Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis.

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose-response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose-response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids.

Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested an impaired medial ganglionic eminence fate and a decreased differentiation of cholinergic and GABAergic interneurons. Transcriptome analyses revealed organoid mispatterning in TS, with a preference for dorsolateral at the expense of ventromedial fates. Our results point to altered expression of GLI transcription factors downstream of the Sonic Hedgehog signaling pathway with cilia disruption at the earliest stages of BG organoid differentiation as a potential mechanism for the BG mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.

Editorial: Developmental considerations in addressing the earlier age of severe eating disorder onset.

The deleterious impact of the COVID-19 pandemic on youth mental health has garnered much attention (Newlove-Delgado et al., 2023). It has been a topic of interest in both research and academic writing, as well as in the public press (e.g., Tanner, 2023). Disorders and mental health concerns of focus have been wide-ranging, with some of the most severe presentations, such as suicidality, highlighted (Asarnow and Chung, 2021). Eating disorders are among the most life-threatening and prominent mental health concerns that have been exacerbated by the pandemic, and our current models of youth mental health care cannot keep up. Given this context, our team read and reviewed the manuscript, 'Shifting age of child eating disorder hospitalizations during the Covid-19 pandemic' (Auger et al., 2023), eagerly. While the increasing severity of eating disorder presentations and increase in pediatric hospitalization has been an area of research (Asch et al., 2021), including at our own institution (Shum et al., 2022), the impact of age of onset, and the consequential impact on current systems of care, requires much greater attention.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.

Meta-Analysis: Efficacy and Tolerability of Vesicular Monoamine Transporter Type 2 Inhibitors in the Treatment of Tic Disorders.

Vesicular monoamine transporter type 2 (VMAT2) inhibitors may be an effective therapy for chronic tic disorders (CTD), including Tourette syndrome (TS), but there has not been a meta-analysis compiling available evidence from randomized controlled trials (RCTs). We performed a systematic review and meta-analysis to evaluate the efficacy, acceptability, and tolerability of VMAT2 inhibitors for CTD/TS. PubMed, CENTRAL, and Embase were searched for double-blinded RCTs of VMAT2 inhibitors versus placebo for the treatment of CTD/TS. Change in tic severity measured by the Yale Global Tic Severity Scale (efficacy) and rates of discontinuation attributed to adverse effects (tolerability) or all causes (acceptability) were extracted closest to 12 weeks. Mean difference (MD) and odds ratio (OR) were the effect size indexes for efficacy and acceptability/tolerability, respectively. Data were pooled through random-effects meta-analysis weighted by inverse variance. Five RCTs involving eight comparisons were included. Meta-analysis found a nonsignificant effect on efficacy (k = 8; N = 583; MD = -0.71; 95% confidence interval [CI], -1.93 to 0.50; P = 0.24), and there was certainty that the true effect is nonclinically meaningful (high quality of evidence). Meta-analysis found decreased tolerability (k = 7; N = 626; OR = 2.67; 95% CI, 1.21-5.92; P = 0.01) and decreased acceptability (k = 8; N = 626; OR = 1.90; 95% CI, 1.14-3.18; P = 0.01), although those comparisons were limited because of the relatively small number of events across trials. Meta-analyses did not support the efficacy of VMAT2 inhibitors in the short-term treatment of tic disorders and suggested no clinically meaningful effect of these agents on tic symptoms. © 2022 International Parkinson and Movement Disorder Society.

Editorial: Schools on the frontline of suicide prevention.

The world has experienced an unprecedented mental health crisis associated with the COVID-19 pandemic (Liu et al., 2020). After more than two years navigating the associated uncertainty and distress, the impact on youth mental health continues to be a pressing concern. Those in the mental health field, as well as the children and families plagued by its impact, are inundated with seeing firsthand the impact on youth's functioning. This includes increases in depression and suicide (Asarnow & Chung, 2021; Manzar et al., 2021), and having to navigate siloes in care and often even an inability when in crisis to access a continuum of services (Zhai, 2021). This has highlighted the significant issues with accessibility of mental health care and inequitable access to care for youth mental health both in the United States and globally. We continue to experience daily the impact of insufficient resources for youth behavioral health. For those in the field who prioritize the need for more robust intervention approaches, the child mental health crisis associated with the pandemic has highlighted the need for us to develop more novel and innovative interventions.

Parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

OBJECTIVES: Whether parental age, i.e., paternal or maternal, at childbirth is associated with the risk of bipolar disorder (BD) in offspring remains unclear. We conducted a meta-analysis of observational studies to address this gap. METHODS: PubMed, PsycINFO, Embase, and Web of Science were searched up to June 2021. Studies investigating the associations between parental age at childbirth (exposure) and the risk of BD in offspring (outcome) were eligible for inclusion in our study. Paternal and maternal age were examined separately. Odds ratio (OR) was used as the effect size index. Data were pooled through random-effects meta-analyses. RESULTS: Seven studies involving 3,183,539 participants and 23,253 individuals with BD were included in our meta-analyses. Meta-analyses indicated an increased risk of BD in the offspring of the older paternal age groups (35-44 years old [k = 5; OR = 1.09; 95% CI 1.05, 1.14; p < 0.0001] and ≥45 years old [k = 5; OR = 1.44; 95% CI 1.19, 1.14; p = 0.0001]) in comparison with the reference category (25-34 years old). Meta-analysis also indicated an increased risk of BD in the offspring of the older maternal age group (≥40 years old [k = 3; OR = 1.20; 95% CI 1.10, 1.31; p < 0.0001]) in comparison with the reference category (20-29 years old). CONCLUSIONS: Advanced paternal and maternal age were both associated with an increased risk of BD in offspring. Further studies are needed to investigate the mechanisms behind this association.

Pharmacological and somatic treatment effects on suicide in adults: A systematic review and meta-analysis.

BACKGROUND: Suicide is a public health crisis. We conducted a systematic review and meta-analysis of the effects of psychopharmacologic and somatic therapies on suicide risk. METHODS: A systematic search of MEDLINE for studies evaluating the effects of pharmacologic (excluding antidepressants) or somatic interventions on suicide risk was conducted. Studies were included if they used a comparison group, reported on suicide death, assessed a psychopharmacological or somatic intervention, and included adults. Study quality was assessed using the Newcastle-Ottawa scale. Fifty-seven studies were included from 2940 reviewed citations. RESULTS: In bipolar disorder, lithium was associated with a reduction in the odds of suicide compared to active controls (odds ratio [OR] = .58, p = .005; k = 12) and compared to placebo/no lithium (OR = .46, p = .009; k = 9). In mixed diagnostic samples, lithium was associated with a reduction in the odds of suicide compared to placebo/no lithium (OR = .27, p < .001; k = 12), but not compared to active controls (OR = .89, p = .468; k = 7). In psychotic disorders, clozapine was associated with a reduction in the odds of suicide (OR = .46, p = .007; k = 7). Associations between suicide death and electroconvulsive therapy (OR = .77, p = .053; k = 11), non-clozapine antipsychotics in bipolar disorder (OR = .73, p = .090; k = 6) and antipsychotics in psychotic disorders (OR = .39, p = .069; k = 6) were not significant. There was no consistent relationship between antiepileptic mood stabilizers and suicide. There were insufficient studies to meta-analyze associations of suicide risk with vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, or transcranial direct current stimulation. CONCLUSION: Lithium and clozapine have consistent data supporting protective effects against suicide in certain clinical contexts.

Editorial: Money cannot buy happiness - but can it prevent depression? A commentary on Su et al.

In this issue, we read with interest Research Review: Developmental origins of depression - a systematic review and meta-analysis (Su et al., 2021). Su et al. (2021) conducted a systematic review and meta-analysis examining prenatal, perinatal and postnatal exposures and their association with depression in offspring. Su et al. (2021) evaluated twenty-eight potential exposures and determined that 12 were associated with increased risk of depression in the offspring. These risk factors included low birth weight, premature birth, being small gestational age, maternal education, socioeconomic status, parental age, parental smoking, maternal stress, maternal anxiety and prenatal depression (Su et al., 2021). Strikingly, each of these developmental risk factors for depression in the offspring is known to be associated with poverty.

Commentary: Identifying individualized predictions of response in ADHD pharmacotherapy - a commentary on Rodrigues et al. (2020).

