Faculty Bibliography

PURPOSE: It is well established that empirically supported treatments reduce depressive symptoms for most adolescents; however, it is not yet known whether these interventions lead to sustained improvements in global functioning. The goal of this study is to assess the clinical characteristics and trajectories of long-term psychosocial functioning among emerging adults who have experienced adolescent-onset major depressive disorder. METHODS: Global functioning was assessed using the Clinical Global Assessment Scale for children (participants /= 19 years) and the Health of the Nation Outcome Scales for Adolescents among 196 adolescents who elected to complete 3.5 years of naturalistic follow-up subsequent to their participation in the Treatment for Adolescents with Depression Study. The Treatment for Adolescents with Depression Study examined the efficacy of cognitive behavior therapy, fluoxetine, and the combination of cognitive behavior therapy and fluoxetine (combination treatment) over the course of 36 weeks. Mixed-effects regression models were used to identify trajectories and clinical predictors of functioning over the naturalistic follow-up. RESULTS: Global functioning and achievement of developmental milestones (college, employment) improved over the course of follow-up for most adolescents. Depressive relapse, initial randomization to the placebo group, and the presence of multiple psychiatric comorbidities conferred risk for relatively poorer functioning. CONCLUSIONS: Functioning generally improves among most adolescents who have received empirically supported treatments. However, the presence of recurrent major depressive disorder and multiple psychiatric comorbidities is associated with poorer functioning trajectories, offering targets for maintenance treatment or secondary prevention.

AIMS: To examine the safety and effectiveness of buprenorphine + naloxone sublingual tablets (BUP, as Suboxone(R)) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol(R)) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. METHODS: This multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York, and Washington D.C., USA to 1 of 3 conditions provided with XR-NTX: 4 mg/day BUP (BUP4, n = 100), 16 mg/day BUP (BUP16, n = 100), or no buprenorphine (placebo; PLB, n = 102). Participants received pharmacotherapy for 8 weeks, with 3 clinic visits per week. Cognitive Behavioral Therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4 weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention, and adverse events. RESULTS: No group differences were found between groups for the primary outcome (BUP4 vs. PLB, p = 0.262; BUP16 vs PLB, p = 0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB (p = 0.022, OR = 1.71) but not for BUP4 (p = 0.105, OR = 1.05). No secondary outcome differences across groups were found for adherence, retention, or adverse events. CONCLUSIONS: Buprenorphine + naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse

The varepsilon4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of varepsilon4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were varepsilon4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in varepsilon4-carriers was episodic memory decline associated with odor identification impairment. In individuals without varepsilon4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by varepsilon4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the varepsilon4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that varepsilon4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the varepsilon4 should be considered when using olfactory assessment as an early-stage indicator.

BACKGROUND: Research supports the efficacy of intensive cognitive behavioral therapy (CBT) for the treatment of adolescent panic disorder with or without agoraphobia (PDA). However, little is known about the conditions under which intensive treatment is most effective. The current investigation examined the moderating roles of baseline fear and avoidance in the intensive treatment of adolescent PDA. METHODS: Adolescents with PDA (ages 11-17; N = 54) were randomized to either an intensive CBT treatment (n = 37) or a waitlist control condition (n = 17). PDA diagnosis, symptom severity, and number of feared and avoided situations were assessed at baseline and 6-week post-treatment/post-waitlist. Hierarchical regression analyses examined the relative contributions of treatment condition, number of baseline feared or avoided situations, and their interactions in the prediction of post-treatment/waitlist PDA symptoms. RESULTS: The main effect of intensive CBT on post-treatment PDA symptoms was not uniform across participants, with larger treatment effects found among participants with lower, relative to higher, baseline levels of fear and avoidance. CONCLUSIONS: Findings help clarify which adolescents suffering with PDA may benefit most from an intensive treatment format.

Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (chi2=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.

BACKGROUND: Both Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults. METHODS: Participants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness. RESULTS: After controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness. DISCUSSION: Young adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.

