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.

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.

The interictal mesial temporal lobe epilepsy network.

OBJECTIVE: Identification of patient-specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network. METHODS: Intracranial recordings from 10 medically refractory MTLE patients were analyzed. In each patient, hour-long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150-millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize the MTLE network at group level. RESULTS: We generated the first graph of connectivity across a cohort of MTLE patients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians. SIGNIFICANCE: Apart from identifying interictal measures that can model patient-specific epileptogenic networks, we also produce a group map of network connectivity from a cohort of MTLE patients.

Predicting students' noncompliance with a smoke-free university campus policy.

The adoption of university campus smoke-free and tobacco-free policies has risen dramatically, but research on effective implementation is scant. Significant challenges exist regarding policy implementation, particularly enforcement. This study examined college students' noncompliance with a recently implemented smoke-free campus policy at a public university. The sample included students who reported past-month smoking of tobacco or e-cigarettes in a 2013 web-based survey, 9 months after a smoke-free campus policy took effect. Ordinal logistic regression was used to examine predictors of students' having smoked on campus since the policy began (n = 1055). Predictor variables included past-month use of cigarettes, e-cigarettes, smokeless tobacco, and non-cigarette tobacco products, secondhand smoke (SHS) exposure, support for a smoke-free campus, tobacco-related social norms, use of strategies to deal with smoking urges, and other variables. In multivariate analysis, policy violation was positively associated with past-month use of cigarettes and non-cigarette combustible tobacco, SHS exposure on campus, living on campus, and use of nicotine gum/patches to handle urges. Violation was negatively associated with smoke-free campus support, age, estimates of student policy support and cigarette smoking, and self-reported absence of smoking urges. Results suggest that nicotine dependence may be an underlying influence on policy violation. Several recommendations are offered. First, upon policy adoption, campuses should ensure student smokers' access to cessation support and assistance with dealing with nicotine cravings. Second, campus information campaigns should focus particularly on younger students and those living on campus. Third, campuses should establish strong anti-tobacco norms, monitor SHS exposure, and communicate levels of students' policy support.

The distribution of cholinergic neurons and their co-localization with FMRFamide, in central and peripheral neurons of the spider Cupiennius salei.

The spider Cupiennius salei is a well-established model for investigating information processing in arthropod sensory systems. Immunohistochemistry has shown that several neurotransmitters exist in the C. salei nervous system, including GABA, glutamate, histamine, octopamine and FMRFamide, while electrophysiology has found functional roles for some of these transmitters. There is also evidence that acetylcholine (ACh) is present in some C. salei neurons but information about the distribution of cholinergic neurons in spider nervous systems is limited. Here, we identify C. salei genes that encode enzymes essential for cholinergic transmission: choline ACh transferase (ChAT) and vesicular ACh transporter (VAChT). We used in-situ hybridization with an mRNA probe for C. salei ChAT gene to locate somata of cholinergic neurons in the central nervous system and immunohistochemistry with antisera against ChAT and VAChT to locate these proteins in cholinergic neurons. All three markers labeled similar, mostly small neurons, plus a few mid-sized neurons, in most ganglia. In the subesophageal ganglia, labeled neurons are putative efferent, motor or interneurons but the largest motor and interneurons were unlabeled. Groups of anti-ChAT labeled small neurons also connect the optic neuropils in the spider protocerebrum. Differences in individual cell labeling intensities were common, suggesting a range of ACh expression levels. Double-labeling found a subpopulation of anti-VAChT-labeled central and mechanosensory neurons that were also immunoreactive to antiserum against FMRFamide-like peptides. Our findings suggest that ACh is an important neurotransmitter in the C. salei central and peripheral nervous systems.

Supportive of a smoke-free campus but opposed to a 100% tobacco-free campus: Identification of predictors among university students, faculty, and staff.