In this issue, Rodrigues et al. (2020) present a systematic review with meta-analyses that reports the efficacy of five treatments for children with attention-deficit hyperactivity disorder symptoms in the context of autism spectrum disorder - (a) methylphenidate; (b) atomoxetine; (c) guanfacine; (d) aripiprazole; and (e) risperidone. In this commentary, we highlight the contrast between the scarce evidence base of treatment for ADHD in the context of autism and other subpopulations, such as tic disorders and intellectual disability, and the extensive evidence base of treatment for ADHD in general. The commentary weighs about the conundrum clinicians face of whether to rely on the limited evidence base of treatment for ADHD in subpopulation, or to derive conclusions from the larger body of evidence of treatment for ADHD in general. The commentary also discusses potential avenues for future research to address this clinical problem.

A Phase-2 Pilot Study of a Therapeutic Combination of Δ9-Tetrahydracannabinol and Palmitoylethanolamide for Adults With Tourette's Syndrome.

OBJECTIVE: There are few effective pharmacological treatments for Tourette's syndrome. Many patients with Tourette's syndrome experience impairing tic symptoms despite use of available evidence-based treatments. The investigators conducted a small, uncontrolled trial to examine the safety, tolerability, and dosing of THX-110, a combination of Δ9-tetrahydracannabinol (Δ9-THC) and palmitoylethanolamide (PEA), in Tourette's syndrome. METHODS: A 12-week uncontrolled trial of THX-110 (maximum daily Δ9-THC dose, 10 mg, and a constant 800-mg dose of PEA) in 16 adults with Tourette's syndrome was conducted. The primary outcome was improvement on the Yale Global Tic Severity Scale (YGTSS) total tic score. Secondary outcomes included measures of comorbid conditions and the number of participants who elected to continue treatment in the 24-week extension phase. RESULTS: Tic symptoms significantly improved over time with THX-110 treatment. Improvement in tic symptoms was statistically significant within 1 week of starting treatment compared with baseline. THX-110 treatment led to an average improvement in tic symptoms of more than 20%, or a 7-point decrease in the YGTSS score. Twelve of the 16 participants elected to continue to the extension phase, and only two participants dropped out early. Side effects were common but were generally managed by decreasing Δ9-THC dosing, slowing the dosing titration, and shifting dosing to nighttime. CONCLUSIONS: Although the initial data from this trial in adults with refractory Tourette's syndrome are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of THX-110 treatment. The challenges raised by the difficulty in blinding trials due to the psychoactive properties of many cannabis-derived compounds need to be further appreciated in these trial designs.

Racial Implicit Associations in Psychiatric Diagnosis, Treatment, and Compliance Expectations.

OBJECTIVE: Racial and ethnic disparities are well documented in psychiatry, yet suboptimal understanding of underlying mechanisms of these disparities undermines diversity, inclusion, and education efforts. Prior research suggests that implicit associations can affect human behavior, which may ultimately influence healthcare disparities. This study investigated whether racial implicit associations exist among medical students and psychiatric physicians and whether race/ethnicity, training level, age, and gender predicted racial implicit associations. METHODS: Participants completed online demographic questions and 3 race Implicit Association Tests (IATs) related to psychiatric diagnosis (psychosis vs. mood disorders), patient compliance (compliance vs. non-compliance), and psychiatric medications (antipsychotics vs. antidepressants). Linear and logistic regression models were used to identify demographic predictors of racial implicit associations. RESULTS: The authors analyzed data from 294 medical students and psychiatric physicians. Participants were more likely to pair faces of Black individuals with words related to psychotic disorders (as opposed to mood disorders), non-compliance (as opposed to compliance), and antipsychotic medications (as opposed to antidepressant medications). Among participants, self-reported White race and higher level of training were the strongest predictors of associating faces of Black individuals with psychotic disorders, even after adjusting for participant's age. CONCLUSIONS: Racial implicit associations were measurable among medical students and psychiatric physicians. Future research should examine (1) the relationship between implicit associations and clinician behavior and (2) the ability of interventions to reduce racial implicit associations in mental healthcare.

Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control After Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial.

