Drug overdose risk with benzodiazepine treatment in young adults: Comparative analysis in privately and publicly insured individuals.

BACKGROUND AND AIMS: Benzodiazepines (BZDs) carry a risk for drug overdose and are prescribed alone or simultaneously with selective-serotonin reuptake inhibitors (SSRIs) for the treatment of anxiety and depression in young adults. We aimed to measure risks of drug overdose following BZD treatment initiation, and simultaneous BZD and SSRI initiation, compared with SSRI treatment alone in young adults with depression or anxiety. DESIGN, SETTING, PARTICIPANTS: The cohort study used administrative databases covering privately (MarketScan, 1/1/2009-12/31/2018) and publicly (Medicaid, 1/1/2015-12/31/2016) insured young adults (18-29 years) in the United States. Those with depression or anxiety diagnoses newly initiating BZD or SSRI treatment (without BZD or SSRI prescriptions in prior year) were included. Simultaneous "BZD + SSRI" initiation was defined as starting BZD and SSRI treatment on the same day. The cohorts included 604 664 privately insured young adults (BZD = 22%, BZD + SSRI = 10%, SSRI = 68%) and 110 493 publicly insured young adults (BZD = 23%, BZD + SSRI = 5%, SSRI = 72%). MEASUREMENTS: Incident medically treated drug overdose events were identified from emergency department and inpatient encounters (ICD poisoning codes) within 6 months of treatment initiation. Crude and propensity-score adjusted cumulative incidence and hazard ratios (HR) were estimated. Sub-analyses evaluated drug overdose intent. FINDINGS: Adjusted HRs of drug overdose for BZD vs. SSRI treatment was 1.36 (95% confidence interval [CI]:1.23-1.51) in privately and 1.59 (95%CI:1.37-1.83) in publicly insured young adults. The adjusted HRs of drug overdose for BZD + SSRI treatment vs. SSRI treatment were 1.99 (95%CI:1.77-2.25) in privately and 1.98 (95%CI:1.47-2.68) in publicly insured young adults. CONCLUSIONS: Among young adults in the United States, initiating benzodiazepine treatment for anxiety and depression, alone or simultaneously with selective-serotonin reuptake inhibitors (SSRI), appears to have an increased risk of medically treated drug overdose compared with SSRI treatment alone. These associations were observed in publicly and privately insured individuals.

Subcortical shape in pediatric and adult obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) implicates alterations in cortico-striato-thalamo-cortical and fronto-limbic circuits. Building on prior structural findings, this is the largest study to date examining subcortical surface morphometry in OCD. METHODS: Structural magnetic resonance imaging data were collected from 200 participants across development (5-55 years): 28 youth and 75 adults with OCD and 27 psychiatrically healthy youth and 70 adults. General linear models were used to assess group differences and group-by-age interactions on subcortical shape (FSL FIRST). RESULTS: Compared to healthy participants, those with OCD exhibited surface expansions on the right nucleus accumbens and inward left amygdala deformations, which were associated with greater OCD symptom severity ([Children's] Yale-Brown Obsessive-Compulsive Scale). Group-by-age interactions indicated that accumbens group differences were driven by younger participants and that right pallidum shape was associated inversely with age in healthy participants, but not in participants with OCD. No differences in the shape of other subcortical regions or in volumes (FreeSurfer) were detected in supplementary analyses. CONCLUSIONS: This study is the largest to date examining subcortical shape in OCD and the first to do so across the developmental spectrum. NAcc and amygdala shape deformation builds on extant neuroimaging findings and suggests subtle, subregional alterations beyond volumetric findings. Results shed light on morphometric alterations in OCD, informing current pathophysiological models.

Simultaneous Benzodiazepine and SSRI Initiation in Young People With Anxiety Disorders.