Many universities are adopting campus tobacco policies, but little research has explored factors influencing the choice between the policy options of smoke-free versus 100% tobacco-free. Students, faculty, and staff at a U.S. state university participated in a web-based survey in 2013, approximately one year after adoption of a smoke-free policy. Respondents who expressed support for the policy were included in an analysis to examine their opinions regarding a 100% tobacco-free policy. The samples included 4138 students and 1582 faculty/staff. Bivariate analyses and multivariate logistic regression were used to identify predictors of opposition to a tobacco-free campus. Independent variables included strength of support for a smoke-free campus, past-month tobacco use (cigarettes, smokeless tobacco, e-cigarettes, non-cigarette combustible tobacco products), campus exposure to secondhand smoke, perceptions of tobacco-related behaviors and norms, and demographics. Of these supporters of a smoke-free campus, 14.3% of students and 10.2% of faculty/staff were opposed to a tobacco-free campus. In the multivariate analyses, in both samples, smokeless tobacco use predicted opposition while smoke-free policy support and female gender predicted support. In addition, among students, current or former cigarette smoking and non-cigarette combustible tobacco use predicted opposition; international student status and secondhand smoke exposure predicted support. Among faculty/staff, age over 55 predicted support. Future research should examine why current and former smokers might oppose policies restricting non-combustible tobacco products, even when they support smoke-free policies. In policy planning, campus administrators should communicate actual tobacco usage levels. International students who do not use tobacco may be a source of policy support.

Meta-analysis: Risk of hyperhidrosis with second-generation antidepressants.

BACKGROUND: Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. METHODS: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. RESULTS: We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin-norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR) = 3.17, 95% CI: 2.63-3.82] and selective serotonin reuptake inhibitors (SSRI) (RR = 2.93, 95% CI: 2.46-3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR = 0.56, 95% CI: 0.12-2.53), bupropion (RR = 1.23, 95% CI: 0.57-2.67), and vortioxetine (RR = 1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. CONCLUSION: Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity.

The efficacy of benzodiazepines as acute anxiolytics in children: A meta-analysis.

OBJECTIVE: Current practice guidelines do not recommend benzodiazepines for acute management of anxiety disorders in pediatric patients. However, in procedural settings, benzodiazepines are commonly used to relieve acute preprocedural stress. This meta-analysis examines the efficacy and tolerability of benzodiazepines as short-term anxiolytics in children. METHOD: PubMed was searched for randomized controlled trials assessing the efficacy of benzodiazepines as short-term anxiolytics in pediatric patients. Twenty-one trials involving 1,416 participants were included. A fixed effects model was used to examine the standardized mean difference of improvement in anxiety levels compared to control conditions. In stratified subgroup and meta-regression, the effect of the specific agent, dose, timing, and setting of benzodiazepine treatment was examined. RESULTS: A significant benefit was seen for benzodiazepines compared to control (standardized mean difference = 0.71 [95% confidence interval, 0.60-0.82], k = 24, z = 12.7, P < .001). There was also funnel plot asymmetry in this meta-analysis, suggesting some evidence of publication bias. Moderator analyses found that when benzodiazepines were used in dental or nonoperating room procedures, they were more effective than when they were used in operating room procedures (test for subgroup differences Q2 = 6.34, P = .04). Tolerability analysis revealed there was no significant difference in the risk of developing irritability or behavioral changes between benzodiazepine and control groups. CONCLUSIONS: Benzodiazepines are effective and well-tolerated when used as short-term anxiolytics in procedural settings for pediatric patients. Further research is needed to determine whether benzodiazepines are effective in pediatric anxiety disorders.

A surface-based technique for mapping homotopic interhemispheric connectivity: Development, characterization, and clinical application.

The functional organization of the human brain consists of a high degree of connectivity between interhemispheric homologous regions. The degree of homotopic organization is known to vary across the cortex and homotopic connectivity is high in regions that share cross-hemisphere structural connections or are activated by common input streams (e.g., the visual system). Damage to one or both regions, as well as damage to the connections between homotopic regions, could disrupt this functional organization. Here were introduce and test a computationally efficient technique, surface-based homotopic interhermispheric connectivity (sHIC), that leverages surface-based registration and processing techniques in an attempt to improve the spatial specificity and accuracy of cortical interhemispheric connectivity estimated with resting state functional connectivity. This technique is shown to be reliable both within and across subjects. sHIC is also characterized in a dataset of nearly 1000 subjects. We confirm previous results showing increased interhemispheric connectivity in primary sensory regions, and reveal a novel rostro-caudal functionally defined network level pattern of sHIC across the brain. In addition, we demonstrate a structural-functional relationship between sHIC and atrophy of the corpus callosum in multiple sclerosis (r = 0.2979, p = 0.0461). sHIC presents as a sensitive and reliable measure of cortical homotopy that may prove useful as a biomarker in neurologic disease. Hum Brain Mapp 37:2849-2868, 2016. © 2016 Wiley Periodicals, Inc.

Predictors of support among students, faculty and staff for a smoke-free university campus.