The present study examined whether the presence of comorbid ODD differentially moderated the outcome of two Behavioral Parent Training (BPT) programs in a sample of preschoolers with ADHD: One designed specifically for ADHD (NFPP: New Forest Parenting Programme) and one designed primarily for ODD (HNC: Helping the Noncompliant Child). In a secondary analysis, 130 parents and their 3-4 year-old children diagnosed with ADHD were assigned to one of the two programs. 44.6 % of the children also met criteria for ODD. Significant interactions between treatment conditions (NFPP vs. HNC) and child ODD diagnosis (presence vs. absence) indicated that based on some parent and teacher reports, HNC was more effective with disruptive behaviors than NFPP but only when children had a comorbid diagnosis. Further, based on teacher report, NFPP was more effective with these behaviors when children had a diagnosis of only ADHD whereas HNC was equally effective across ADHD only and comorbid ODD diagnoses. Comorbidity profile did not interact with treatment program when parent or teacher reported ADHD symptoms served as the outcome. Implications for clinical interventions are discussed and directions for future work are provided.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.Molecular Psychiatry advance online publication, 23 February 2016; doi:10.1038/mp.2016.5.

OBJECTIVE: Diffusion tensor imaging (DTI) can identify structural connectivity alterations in attention-deficit/hyperactivity disorder (ADHD). Most ADHD DTI studies have concentrated on regional differences in fractional anisotropy (FA) despite its limited sensitivity to complex white matter architecture and increasing evidence of global brain differences in ADHD. Here, we examine multiple DTI metrics in separate samples of children and adults with and without ADHD with a principal focus on global between-group differences. METHOD: Two samples: adults with ADHD (n = 42) and without (n = 65) and children with ADHD (n = 82) and without (n = 80) were separately group matched for age, sex, and head motion. Five DTI metrics (FA, axial diffusivity, radial diffusivity, mean diffusivity, and mode of anisotropy) were analyzed via tract-based spatial statistics. Group analyses tested for diagnostic differences at the global (averaged across the entire white matter skeleton) and regional level for each metric. RESULTS: Robust global group differences in diffusion indices were found in adults, with the largest effect size for mode of anisotropy (MA; Cohen's d = 1.45). Global MA also differed significantly between groups in the pediatric sample (d = 0.68). In both samples, global MA increased classification accuracy compared to the model with clinical Conners' ADHD ratings alone. Regional diagnostic differences did not survive familywise correction for multiple comparisons. CONCLUSION: Global DTI metrics, particularly the mode of anisotropy, which is sensitive to crossing fibers, capture connectivity abnormalities in ADHD across both pediatric and adult samples. These findings highlight potential diffuse white matter microarchitecture differences in ADHD.

Little is known about how professional development models can be used to address exclusionary disciplinary practices in response to behavior management challenges in classrooms and schools. This is of great concern given data that suggests that such practices predict negative outcomes for students, including repeat suspensions, dropout and incarceration. Instead, the professional development literature has focused largely on instructional practices in the classroom. Using secondary data, the current paper sought to address this limitation by examining the potential impact of a professional development intervention, focused on classroom management strategies through training and one-on-one coaching, on reductions in disciplinary practices. School-level suspension and behavioral incidence data were available for 70 schools participating in the intervention and 1605 schools that did not participate in the intervention during the 2011-2012 school year. First, differences in demographics between the schools receiving the professional development intervention and schools that did not receive the intervention were explored. Next, a series of hierarchical regression models were estimated in order to test the level of dosage as a predictor of change in suspensions and behavior incidents. Results reveal that intervention schools experienced significantly reduced suspensions and behavior incidents in the school year following the intervention. The number of coaching sessions also predicted significant decreases in suspensions and marginally significant decreases in behavioral incidences. These findings suggest that professional development interventions may have the potential to shift teacher behavior management practices that reduce exclusionary disciplinary practices known to be detrimental to student outcomes