Objective: There are potential risks and benefits of combining benzodiazepine (BZD) and selective serotonin reuptake inhibitor (SSRI) therapy at anxiety disorder treatment onset. We investigated how often adolescents and young adults with anxiety disorders simultaneously initiate BZD treatment with SSRI treatment and examined whether SSRI treatment duration varies by simultaneous BZD initiation.Methods: In a United States commercial claims database (January 2008-December 2016), we identified adolescents (10-17 years) and young adults (18-24 years) with ICD-9-CM/ICD-10-CM anxiety disorder diagnoses initiating SSRI treatment, without past-year SSRI and BZD treatment. We defined simultaneous initiation as filling a new BZD prescription on the date of SSRI initiation. We estimated time to SSRI treatment discontinuation and used stabilized inverse probability of treatment weighting for adjusted estimates.Results: The study included 94,399 adolescents and 130,971 young adults initiating SSRI treatment with an anxiety disorder. Four percent of adolescents and 17% of young adults simultaneously initiated BZD treatment, varying by age, anxiety disorder, comorbidities, health care utilization, and provider type. Simultaneous BZD initiation among SSRI initiators declined from 2008 to 2016. SSRI treatment duration was similar in initiators of simultaneous therapy vs SSRI monotherapy: ≥ 6 months in adolescents (55% vs 56%, respectively) and in young adults (39% vs 40%). Nine percent of simultaneous initiators continued BZDs for ≥ 6 months.Conclusions: Simultaneous initiation of BZD and SSRI treatment is relatively common in young adults with anxiety disorders and was not associated with longer SSRI persistence. Given risks of BZD treatment, potential benefits and risks of adding a BZD at SSRI treatment initiation must be carefully weighed.

Machine learning approach to measurement of criticism: The core dimension of expressed emotion.

Expressed emotion (EE), a measure of the family's emotional climate, is a fundamental measure in caregiving research. A core dimension of EE is the level of criticism expressed by the caregiver to the care recipient, with a high level of criticism a marker of significant distress in the household. The Five-Minute Speech Sample (FMSS), the most commonly used brief measure of EE, requires time-consuming manual processing and scoring by a highly trained expert. In this study, we used natural language processing and supervised machine learning techniques to develop a fully automated framework to evaluate caregiver criticism level based on the verbatim transcript of the FMSS. The success of the machine learning algorithm was established by demonstrating that the classification of maternal caregivers as high versus low EE was consistent with the classification of these 298 maternal caregivers of adult children with schizophrenia using standard manual coding procedures, with area under the receiver operating characteristic curve (AUROC) of 0.76. Evidence of construct validity was established by demonstrating that maternal caregivers of adults with schizophrenia, who were classified as having a high level of criticism had higher levels of caregiver burden, reported that their child had more psychiatric symptoms and behaviors and perceived that their child had greater control over these symptoms and behaviors. Additionally, maternal caregivers who had high levels of criticism reported having a poorer quality of relationship with their child with schizophrenia than maternal caregivers low on criticism. Rapid measurement of criticism facilitates the incorporation of this dimension into research across a broad range of caregiving contexts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Altered fronto-amygdalar functional connectivity predicts response to cognitive behavioral therapy in pediatric obsessive-compulsive disorder.

BACKGROUND: Based on findings from adults with obsessive-compulsive disorder (OCD), this study examined alterations in resting-state functional connectivity (rs-fc) between the basolateral amygdala (BLA) and the ventromedial prefrontal cortex (vmPFC) in children and adolescents with OCD. We also assessed whether such BLA-vmPFC connectivity changed with or predicted response to exposure and response prevention (E/RP), the first-line treatment for pediatric OCD, given the involvement of these regions in fear processing, regulation, and extinction learning-a probable mechanism of action of E/RP. METHODS: Resting state functional magnetic resonance imaging scans were acquired from 25 unmedicated, treatment-naïve pediatric patients with OCD (12.8 ± 2.9 years) and 23 age- and sex-matched healthy controls (HCs; 11.0 ± 3.3 years). Patients completed a 12-16-week E/RP intervention for OCD. Participants were rescanned after the 12-16-week period. ANCOVAs tested group differences in baseline rs-fc. Cross-lagged panel models examined relationships between BLA-vmPFC rs-fc and OCD symptoms pre- and posttreatment. All tests were adjusted for participants' age, sex, and head motion. RESULTS: Right BLA-vmPFC rs-fc was significantly reduced (more negative) in patients with OCD relative to HCs at baseline, and increased following treatment. In patients, more positive (less negative) right BLA-vmPFC rs-fc pretreatment predicted greater OCD symptoms reduction posttreatment. Changes in BLA-vmPFC rs-fc was unassociated with change in OCD symptoms pre- to posttreatment. CONCLUSIONS: These results provide further evidence of the BLA-vmPFC pathway as a potential target for novel treatments or prevention strategies aimed at facilitating adaptive learning and fear extinction in children with OCD or subclinical OCD symptoms.

Specialty knowledge and competency standards for pharmacotherapy for pediatric obsessive-compulsive disorder.