OBJECTIVES: Students, faculty, and staff at a Pacific Northwest public university were surveyed one year after enactment of a smoke-free campus policy. Objectives were to assess levels of support for a smoke-free campus, ascertain exposure levels to outdoor tobacco smoke, and identify correlates of policy support. METHOD: A 2013 Web-based survey included 5691 students (response rate 26%) and 2051 faculty/staff (response rate 43%). Measures included support for a smoke-free campus, smoking status, exposure to secondhand smoke, and perceptions of levels of policy support and campus smoking. Logistic regression was used to examine predictors of support. RESULTS: Seventy-two percent of students and 77% of faculty/staff supported a smoke-free campus. Respondents reported limited exposure to smoke near building entrances, but exposure near campus boundaries was reported by majorities of students (77%) and faculty/staff (55%). Predictors of students' policy support included never-smoker status, perceived support by peers, perceived student smoking prevalence, campus smoke exposure, and female gender, among others. Predictors of faculty/staff support included never-smoker status, perceived policy support by students and peers, campus smoke exposure, female gender, and age. CONCLUSION: Students, faculty, and staff were strongly supportive of the existing smoke-free campus policy. However, the policy led to smoking activity shifting to the campus periphery.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis.

INTRODUCTION: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. METHODS: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. RESULTS: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. CONCLUSION: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Evaluating the impact of naloxone dispensation at public health vending machines in Clark County, Nevada.

INTRODUCTION: Implementing public health vending machines (PHVMs) is an evidence-based strategy for mitigating substance use-associated morbidity and mortality via the dispensation of essential supplies to people who use drugs, including overdose prevention resources. PHVMs have been implemented throughout the world; however, their implementation in the United States (US) is a recent phenomenon. In 2017, Trac-B Exchange (a syringe services program in Clark County, Nevada) installed three PHVMs. In 2019, naloxone dispensation was launched at PHVMs in Clark County. The purpose of this research is to examine the extent to which naloxone dispensation at PHVMs was associated with changes in opioid-involved overdose fatalities. METHODS: Monthly counts of opioid-involved overdose fatalities among Clark County residents that occurred from January 2015 to December 2020 were used to build an autoregressive integrated moving averages (ARIMA) model to measure the impact of naloxone dispensation at PHVMs. We forecasted the number of expected opioid-involved overdose fatalities had naloxone dispensation at PHVMs not occurred and compared to observed monthly counts. Interrupted time series analyses (ITSA) were used to evaluate the step (i.e. the immediate impact of naloxone dispensation at PHVMs on opioid-involved overdose fatalities) and slope change (i.e. changes in trend and directionality of monthly counts of opioid-involved overdose fatalities following naloxone dispensation at PHVMs). RESULTS: During the 12-months immediately following naloxone dispensation at PHVMs, our model forecasted 270 opioid-involved overdose fatalities, but death certificate data indicated only 229 occurred, suggesting an aversion of 41 deaths. ITSA identified a significant negative step change in opioid-involved overdose fatalities at the time naloxone dispensation at PHVMs was launched (B = -8.52, p = .0022) and a significant increasing slope change (B = 1.01, p<.0001). Forecasts that extended into the COVID-19 pandemic suggested worsening trends in overdose fatalities. CONCLUSION: Naloxone dispensation at PHVMs was associated with immediate reductions in opioid-involved overdose fatalities. Key MessagesNaloxone dispensation at PHVMs was associated with immediate reductions in opioid-involved overdose fatalities.Communities should consider implementing public health vending machines in efforts to prevent opioid-involved overdose fatalities.The COVID-19 pandemic worsened the overdose crisis.

Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial.

Objective: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents. Methods: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. Results: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. Conclusions: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.Reprinted from Am J Psychiatry 2021; 178:352-362 with permission from American Psychiatric Association Publishing.

Systematic Review and Meta-analysis: An Empirical Approach to Defining Treatment Response and Remission in Pediatric Obsessive-Compulsive Disorder.

