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.

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.

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.

Pharmacological Interventions for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Tourette Disorder: A Systematic Review and Network Meta-Analysis.

Objective: To evaluate the comparative efficacy of pharmacological interventions for children and adolescents with a dual diagnosis of persistent tic disorders or Tourette disorder and attention-deficit/hyperactivity disorder (TD + ADHD). Methods: We searched CENTRAL, Embase, PubMed, PsycInfo, Web of Sciences, ClinicalTrials.gov, and WHO ICTRP up to September 2023 to identify double-blinded randomized controlled trials (RCTs) assessing pharmacological interventions for children and adolescents with TD + ADHD. Outcomes were change in ADHD symptoms (primary) and tics (secondary) severity. Standardized mean difference (SMD) was calculated and pooled in random-effects network meta-analysis. The Confidence in Network Meta-Analysis framework was adopted to determine certainty of evidence. Results: We included 8 RCTs involving 575 participants. Network meta-analyses demonstrated that α2 agonists (SMD, 95% confidence interval [CI] ADHD: -0.72 [-1.13 to -0.31]; TD: -0.70 [-0.96 to -0.45]) and stimulants + α2 agonists (ADHD: -0.84 [-1.54 to -0.13]; TD: -0.60 [-1.04 to -0.17]) were more efficacious than placebo for ADHD symptoms and tics severity. Stimulants alone were more efficacious than placebo for ADHD symptoms severity only, but they did not worsen tics (ADHD: -0.54 [-1.05 to -0.03]; TD: -0.22 [-0.49 to 0.05]). There were no significant differences between any pairs of medications that were found efficacious against placebo for ADHD symptoms or tics severity. Certainty in the evidence varied from low to very low. Conclusions: Stimulants are efficacious for ADHD symptoms severity and do not increase tics severity in TD + ADHD. α2 agonists are efficacious for both ADHD symptoms and tics severity in TD + ADHD. These findings should inform guidelines and help guide shared decision-making to choose a medication for children with TD + ADHD.

Racial Implicit Associations in Child Psychiatry.

OBJECTIVE: Racial disparities in diagnosis and treatment are prevalent in child psychiatry, including disparate diagnosis rates of internalizing and externalizing disorders in Black and White children. However, limited research has investigated mechanisms that contribute to these disparities. This study examined child racial implicit associations in psychiatric clinicians and medical students to address this gap. METHOD: Psychiatrists and trainees completed an online survey including 2 race Implicit Association Tests (IATs) pairing child faces to words with either positive or negative valence, and words related to internalizing or externalizing behavioral problems. Psychiatrists and trainees' demographic predictors of implicit associations were also investigated. RESULTS: Data were analyzed from 235 psychiatrists and trainees (112 child and adolescent psychiatrists and fellows) who met inclusion criteria. Psychiatrists and trainees demonstrated greater moderate-to-strong association between Black child faces and "bad" (ie, negatively valenced) words (44.3%) vs "good" (ie, positively valenced) words (6.4%), and between externalizing words (41.7%) vs internalizing words (7.2%). Psychiatrists and trainees' demographic characteristics including being female (ß = -0.12; 95% CI = -0.23 to -0.01; p < .05), Black (ß = -0.36; 95% CI = -0.54 to -0.18; p < .001), or an attending physician (ß = -0.26; 95% CI = -0.45 to -0.06; p = .01) were significant predictors of decreased association between Black child faces and negative valence words. Being female was a significant predictor of decreased association between Black child faces and externalizing words (ß = -0.26; 95% CI = -0.45 to -0.06; p = .01). CONCLUSION: Participating psychiatrists and trainees demonstrated bias toward associating Black rather than White child faces with negative words and externalizing behavioral problems. Future research should examine the following: racial implicit associations in a more generalizable sample; the relationship between race IATs and provider behavior; and interventions to reduce racial inequities in psychiatry, including individual and systemic solutions. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

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.