Evidence based treatments for pediatric Obsessive-Compulsive Disorder (OCD) are delivered with varying levels of expertise. This paper is part of the phase two series by the International OCD Accreditation Task Force (ATF) to advance a standardized high level of care globally. This paper presents specific knowledge and competencies recommended for specialized practice for pediatric psychopharmacologists working with OCD, developed by an international group of clinicians with extensive expertise in assessment and treatment of OCD. Tabulated knowledge and competency standards are operationalized as clinician abilities with specification of evidence for each standard. The distinction between current practice guidelines and ATF standards is discussed. Drug treatment has a solid evidence base. However, it should not be applied isolated, but informed by broad competence in general child and adolescent psychiatry and pediatrics. Other treatment relevant areas such as specialty CBT, family functioning, developmental issues, and neurobiology require consideration. Drug treatment includes several phases with varying degrees of evidence: Starting up medication, titration to maximum tolerated dose, maintenance, termination, and relapse prevention. In complex cases, pharmacotherapy with weak evidence may be needed to target symptoms and/or co-morbidity. The ATF knowledge and competency standards presented will be reviewed and updated commensurate with research.

Correction: Altered network connectivity predicts response to cognitive-behavioral therapy in pediatric obsessive-compulsive disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structural neural markers of response to cognitive behavioral therapy in pediatric obsessive-compulsive disorder.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective, first-line treatment for pediatric obsessive-compulsive disorder (OCD). While neural predictors of treatment outcomes have been identified in adults with OCD, robust predictors are lacking for pediatric patients. Herein, we sought to identify brain structural markers of CBT response in youth with OCD. METHODS: Twenty-eight children/adolescents with OCD and 27 matched healthy participants (7- to 18-year-olds, M = 11.71 years, SD = 3.29) completed high-resolution structural and diffusion MRI (all unmedicated at time of scanning). Patients with OCD then completed 12-16 sessions of CBT. Subcortical volume and cortical thickness were estimated using FreeSurfer. Structural connectivity (streamline counts) was estimated using MRtrix. RESULTS: Thinner cortex in nine frontoparietal regions significantly predicted improvement in Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores (all ts > 3.4, FDR-corrected ps < .05). These included middle and superior frontal, angular, lingual, precentral, superior temporal, and supramarginal gyri (SMG). Vertex-wise analyses confirmed a significant left SMG cluster, showing large effect size (Cohen's d = 1.42) with 72.22% specificity and 90.00% sensitivity in predicting CBT response. Ten structural connections between cingulo-opercular regions exhibited fewer streamline counts in OCD (all ts > 3.12, Cohen's ds > 0.92) compared with healthy participants. These connections predicted post-treatment CY-BOCS scores, beyond pretreatment severity and demographics, though not above and beyond cortical thickness. CONCLUSIONS: The current study identified group differences in structural connectivity (reduced among cingulo-opercular regions) and cortical thickness predictors of CBT response (thinner frontoparietal cortices) in unmedicated children/adolescents with OCD. These data suggest, for the first time, that cortical and white matter features of task control circuits may be useful in identifying which pediatric patients respond best to individual CBT.

Altered network connectivity predicts response to cognitive-behavioral therapy in pediatric obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is commonly associated with alterations in cortico-striato-thalamo-cortical brain networks. Yet, recent investigations of large-scale brain networks suggest that more diffuse alterations in brain connectivity may underlie its pathophysiology. Few studies have assessed functional connectivity within or between networks across the whole brain in pediatric OCD or how patterns of connectivity associate with treatment response. Resting-state functional magnetic resonance imaging scans were acquired from 25 unmedicated, treatment-naive children and adolescents with OCD (12.8 ± 2.9 years) and 23 matched healthy control (HC) participants (11.0 ± 3.3 years) before participants with OCD completed a course of cognitive-behavioral therapy (CBT). Participants were re-scanned after 12-16 weeks. Whole-brain connectomic analyses were conducted to assess baseline group differences and group-by-time interactions, corrected for multiple comparisons. Relationships between functional connectivity and OCD symptoms pre- and post-CBT were examined using longitudinal cross-lagged panel modeling. Reduced connectivity in OCD relative to HC participants was detected between default mode and task-positive network regions. Greater (less altered) connectivity between left angular gyrus and left frontal pole predicted better response to CBT in the OCD group. Altered connectivity between task-positive and task-negative networks in pediatric OCD may contribute to the impaired control over intrusive thoughts early in the illness. This is the first study to show that altered connectivity between large-scale network regions may predict response to CBT in pediatric OCD, highlighting the clinical relevance of these networks as potential circuit-based targets for the development of novel treatments.