OBJECTIVE: A lack of universal definitions for response and remission in pediatric obsessive-compulsive disorder (OCD) has hampered the comparability of results across trials. To address this problem, we conducted an individual participant data diagnostic test accuracy meta-analysis to evaluate the discriminative ability of the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in determining response and remission. We also aimed to generate empirically derived cutoffs on the CY-BOCS for these outcomes. METHOD: A systematic review of PubMed, PsycINFO, Embase and CENTRAL identified 5,401 references; 42 randomized controlled clinical trials were considered eligible, and 21 provided data for inclusion (N = 1,234). Scores of ≤2 in the Clinical Global Impressions Improvement and Severity scales were chosen to define response and remission, respectively. A 2-stage, random-effects meta-analysis model was established. The area under the curve (AUC) and the Youden Index were computed to indicate the discriminative ability of the CY-BOCS and to guide for the optimal cutoff, respectively. RESULTS: The CY-BOCS had sufficient discriminative ability to determine response (AUC = 0.89) and remission (AUC = 0.92). The optimal cutoff for response was a ≥35% reduction from baseline to posttreatment (sensitivity = 83.9, 95% CI = 83.7-84.1; specificity = 81.7, 95% CI = 81.5-81.9). The optimal cutoff for remission was a posttreatment raw score of ≤12 (sensitivity = 82.0, 95% CI = 81.8-82.2; specificity = 84.6, 95% CI = 84.4-84.8). CONCLUSION: Meta-analysis identified empirically optimal cutoffs on the CY-BOCS to determine response and remission in pediatric OCD randomized controlled clinical trials. Systematic adoption of standardized operational definitions for response and remission will improve comparability across trials for pediatric OCD.

Mechanotransduction channel Piezo is widely expressed in the spider, Cupiennius salei, mechanosensory neurons and central nervous system.

Mechanosensory neurons use mechanotransduction (MET) ion channels to detect mechanical forces and displacements. Proteins that function as MET channels have appeared multiple times during evolution and occur in at least four different families: the DEG/ENaC and TRP channels, as well as the TMC and Piezo proteins. We found twelve putative members of MET channel families in two spider transcriptomes, but detected only one, the Piezo protein, by in situ hybridization in their mechanosensory neurons. In contrast, probes for orthologs of TRP, ENaC or TMC genes that code MET channels in other species did not produce any signals in these cells. An antibody against C. salei Piezo detected the protein in all parts of their mechanosensory cells and in many neurons of the CNS. Unspecific blockers of MET channels, Ruthenium Red and GsMTx4, had no effect on the mechanically activated currents of the mechanosensory VS-3 neurons, but the latter toxin reduced action potential firing when these cells were stimulated electrically. The Piezo protein is expressed throughout the spider nervous system including the mechanosensory neurons. It is possible that it contributes to mechanosensory transduction in spider mechanosensilla, but it must have other functions in peripheral and central neurons.

Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial.

OBJECTIVE: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents. METHODS: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. RESULTS: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. CONCLUSIONS: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.

Visual field deficits following laser ablation of the hippocampus.

OBJECTIVE: To qualify the incidence of and risk factors for visual field deficits (VFD) following laser interstitial thermal ablation (LITT) for mesial temporal lobe epilepsy (MTLE) and to relate this to anterior temporal lobectomy (ATL). METHODS: Fifty-seven patients underwent LITT of the amygdalo-hippocampal complex (AH) for MTLE. Masks of ablation volumes, laser probe trajectories, and visual radiations (VRs) from individual subject space were transformed into standardized space using nonlinear registration. Voxel-wise statistics were performed to model relationships between VFDs vs ablation volumes, laser trajectories, VRs, and AH asymmetry. A review of VFDs following ATLs was performed. RESULTS: The incidence of VFD after LITT is much lower than after ATLs. A total of 37.5% of patients developed a VFD, with the probability of this being much higher after left (50%) vs right hemisphere LITT (10%) (Fisher test, p = 0.05). This laterality effect on VFDs is mirrored but underappreciated in ATL series. The most consistent LITT-VFD occurred in the superior vertical octant. Ablation of Meyer loop as well as the summed probability of VRs within laser trajectories correlated with VFDs (p < 0.05). Left and right hippocampi have significantly distinct orientations in axial and coronal planes, which may be one reason for the variation in VFD probability. CONCLUSIONS: LITT results in lower rates of and smaller VFDs-typically an octantanopsia. VRs are at greater risk during surgery for left than right MTLE. Anatomical asymmetries in hippocampal anatomy may explain the hemispheric differences in deficits, and should factor into trajectory planning and also into preoperative patient counseling. Overall the incidence and extent of visual deficits following LITT for MTLE is lower than the reported data following anterior temporal lobectomy. VF tractography incorporated into LITT planning may reduce the occurrence of VFDs.