Long-term outcome in adults with obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic condition that often produces lifelong morbidity, but few studies have examined long-term outcome (greater than 5 years) in adult patients. Available studies suggest that 32-74% of adult OCD patients will experience clinical improvement over the long term. However, these studies were conducted before validated OCD rating scales were established and the development of evidence-based treatments for OCD. METHODS: We investigated the 10-20 year outcome of 83 of 165 eligible subjects previously enrolled after participation in placebo-controlled trials of serotonin reuptake inhibitor (SRI) medications for OCD. We examined the association between clinical characteristics at initial assessment and OCD symptom severity at follow-up. We hypothesized that primary OCD symptom dimension and initial response to pharmacotherapy with serotonin reuptake inhibitors would be associated with later symptom severity. RESULTS: Only 20% (17 of 83) of subjects had experienced a remission of their OCD symptoms at follow-up (Y-BOCS ≤ 8). Forty-nine percent (41 of 83) of subjects were still experiencing clinically significant OCD symptoms. Response to initial SRI pharmacotherapy was significantly associated with long-term outcome: 31% (13 of 42) of subjects who responded (CGI < 3) to initial SRI pharmacotherapy were remitted at follow-up, compared to 12% (3 of 25) of partial responders and none of the 16 subjects who had no response to initial SRI pharmacotherapy. We did not find a significant association between long-term clinical outcome and any of the OCD symptom dimensions. CONCLUSION: Despite the introduction and dissemination of several evidence-based treatments for OCD, most adult OCD patients do not achieve remission. Initial response to pharmacotherapy was strongly associated with long-term outcome.

Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette's syndrome: a systematic review and network meta-analysis.

BACKGROUND: In clinical practice guidelines there is no consensus about the medications that should be initially offered to children and young people with Tourette's syndrome. To provide a rigorous evidence base that could help guide decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of pharmacological interventions for Tourette's syndrome. METHODS: For this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We included double-blind randomised controlled trials of any medication administered as a monotherapy for at least 1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (>18 years), or both, diagnosed with Tourette's syndrome according to standardised criteria. We excluded studies that exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions were examined considering medication categories and medications individually in separate analyses. Summary data were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO (CRD42022296975). FINDINGS: Of the 12 088 records identified through the database search, 88 records representing 39 randomised controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised 4578 participants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual medications distributed across six medication categories. When considering medication categories, first-generation (standardised mean difference [SMD] -0·65 [95% CI -0·79 to -0·51]; low certainty of evidence) and second-generation (-0·71 [-0·88 to -0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists (-0·21 [-0·39 to -0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI -0·14 to 0·25]; low certainty of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation (0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence. Similar findings were observed when individual medications were considered: aripiprazole (SMD -0·60 [95% CI -0·83 to -0·38]), haloperidol (-0·51 [-0·88 to -0·14]), olanzapine (-0·83 [-1·49 to -0·18]), pimozide (-0·48 [-0·84 to -0·12]), risperidone (-0·66 [-0·98 to -0·34]), and clonidine (-0·20 [-0·37 to -0·02]) all outperformed placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD -0·40 [95% CI -0·69 to -0·12]) and risperidone (-0·46 [-0·82 to -0·11]) outperformed clonidine, with moderate certainty of evidence. Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there were no relevant findings for any of the efficacious medication categories or individual medications against each other or placebo, but there was low to very low certainty of evidence associated with these comparisons. INTERPRETATION: Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette's syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment, the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual factors that could not be addressed in the present analysis, should guide the choice of medication for children and young people with Tourette's syndrome. FUNDING: None.

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.

Poor fine-motor and visuospatial skills predict persistence of pediatric-onset obsessive-compulsive disorder into adulthood.