The Effects of Youth Anxiety Treatment on School Impairment: Differential Outcomes Across CBT, Sertraline, and their Combination.

Youth anxiety disorders are highly prevalent and are associated with considerable school impairment. Despite the identification of well-supported strategies for treating youth anxiety, research has yet to evaluate the differential effects of these treatments on anxiety-related school impairment. The present study leveraged data from the Child/Adolescent Anxiety Multimodal Study to examine differential treatment effects of CBT, sertraline, and their combination (COMB), relative to placebo (PBO), on anxiety-related school impairment among youth (N = 488). Latent growth modeling revealed that all three active treatments demonstrated superiority over PBO in reducing anxiety-related school impairment over time, with COMB showing the most robust effects. According to parent report, medication strategies may have stronger effects on anxiety-related school impairment among males than among females. Results were discrepant across parents and youth. Findings are discussed in terms of clinical implications for anxious youth and the need for continued research to examine treatment effects on anxiety-related school impairment.

Primary Care: Meeting the Mental Health Care Needs of Adolescents With Depression.

There is considerable evidence demonstrating the negative impact adolescent depression has on youth outcomes, such as poor school performance, social isolation, comorbid substance abuse, lack of employment, and, most concerning, the development of suicidal behaviors.1 Currently, the health system cannot meet the needs of youths with depression due to lack of access, shortage of trained clinicians, and inability to consistently deliver evidence-based care, especially in low-resource communities.2 To address this problem, we are turning to other health practitioners, specifically our primary care colleagues, to help provide effective care for adolescent depression and other mental health conditions.

Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

The Interplay of Familial and Individual Risk in Predicting Clinical Improvements in Pediatric Anxiety Disorders.

Bioecological models of developmental psychopathology underscore the role of familial experiences of adversity and children's individual-level characteristics in heightening risk for pediatric anxiety through direct, combined, and interactive effects. To date, much of the existing research dedicated to pediatric anxiety disorders has largely been examined in bioecological models of diathesis-stress using community samples. This study extends our understanding of children's differential responsiveness to familial adversity by examining the diathesis-stress interaction of cumulative risk and children's individual-level vulnerabilities (negative affectivity and coping efficacy) within a clinic-referred treatment study for pediatric anxiety disorders. A cumulative risk index assessing exposure to familial adversity (e.g., socioeconomic status [SES], parent psychiatric illness) and self-reported measures of children's negative affectivity and coping efficacy were each measured at the intake of a randomized controlled clinical trial for the treatment of pediatric anxiety disorders (N = 488; 7-17 years of age). Trajectories of interviewer-rated anxiety symptoms were assessed across 12 weeks of treatment at baseline, 4 weeks, 8 weeks, and 12 weeks. Consistent with models of temperamental risk for mental health problems, negative affectivity predicted higher anxiety symptoms at intake. A significant diathesis-stress interaction between cumulative risk and coping efficacy emerged, as high risk and perceptions of lower coping efficacy attenuated declines in anxiety across 12 weeks. These patterns did not differ across treatment conditions. The results indicate that for youth experiencing high levels of stress, additional treatment efforts targeting familial stressors and coping efficacy may be important in maximizing treatment outcomes.

Stepped Care Interpersonal Psychotherapy Treatment for Depressed Adolescents: A Pilot Study in Pediatric Clinics.

Adolescents with depression are at risk for negative long-term consequences and recurrence of depression. Many do not receive nor access treatment, especially Latino youth. New treatment approaches are needed. This study examined the feasibility and acceptability of a stepped collaborative care treatment model (SCIPT-A) for adolescents with depression utilizing interpersonal psychotherapy for adolescents (IPT-A) and antidepressant medication (if needed) compared to Enhanced Treatment as Usual (E-TAU) in urban pediatric primary care clinics serving primarily Latino youth. Results suggest the SCIPT-A model is feasible, acceptable and potentially beneficial for urban Latino adolescents. Clinicians delivered the SCIPT-A model with fidelity using supervision successfully implemented in a community setting.

Treating Pediatric Anxiety: Initial Use of SSRIs and Other Antianxiety Prescription Medications.