Minor change in initial PEEP setting decreases rates of ventilator-associated events in mechanically ventilated trauma patients.

BACKGROUND: Surveillance of ventilator-associated events (VAEs) as defined by the National Healthcare Safety Network (NHSN) is performed at many US trauma centers and considered a measure of healthcare quality. The surveillance algorithm relies in part on increases in positive end-expiratory pressure (PEEP) to identify VAEs. The purpose of this cohort study was to evaluate the effect of initiating mechanically ventilated trauma patients at marginally higher PEEP on incidence of VAEs. METHODS: Analysis of level-1 trauma center patients mechanically ventilated 2+ days from 2017 to 2018 was performed after an institutional ventilation protocol increased initial PEEP setting from 5 (2017) to 6 (2018)cm H2O. Incidence of VAEs per 1000 vent days was compared between PEEP groups. Logistic regression modelling was performed to evaluate the impact of the PEEP setting change adjusted to account for age, ventilator days, injury mechanism and injury severity. RESULTS: 519 patients met study criteria (274 PEEP 5 and 245 PEEP 6). Rates of VAEs were significantly reduced among patients with initial PEEP 5 versus 6 (14.61 per 1000 vent days vs. 7.13 per 1000 vent days; p=0.039). Logistic regression demonstrated that initial PEEP 6 was associated with 62% reduction in VAEs. CONCLUSIONS: Our data suggest that an incrementally increased baseline PEEP setting was associated with a significantly decreased incidence of VAEs among trauma patients. This minor change in practice may have a major impact on a trauma center's quality metrics. LEVEL OF EVIDENCE: IV.

N-Acetylcysteine for Pediatric Obsessive-Compulsive Disorder: A Small Pilot Study.

Background: Many children and adults with Obsessive-Compulsive Disorder (OCD) fail to respond to first-line pharmacological and behavioral treatments. Glutamate dysfunction may contribute to the development of OCD. N-acetylcysteine (NAC), a glutamate modulating drug, has shown to be a promising agent in adults with OCD. Methods: We conducted a double-blind, placebo-controlled clinical trial from July 2012 to January 2017. Children ages 8 to 17 years with OCD were assigned to receive NAC (up to 2700 mg/day) or the matching placebo for a period of 12 weeks. Children were required to be on stable psychiatric treatment (both medication and therapy) but were not required to be treatment-refractory. The primary outcome was OCD symptom severity as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We used linear mixed models to analyze the effect of NAC compared to placebo. Results: Due to poor recruitment and eventual expiration of the study medication, enrollment was stopped at 11 children out of a planned sample size of 40. Nonetheless, NAC was associated with significant reduction in CY-BOCS total score compared to placebo (Satterthwaite's test: t (37) = 2.36, p = 0.024) with effects separating from placebo beginning at week 8. Mean CY-BOCS total score decreased in the NAC group from 21.4 ± 4.65 at baseline to 14.4 ± 5.55 at week 12. In the placebo group, mean CY-BOCS total score remained unchanged (21.3 ± 4.65). In the NAC group, 1 out of 5 participants achieved >35% improvement in CY-BOCS total score, while none of the six patients in placebo group reached this improvement level. NAC and placebo were well tolerated. One mild adverse event was reported in each group. Conclusions: Our trial suggests that there may be some initial improvement in OCD symptom severity with NAC treatment. NAC was well tolerated in the study population. Future trials should employ multiple sites and have a larger study population to further confirm any benefits of NAC.

Analysis of Morbidity and Outcomes Associated With Use of Subdural Grids vs Stereoelectroencephalography in Patients With Intractable Epilepsy.

Importance: A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown. Objective: To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center. Design, Setting and Participants: Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018. Interventions: Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus. Main Outcomes and Measures: Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale. Results: Of the 260 cases included in the study (54.6% female; mean [SD] age at evaluation, 30.3 [13.1] years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean [SD], 30.1 [12.2] vs 30.6 [13.8] years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean [SD], 5.7 [2.5] vs 5.6 [2.5]), and duration of epilepsy (mean [SD], 16.4 [12.0] vs17.2 [12.1] years). A much greater proportion of SDE vs SEEG cases were lesional (99 [71.2%] vs 53 [43.8%]; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 [91.4%] vs 90 [74.4%]; P < .001). Favorable epilepsy outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 [47.1%] vs 59 of 139 [42.4%] at 1 year; P = .45). Conclusions and Relevance: This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.