Faculty Bibliography

OBJECTIVE:To determine if the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) improves functional impairment, psychiatric symptoms, and sleep and circadian functioning. METHOD/METHODS:Adults diagnosed with serious mental illness (SMI) and sleep and circadian dysfunction (N = 121) were randomly allocated to TranS-C plus usual care (TranS-C + UC; n = 61; 8 individual weekly sessions) or 6 months of Usual Care followed by Delayed Treatment with TranS-C (UC-DT; n = 60). Schizophrenia (45%) and anxiety disorders (47%) were common. Blind assessments were conducted pre-treatment, post-treatment, and 6 months later (6FU). The latter two were the post-randomization points of interest. The location was Alameda County Behavioral Health Care Services (ACBHCS), a Community Mental Health Center (CMHC) in California. RESULTS:For the primary outcomes, relative to UC-DT, TranS-C + UC was associated with reduction in functional impairment (b = -3.18, p = 0.025, d = -0.58), general psychiatric symptoms (b = -5.88, p = 0.001, d = -0.64), sleep disturbance (b = -5.55, p < .0001, d = -0.96), and sleep-related impairment (b = -9.14, p < .0001, d = -0.81) from pre-treatment to post-treatment. These effects were maintained to 6-month follow-up (6FU; d = -0.42 to -0.82), except functional impairment (d = -0.37). For the secondary outcomes, relative to UC-DT, TranS-C + UC was associated with improvement in sleep efficiency and on the Sleep Health Composite score from pre-treatment to 6FU. TranS-C + UC was also associated with reduced total wake time and wake time variability from pre-treatment to post-treatment, as well as reduced hallucinations and delusions, bedtime variability, and actigraphy measured waking activity count variability from pre-treatment to 6FU. CONCLUSIONS:A novel transdiagnostic treatment, delivered within a CMHC setting, improves selected measures of functioning, symptoms of comorbid disorders, and sleep and circadian outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BACKGROUND AND OBJECTIVES/OBJECTIVE:Attention-deficit/hyperactivity disorder (ADHD) and obesity are 2 frequent conditions that co-occur, which has implications for the management of both conditions. We hypothesized that ADHD symptoms predict BMI and vice versa from late childhood (10-12 years) up to early adulthood (20-22 years). METHODS:= 2773, 52.5% male, mean age = 11 years at baseline, 5 waves up to mean age 22) from the Tracking Adolescents' Individual Lives Survey cohort. We examined bidirectional relationship between ADHD symptoms (hyperactivity/impulsivity and inattention) and BMI using the random intercept cross-lagged panel model. Time-varying covariates were pubertal status, stimulant use, depressive symptoms, and family functioning, and socioeconomic status was a time-invariant covariate. RESULTS:< .05). No longitudinal direct effects were found between ADHD symptoms and BMI during this period. CONCLUSIONS:Over the course of adolescence, the link between ADHD and BMI is stable and is predominantly with hyperactive and impulsive symptoms rather than inattention. There was no direct effect of ADHD symptoms on BMI increase nor of BMI on enhanced ADHD symptoms during this developmental period. The findings point to a shared genetic or familial background and/or potential causal effects established already earlier in childhood, thus suggesting that intervention and prevention programs targeting overweight and obesity in children with ADHD should be implemented in early childhood.

Top-tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour-nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter-ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta-analyses (NMAs) and meta-analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co-primary outcomes were disease-specific symptom reduction and all-cause discontinuation ("acceptability"). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co-primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta-analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention-deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive-compulsive disorder; CBT in post-traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence-based information for clinical decision making.