OBJECTIVE: Multiple pharmacotherapies for treating anxiety disorders exist, including selective serotonin reuptake inhibitors (SSRIs), the recommended first-line pharmacotherapy for pediatric anxiety. We sought to describe initial antianxiety medication use in children and estimate how long antianxiety medications were continued. METHODS: In a large commercial claims database, we identified children (3-17 years) initiating prescription antianxiety medication from 2004 to 2014 with a recent anxiety diagnosis (ICD-9-CM = 293.84, 300.0x, 300.2x, 300.3x, 309.21, 309.81, 313.23). We estimated the proportion of children initiating each medication class across the study period and used multivariable regression to evaluate factors associated with initiation with an SSRI. We evaluated treatment length for each initial medication class. RESULTS: Of 84,500 children initiating antianxiety medication, 70% initiated with an SSRI (63% [95% CI, 62%-63%] SSRI alone, 7% [95% CI, 7%-7%] SSRI + another antianxiety medication). Non-SSRI medications initiated included benzodiazepines (8%), non-SSRI antidepressants (7%), hydroxyzine (4%), and atypical antipsychotics (3%). Anxiety disorder, age, provider type, and comorbid diagnoses were associated with initial medication class. The proportion of children refilling their initial medication ranged from 19% (95% CI, 18%-20%) of hydroxyzine initiators and 25% (95% CI, 24%-26%) of benzodiazepine initiators to 81% (95% CI, 80%-81%) of SSRI initiators. Over half (55%, 95% CI, 55%-56%) of SSRI initiators continued SSRI treatment for 6 months. CONCLUSIONS: SSRIs are the most commonly used first-line medication for pediatric anxiety disorders, with about half of SSRI initiators continuing treatment for 6 months. Still, a third began therapy on a non-SSRI medication, for which there is limited evidence of effectiveness for pediatric anxiety, and a notable proportion of children initiated with 2 antianxiety medication classes.

Secondary Outcomes From the Child/Adolescent Anxiety Multimodal Study: Implications for Clinical Practice.

BACKGROUND: Controlled evaluations comparing medication, cognitive-behavioral therapy (CBT), and their combination in the treatment of youth anxiety have predominantly focused on global ratings by independent evaluators. Such ratings are resource-intensive, may be of limited generalizability, and do not directly inform our understanding of treatment responses from the perspective of treated families. We examined outcomes from the perspective of treated youth and parents in the Child/Adolescent Anxiety Multimodal Study (CAMS). METHODS: Participants (N=488; ages 7-17 years) who had a primary diagnosis of separation, social, and/or generalized anxiety disorder were randomly assigned to a treatment condition in the CAMS trial. Linear mixed-effects and ANCOVA models examined parent- and youth-reported anxiety symptoms, impact of anxiety, broader internalizing and externalizing psychopathology, depressive symptoms, and family burden throughout the 12-week acute treatment phase and 6-month follow-up. RESULTS: At week 12, combination treatment showed superiority over placebo, sertraline, and CBT with regard to parent-reported youth anxiety symptoms, and sertraline and CBT as monotherapies showed superiority over placebo with regard to parent-reported youth anxiety. Combination therapy and sertraline also showed week 12 superiority over placebo with regard to parent-reported internalizing psychopathology, and superiority over placebo and CBT with regard to parent-reported impact of anxiety, family burden, and youth depressive symptoms. By week 36, parent reports of many youth outcomes were comparable across active conditions. Youth measures tracked parent measures on many outcomes. CONCLUSIONS: Findings were drawn on brief, readily available questionnaires that in conjunction with clinician measures can inform patient-centered care and collaborative decision-making.Trial Registry Name: Child and Adolescent Anxiety Disorders (CAMS)Registry identification number: NCT00052078Registry URL: https://www.clinicaltrials.gov/ct2/show/NCT00052078.

Placebo Response in Pediatric Anxiety Disorders: Results from the Child/Adolescent Anxiety Multimodal Study.

OBJECTIVES: The aim of this study is to identify predictors of pill placebo response and to characterize the temporal course of pill placebo response in anxious youth. METHODS: Data from placebo-treated patients (N = 76) in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multisite, randomized controlled trial that examined the efficacy of cognitive-behavioral therapy, sertraline, their combination, and placebo for the treatment of separation, generalized, and social anxiety disorders, were evaluated. Multiple linear regression models identified features associated with placebo response and models were confirmed with leave-one-out cross-validation. The likelihood of improvement in patients receiving pill placebo-over time-relative to improvement associated with active treatment was determined using probabilistic Bayesian analyses. RESULTS: Based on a categorical definition of response (Clinical Global Impressions-Improvement Scale score ≤2), nonresponders (n = 48), and pill placebo responders (n = 18) did not differ in age (p = 0.217), sex (p = 0.980), race (p = 0.743), or primary diagnosis (all ps > 0.659). In terms of change in anxiety symptoms, separation anxiety disorder and treatment expectation were associated with the degree of pill placebo response. Greater probability of placebo-related anxiety symptom improvement was observed early in the course of treatment (baseline to week 4, p < 0.0001). No significant change in the probability of placebo-related improvement was observed after week 4 (weeks 4-8, p = 0.07; weeks 8-12, p = 0.85), whereas the probability of improvement, in general, significantly increased week over week with active treatment. CONCLUSIONS: Pill placebo-related improvement occurs early in the course of treatment and both clinical factors and expectation predict this improvement. Additionally, probabilistic approaches may refine our understanding and prediction of pill placebo response.