BACKGROUND: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. METHODS: Patients with a daytime ambulatory BP ≥135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of up to 2 antihypertensive medications, and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mm Hg, a standardized stepped-care antihypertensive treatment was recommended consisting of the sequential addition of amlodipine (5 mg/d), a standard dose of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide (12.5 mg/d), followed by the sequential uptitration of hydrochlorothiazide (25 mg/d) and amlodipine (10 mg/d). Outcomes included the 6-month (1) change in daytime ambulatory systolic BP adjusted for medications and baseline systolic BP, (2) medication burden, and (3) safety. RESULTS: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group (P=0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P=0.010 and 1.4±1.5 versus 2.0±1.8, P=0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 versus -15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mm Hg, 95% confidence interval, -7.9 to -0.6, P=0.024). There were no major adverse events in either group through 6 months. CONCLUSIONS: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02649426.

Annual Research Review: Defining and treating pediatric treatment-resistant depression.

BACKGROUND: Adolescent major depressive disorder (MDD) is a significant health problem, associated with substantial morbidity, cost, and mortality. Depression is a significant risk factor for suicide, which is now the second leading cause of death in young people. Up to twenty per cent of adolescents will experience MDD before adulthood, and while a substantial proportion will improve with standard-of-care treatments (psychotherapy and medication), roughly one third will not. METHODS: Here, we have reviewed the literature in order to discuss the concept of treatment-resistant depression (TRD) in adolescence, examine risk factors, diagnostic difficulties, and challenges in evaluating symptom improvement, and providing guidance on how to define adequate medication and psychotherapy treatment trials. RESULTS: We propose a staging model for adolescent TRD and review the treatment literature. The evidence base for first- and second-line treatments primarily derives from four large pediatric clinical trials (TADS, TORDIA, ADAPT, and IMPACT). After two medications and a trial of evidence-based psychotherapy have failed to alleviate depressive symptoms, the evidence becomes quite thin for subsequent treatments. Here, we review the evidence for the effectiveness of medication switches, medication augmentation, psychotherapy augmentation, and interventional treatments (i.e., transcranial magnetic stimulation, electroconvulsive therapy, and ketamine) for adolescent TRD. Comparisons are drawn to the adult TRD literature, and areas for future pediatric depression research are highlighted. CONCLUSIONS: As evidence is limited for treatments in this population, a careful consideration of the known risks and side effects of escalated treatments (e.g., mood stabilizers and atypical antipsychotics) is warranted and weighed against potential, but often untested, benefits.

Pharmacological and behavioral treatment for trichotillomania: An updated systematic review with meta-analysis.

BACKGROUND: Trichotillomania (TTM) is a difficult-to-treat psychiatric condition with no first-line medications approved by the Food and Drug Administration. Individuals with TTM often feel that clinicians know little about this disorder. Here, we present an updated meta-analysis of randomized controlled trials (RCTs) examining treatments for TTM. METHODS: Pubmed, PsychINFO, Embase, and CENTRAL were searched with the terms "Trichotillomania OR Hair Pulling Disorder" to identify randomized controlled clinical trials evaluating treatments for TTM. RESULTS: Twenty-four trials involving 26 comparisons and 857 participants were included in this meta-analysis. Behavioral therapy with habit-reversal training components (BT-HRT) demonstrated a large benefit compared to control conditions (standardized mean difference [SMD] [95% CI] = -1.22 [-1.71, -0.73], p < .0001) for improving TTM symptoms. Clomipramine (SMD [95% CI] = -0.71 [-1.38, -0.05], p = .036), N-acetylcysteine (SMD [95% CI] = -0.75 [-1.36, -0.13], p = .017) and olanzapine (SMD [95% CI] = -0.94 [-1.77, -0.12], p = .025) demonstrated significant benefits compared to placebo in RCTs. CONCLUSIONS: BT-HRT has demonstrated the largest treatment effects and has the strongest evidence base for reducing TTM symptoms. In contrast, several pharmacological agents have demonstrated efficacy in single randomized clinical trials that would benefit from replication. Additional trials are needed to identify other effective medications for TTM and determine the relative efficacy of available agents.

Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.

BACKGROUND: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications. METHODS: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426. FINDINGS: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group. INTERPRETATION: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications. FUNDING: ReCor Medical.

Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders.

BACKGROUND: We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability. METHODS: We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo-controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks. RESULTS: Meta-analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects. CONCLUSIONS: SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not.