Background: ECHELON-2 (NCT01777152), a phase 3, randomised, double-blind, double-dummy, placebo-controlled, active-comparator, multicentre study, established the superiority of frontline brentuximab vedotin + cyclophosphamide, doxorubicin, and prednisone (A+CHP) vs cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCLs) (Horwitz, Lancet 2019). Both risk of progression-free survival (PFS) per blinded independent central review (primary endpoint) and overall survival (OS) events favoured A+CHP over CHOP at the primary analysis. A+CHP was the first treatment regimen to increase OS compared with CHOP in this population.
Aim(s): We report the 5-year data from ECHELON-2, including PFS per investigator (INV) data and the following key secondary endpoints: OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR) in re-treated pts.
Method(s): Adults with untreated CD30-positive PTCL (targeting 75% +/- 5% with sALCL) were randomized 1:1 to receive 6-8 cycles of A+CHP or CHOP. Pts were stratified by histological subtype and international prognostic index (IPI) score. Brentuximab vedotin-based subsequent therapies were allowed.
Result(s): Of 452 pts enrolled, the majority had sALCL (n=316 [70%]; 218 [48%] anaplastic lymphoma kinase [ALK]-negative, and 98 pts [22%] ALK-positive) and had advanced disease (27% Stage III, 53% Stage IV; 78% IPI >=2). At data cutoff, median follow-up was 47.6 months for PFS and 66.8 months for OS. A+CHP was favoured over CHOP with a hazard ratio (HR) for PFS per INV of 0.70 (95% confidence interval [CI]: 0.53, 0.91; p=0.0077) and OS HR of 0.72 (95% CI: 0.53, 0.99; p=0.0424). Median PFS was 62.3 months (95% CI: 42.0, not evaluable) for A+CHP, and 23.8 months (95% CI: 13.6, 60.8) for CHOP. Estimated 5-year PFS was 51.4% (95% CI: 42.8, 59.4) and 43.0% (95% CI: 35.8, 50.0) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. Estimated 5-year OS was 70.1% (95% CI: 63.3, 75.9) for A+CHP vs 61.0% (95% CI: 54.0, 67.3) for CHOP. PFS in prespecified subgroups and overall PFS were generally consistent (Figure). The HR for PFS (0.55 [95% CI: 0.39, 0.79]) also favoured A+CHP over CHOP in pts with sALCL, with an estimated 5-year PFS of 60.6% (95% CI: 49.5, 69.9) for the A+CHP arm vs 48.4% (95% CI: 39.6, 56.7) for the CHOP arm. Subsequent systemic therapy with brentuximab vedotin was administered to a total of 29 pts (13%) in the A+CHP arm (sALCL [n=19]; PTCL not otherwise specified [n=5], angioimmunoblastic T-cell lymphoma [n=5]) and 54 pts (24%) in the CHOP arm. Median time to retreatment for pts in the A+CHP arm was 15.0 months (range, 3-64); 17 pts (ORR: 59%) had CR (n=11) or partial remission (n=6) after retreatment with brentuximab vedotin monotherapy (n=25) or a brentuximab vedotin-containing regimen (n=4). Of the treatment-emergent peripheral neuropathy (PN) in the A+CHP (n=117) and CHOP arms (n=124), 72% in the A+CHP arm and 78% in the CHOP arm had resolved or improved. In pts with ongoing events at last follow-up (A+CHP [n=47] vs CHOP [n=42]) PN was grade 1, 2 and 3 in 70% vs 71%, 28% vs 26% and 2% vs 2%, respectively. Summary/Conclusion: After 5 years' follow-up, frontline A+CHP continued to provide clinically meaningful improvements in PFS and OS vs CHOP, including sustained remission in 59% of re-treated pts with sALCL, as well as a manageable safety profile, including continued resolution or improvement of PN

BACKGROUND:Adults with bipolar disorder (BD) often experience neurocognitive impairment that negatively impacts functioning and quality of life. Previous trials have found that dopamine agonist agents improve cognition in healthy volunteers and that adults with BD who have stable mood and mild cognitive deficits may also benefit. We hypothesized that pramipexole, a dopamine agonist, would improve neurocognitive function in patients with BD. METHODS:We recruited 60 adults (aged 18-65 years) with a diagnosis of BD I or II for an 8-week, double-blind, placebo-controlled trial (NCT02397837). All had stable mood and clinically significant neurocognitive impairment at baseline. Participants were randomized to receive pramipexole (n = 31) or a placebo (n = 29), dose was initiated at 0.125 mg 2 times a day and increased to a target of 4.5 mg/d. RESULTS:At trial end, the primary outcome, MATRICS Consensus Cognitive Battery composite score, had not improved more in the pramipexole group (mean [SD] = 1.15 [5.4]) than in the placebo group (mean [SD] = 4.12 [5.2], Cohen's d = 0.56, P = 0.049), and mixed models, controlling for symptoms, showed no association between treatment group and MATRICS Consensus Cognitive Battery scores. No serious adverse events were reported. CONCLUSIONS:These results suggest that pramipexole is not an efficacious cognitive enhancement agent in BD, even in a sample enriched for characteristics that were associated with a beneficial response in prior work. There are distinct cognitive subgroups among adults with BD and may be related differences in neurobiology that affect response to pramipexole. Additional research to better understand the onset and nature of the cognitive deficits in people with BD will be an important step toward a more personalized approach to treatment.