Evidence for the Risks and Consequences of Adolescent Cannabis Exposure.

OBJECTIVE: This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. METHOD: A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were "adolescent" and "adult," and either "cannabis," "marijuana," "delta-9-tetra-hydrocannabinol," or "cannabinoid," which was then crossed with one or more of the following terms: "deficit," "impairment," "alteration," "long-term," "persistent," "development," "maturation," and "pubescent." RESULTS: The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. CONCLUSION: Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence.

Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial.

OBJECTIVE: This is a feasibility study evaluating the safety, tolerability, and potential anxiolytic efficacy of the α2 agonist guanfacine extended-release (GXR) in children and adolescents with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), or social phobia/social anxiety disorder. METHODS: Youth aged 6-17 years with a primary diagnosis of GAD, SAD, and/or social anxiety disorder were treated with flexibly dosed GXR (1-6 mg daily, n = 62) or placebo (n = 21) for 12 weeks. The primary aim of this study was to determine the safety and tolerability of GXR in youth with anxiety disorders, which involved the analysis of treatment-emergent adverse events (TEAEs), the emergence of suicidal ideation and behaviors, vital signs, and electrocardiographic/laboratory parameters. Exploratory efficacy measures included dimensional anxiety scales (Pediatric Anxiety Rating Scale [PARS] and Screen for Child Anxiety Related Emotional Disorders [SCARED]), as well as the Clinical Global Impression-Improvement (CGI-I) scale. As this was an exploratory study, no inferential statistical analyses were performed. RESULTS: GXR was safe and well tolerated. Treatment-related mean ± standard deviation changes in heart rate (GXR: 1.8 ± 12 beats per minute [bpm] decrease; placebo: 0.5 ± 11 bpm decrease), systolic blood pressure (GXR: 2.3 ± 11 mm Hg decrease; placebo: 1.7 ± 11 mm Hg decrease), or diastolic blood pressure (GXR: 1.3 ± 9 mm Hg decrease; placebo: 0.9 ± 7 mm Hg increase) were similar between treatment groups. TEAEs, including headache, somnolence/fatigue, abdominal pain, and dizziness, were consistent with the known safety profile of GXR. No differences were observed between treatment groups for PARS and SCARED scores, although at endpoint, a higher proportion of subjects receiving GXR versus placebo demonstrated CGI-I scores ≤2 (54.2% vs. 31.6%), as rated by the clinician investigator. CONCLUSIONS: GXR was well tolerated in pediatric subjects with GAD, SAD, and/or social anxiety disorder. ClinicalTrials.gov Identifier: NCT01470469.

Assessment and Treatment of Anxiety Among Children and Adolescents.

Among children and adolescents, anxiety disorders are common psychiatric disorders that confer risk of comorbid psychiatric disorders and social and academic impairment. This review focuses on the assessment and treatment of anxiety disorders among children and adolescents, with attention to separation anxiety disorder, social phobia disorder (social anxiety disorder), panic disorder, and generalized anxiety disorder. Comprehensive assessment of child and adolescent anxiety disorders benefits from a multimethod approach to evaluation and diagnosis, including semistructured interviews; child and informant questionnaires; collateral information from parents, teachers, pediatricians, and school psychologists; and behavioral observations. Because anxiety symptoms can include avoidance behaviors, somatic complaints, social difficulties, and sleep disturbances, consideration of a differential diagnosis is important. Among the available psychosocial interventions, cognitive-behavioral therapy (CBT) and exposure-based therapies have emerged as the most well-established treatment approaches for addressing anxiety disorders among children and adolescents. Pharmacologically, selective serotonin reuptake inhibitors (SSRIs) have been established to be safe and efficacious for the treatment of pediatric anxiety and are considered the medications of choice for this population. Research indicates that CBT plus SSRI medication is the most effective treatment of anxiety for youths ages seven to 17, compared with either CBT or medication alone. Medication monotherapy and CBT monotherapy have also been demonstrated to be effective treatments.