BACKGROUND: Half of pediatric-onset OCD cases remit by adulthood. Studies have demonstrated that initial response to pharmacotherapy, age of onset, prominent hoarding symptoms, and the presence of comorbid tic disorders are associated with long-term outcome. Our goal was to examine the association between childhood performance on neuropsychological testing and persistence of OCD into adulthood. METHODS: Twenty-four children with OCD were followed for an average of 7.5 years into early adulthood. Neuropsychological performance in childhood (<16 years) was measured. The battery included the Wechsler Intelligence Scale for Children (WISC-III), the Purdue pegboard test, the Rey-Osterreith Complex Figure Task (RCFT) and the Beery-Buktenica test of Visual Motor Integration (VMI). We hypothesized that deficits in fine-motor skills, visuospatial skills, and nonverbal memory as well as overall intelligence would be associated with adulthood outcome. We used a Cox proportional hazard model of survival analysis in which time to remission of OCD symptoms was the main outcome variable. RESULTS: Poor childhood performance on the Purdue pegboard task and the block design subscale of WISC-III was associated with persistence of OCD symptoms into adulthood. IQ, VMI, and nonverbal memory performance did not predict significantly the persistence of OCD. CONCLUSIONS: These results suggest that visuospatial and fine-motor skill deficits are predictive of poor long-term outcome in pediatric-onset OCD. Future longitudinal studies are needed to chart the course of these deficits relative to the course of symptoms in OCD and to determine whether the association of these neuropsychiatric deficits with long-term outcome is specific to pediatric-onset OCD or generalizes to other psychiatric disorders.

Predictors of early adulthood quality of life in children with obsessive-compulsive disorder.

OBJECTIVES: The goal of this study was to determine childhood clinical predictors of quality of life (QoL) in early adulthood in children with obsessive-compulsive disorder (OCD). METHODS: A longitudinal cohort study was conducted with 36 (out of 62 eligible) children with OCD, interviewed once at childhood baseline (mean age 12.1 ± 2.1, range 8.0-15.8), and again in early adulthood after an average follow-up interval of 9 years. QoL was measured in adulthood with the longitudinal interval follow-up evaluation range of impaired functioning tool (LIFE-RIFT). RESULTS: Forty-two percent of children experienced a remission of OCD symptoms by early adulthood. OCD appeared to most strongly impair the interpersonal relationships and work domains of QoL. QoL and severity of OCD and anxiety symptoms were significantly associated in early adulthood. Primary hoarding symptoms in childhood predicted poor QoL in adulthood. Increased symptoms in the forbidden thoughts dimension in both childhood and adulthood were associated with improved adulthood QoL. CONCLUSIONS: Children for whom OCD symptoms remitted by adulthood showed no evidence of residual impairment in QoL, whereas children whose OCD symptoms failed to remit by adulthood showed at most mild impairment in QoL. Hoarding symptoms in childhood appear to portend not only the persistence of OCD symptoms but also poorer QoL in early adulthood.

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.

Refractory Gilles de la Tourette Syndrome-Many Pieces That Define the Puzzle.

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.

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.

Association of the serotonin transporter polymorphism and obsessive-compulsive disorder: systematic review.

We investigated the association between the long (l) and short (s) alleles of the serotonin transporter polymorphism (5-HTTLPR) in the promoter region of the SLC6A4 gene and obsessive-compulsive disorder (OCD) using meta-analysis to combine all published data from case-control and family based association studies (2,283 cases). In stratified meta-analysis we investigated whether age of sample (child and adult), ethnicity (Caucasian and Asian) and study design (case-control and family-based association studies) moderated any association. In the overall meta-analysis we found no evidence of association between genetic variation at the 5-HTTLPR locus and OCD. We did find significant heterogeneity between studies. In the stratified meta-analyses, we demonstrated a significant association between the l-allele and OCD in family-based association studies and in studies involving children and Caucasians. Our meta-analysis suggests the possibility that the l-allele may be associated with OCD in specific OCD subgroups such as childhood-onset OCD and in Caucasians. Further meta-analyses based on individual patient data would be helpful in determining whether age of OCD onset, gender and the presence of comorbid illness (e.g., tics) moderates the relationship between 5-HTTLPR and OCD.

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial.

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.