We consider a single-index regression model, uniquely constrained to estimate interactions between a set of pretreatment covariates and a treatment variable on their effects on a response variable, in the context of analyzing data from randomized clinical trials. We represent interaction effect terms of the model through a set of treatment-specific flexible link functions on a linear combination of the covariates (a single index), subject to the constraint that the expected value given the covariates equals zero, while leaving the main effects of the covariates unspecified. We show that the proposed semiparametric estimator is consistent for the interaction term of the model, and that the efficiency of the estimator can be improved with an augmentation procedure. The proposed single-index regression provides a flexible and interpretable modeling approach to optimizing individualized treatment rules based on patients' data measured at baseline, as illustrated by simulation examples and an application to data from a depression clinical trial. This article is protected by copyright. All rights reserved.

Functional abdominal pain (FAP) is one of the most common childhood medical complaints, associated with significant distress and impairment. Little is known about how children understand their pain. Do they attribute it to personal weakness? Do they perceive pain as having global impact, affecting a variety of activities? How do they cope with pain? We explored the pain beliefs of 5- to 9-year-old children with FAP using a novel Teddy Bear Interview task in which children answered questions about a Teddy bear's pain. Responses were analyzed quantitatively and qualitatively. Results indicate that the majority of young children with FAP are optimistic about pain outcomes. Children generated many types of coping strategies for Teddy's pain and adjusted their calibration of Teddy's pain tolerance dependent on the activity being performed. Early warning signs also emerged: a subset of children were pessimistic about Teddy's pain, and several children identified coping strategies that, while developmentally appropriate, could lead to excessive help seeking if not intervened upon (e.g., physician consultation and shot). The Teddy Bear Interview allows children to externalize their pain, making it a useful tool to access cognitive pain constructs in younger children. Thus, these findings highlight the importance of early intervention for childhood FAP.

Alcohol consumption is mediated by several important neuromodulatory systems, including the endocannabinoid and neuropeptide Y (NPY) systems in the limbic brain circuitry. However, molecular mechanisms through which cannabinoid-1 (CB1) receptors regulate alcohol consumption are still unclear. Here, we investigated the role of the CB1 receptor-mediated downstream regulation of NPY via epigenetic mechanisms in the amygdala. Alcohol drinking behavior was measured in adult male C57BL/6J mice treated with a CB1 receptor neutral antagonist AM4113 using a two-bottle choice paradigm while anxiety-like behavior was assessed in the light-dark box (LDB) test. The CB1 receptor-mediated changes in the protein levels of phosphorylated cAMP-responsive element binding protein (pCREB), CREB binding protein (CBP), H3K9ac, H3K14ac and NPY, and the mRNA levels of Creb1, Cbp, and Npy were measured in amygdaloid brain structures. Npy-specific changes in the levels of acetylated histone (H3K9/14ac) and CBP in the amygdala were also measured. We found that the pharmacological blockade of CB1 receptors with AM4113 reduced alcohol consumption and, in an ethanol-naïve cohort, reduced anxiety-like behavior in the LDB. Treatment with AM4113 also increased the mRNA levels of Creb1 and Cbp in the amygdala as well as the protein levels of pCREB, CBP, H3K9ac and H3K14ac in the central and medial nucleus of amygdala, but not in the basolateral amygdala. Additionally, AM4113 treatment increased occupancy of CBP and H3K9/14ac at the Npy gene promoter, leading to an increase in both mRNA and protein levels of NPY in the amygdala. These novel findings suggest that CB1 receptor-mediated CREB signaling plays an important role in the modulation of NPY function through an epigenetic mechanism and further support the potential use of CB1 receptor neutral antagonists for the treatment of alcohol use disorder.

Within the autistic spectrum, there is remarkable variability in the etiology, presentation, and treatment response. This prospective study was designed to identify, through cluster analysis, subgroups of individuals with ASD without intellectual disability (ID) based on the severity of the core symptoms in childhood. The secondary aim was to explore whether these subgroups and a group with typical development (TD) differ in cognitive, adaptive, and social aspects measured in adolescence. The sample at baseline was comprised of 52 children with ASD without ID and 37 children with TD, aged 7-11. Among the ASD group, three clusters were identified. Cluster 1 (40%), 'high severity', presented high symptom severity on the DSM-5 criteria and the Social Communication Questionnaire. Cluster 2 (34%) showed 'moderate severity' on most of the scores. Cluster 3 (25%) corresponded to 'low severity', showing moderate social impairment and low restrictive, repetitive patterns of behavior, interests and activities. At 5-year follow-up, 45 adolescents with ASD without ID and 27 adolescents with TD were assessed. All clusters had significantly more difficulties in EF, ToM, socialization and adaptive behavior compared to TD. Social and adaptive trajectories between the ASD subgroups were relatively different; Cluster 3 showed poorer socialization and daily living skills than the other two subgroups. These findings highlight the importance of fully assessing social, cognitive, and adaptive profiles to develop care plans tailored to specific needs.