant improvement occurred in children initially treated with either FLX or GCBT. Each time point was statistically significant, showing a linear trend of symptom reduction. Effect sizes were large within (0.76-0.78) and small between (-0.05) groups. Conclusions: Fluoxetine and GCBT are similarly effective initial treatments for childhood OCD considering treatment failures over time. Consequently, provision of treatment for childhood OCD could be tailored according to the availability of local resources.

This chapter begins by stating the importance of considering the concept of anxiety and its heterogeneity. It defines anxiety to set the scene for the rest of the discussion in this chapter. The chapter then makes a distinction between anxiety and anxiety disorders. The chapter looks at research in the areas of anxiety and anxiety disorders. Recent research has expanded our understanding of the phenomena linked to the concepts of anxiety and anxiety disorder. The chapter states a hope that major advances in research will now occur thanks to a better understanding of the conditions, which hopefully will lead to a more fruitful set of psychiatric classifications.

The efficacy of cognitive-behavioral therapy (CBT) for pediatric obsessive-compulsive disorder (OCD) has been the subject of much study over the past fifteen years. Building on a foundation of case studies and open clinical trials, the literature now contains many methodologically sound studies that have compared full CBT protocols to waitlist controls, pill placebo, psychosocial comparison conditions, active medication, combined treatments, and brief CBT. This review is part of a series commissioned by The Canadian Institute for Obsessive Compulsive Disorders (CIOCD) in an effort to publish in one place what is known about the efficacy of treatments for OCD. A total of fourteen studies were identified; collectively their findings support the efficacy of CBT for youth with OCD. CBT protocols that emphasized either strictly behavioral or cognitive conceptualizations have each been found efficacious relative to waitlist controls. Efforts to enhance CBT׳s efficacy and reach have been undertaken. These trials provide guidance regarding next steps to be taken to maximize efficacy and treatment availability. Findings from studies in community clinics suggest that significant treatment benefits can be realized and are not reported only from within academic contexts. These findings bode well for broader dissemination efforts. Recommendations for future research directions are provided. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Serotonin reuptake inhibiting drugs (SRI) have been used in the treatment of paediatric obsessive-compulsive disorder over the past thirty years.We performed a systematic review and meta-analysis of the literature to discuss the place of and evidence for the use of SRI in paediatric OCD, based on fourteen publications of methodologically sound, randomized and controlled studies. Both SRI and specific SRIs were examined and comparisons of SRI, placebo, cognitive behaviour therapy (CBT), combined (COMBO) treatments (SRI+CBT) made to investigate their relative efficacy. Using the Cochrane methodology, and as measures of effect size mean difference and Hedge’s g, SRIs proved to be superior to drug placebo, with a modest effect size. From direct comparisons of CBT and SRI treatments, we conclude that CBT has the superior efficacy. COMBO versus CBT shows that SRI treatment adds little to concomitant CBT, while COMBO shows favourable outcome versus SRI alone. In pre-trial partial treatment responders, those who failed a SRI had better outcome from adding CBT as compared to continuing a SRI. Those who failed CBT treatment did as well with continued CBT as with switching to a SRI. The studies of combinations and sequences of treatments need to be developed further.

To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents. Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC). There were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (≤12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups. The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (≤12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. All rights reserved.

Objective: To evaluate changes in the trajectory of youth anxiety following the introduction of specific cognitive-behavior therapy (CBT) components: relaxation training, cognitive restructuring, and exposure tasks. Method: Four hundred eighty-eight youths ages 7-17 years (50% female; 74% ≤ 12 years) were randomly assigned to receive either CBT, sertraline (SRT), their combination (COMB), or pill placebo (PBO) as part of their participation in the Child/Adolescent Anxiety Multimodal Study (CAMS). Youths in the CBT conditions were evaluated weekly by therapists using the Clinical Global Impression Scale-Severity (CGI-S; Guy, 1976) and the Children's Global Assessment Scale (CGAS; Shaffer et al., 1983) and every 4 weeks by blind independent evaluators (IEs) using the Pediatric Anxiety Ratings Scale (PARS; RUPP Anxiety Study Group, 2002). Youths in SRT and PBO were included as controls. Results: Longitudinal discontinuity analyses indicated that the introduction of both cognitive restructuring (e.g., changing self-talk) and exposure tasks significantly accelerated the rate of progress on measures of symptom severity and global functioning moving forward in treatment; the introduction of relaxation training had limited impact. Counter to expectations, no strategy altered the rate of progress in the specific domain of anxiety that it was intended to target (i.e., somatic symptoms, anxious self-talk, avoidance behavior). Conclusions: Findings support CBT theory and suggest that cognitive restructuring and exposure tasks each make substantial contributions to improvement in youth anxiety. Implications for future research are discussed. (PsycINFO Database Record

This study examined racial differences in anxious youth using data from the Child/Adolescent Anxiety Multimodal Study (CAMS) [1]. Specifically, the study aims addressed whether African American (n = 44) versus Caucasian (n = 359) children varied on (1) baseline clinical characteristics, (2) treatment process variables, and (3) treatment outcomes. Participants were ages 7-17 and met DSM-IV-TR criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Baseline data, as well as outcome data at 12 and 24 weeks, were obtained by independent evaluators. Weekly treatment process variables were collected by therapists. Results indicated no racial differences on baseline clinical characteristics. However, African American participants attended fewer psychotherapy and pharmacotherapy sessions, and were rated by therapists as less involved and compliant, in addition to showing lower mastery of CBT. Once these and other demographic factors were accounted for, race was not a significant predictor of response, remission, or relapse. Implications of these findings suggest African American and Caucasian youth are more similar than different with respect to the manifestations of anxiety and differences in outcomes are likely due to treatment barriers to session attendance and therapist engagement.