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.

Meta-Analysis: Pediatric Placebo Response in Depression Trials Does Not Replicate in Anxiety and Obsessive-Compulsive Disorder Trials.

Background: Placebo response has been identified as an important factor influencing the success of adult antidepressant trials, yet little research of placebo response has been conducted in pediatric populations. Understanding disorder-specific and transdiagnostic predictors of pediatric placebo response is important in designing successful child psychopharmacological trials. Methods: A PubMed search was conducted for all pediatric antidepressant randomized controlled trials treating depression, anxiety, or obsessive-compulsive disorder (OCD). A random-effects model was utilized to examine the magnitude of placebo symptom improvement using standardized mean difference (SMD) and placebo response rates. Stratified subgroup analysis was performed by diagnostic indication. Meta-regression was utilized to search possible correlates of placebo symptom improvement and placebo response rate. Results: Thirty antidepressant trials involving 2911 participants receiving placebo were included in this meta-analysis. Magnitude of placebo improvement and placebo response rates varied significantly across disorders; being greater in depression (SMD = 1.44, 95% confidence interval [CI]: 1.18 to 1.71) than anxiety disorders (SMD = 1.09, 95% CI: 0.77 to 1.41) and the lowest in OCD (SMD = 0.71, 95% CI: 0.32 to 1.12). Different predictors were associated with placebo response in different indications. Conclusions: Both the magnitude and predictors of placebo response in pediatric depression trials do not replicate across anxiety and OCD. Based on our results, across disorders, minimizing the number of sites might significantly reduce placebo improvement. In addition to these, we could potentially decrease the placebo response in depression trials by increasing the number of subjects enrolled per study site, minimizing the number of study visits and conducting the studies in the United States. Further research is needed into the predictors of placebo response in pediatric anxiety and OCD.

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.

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.

Meta-analysis: Pharmacologic Treatment of Restricted and Repetitive Behaviors in Autism Spectrum Disorders.

OBJECTIVE: To examine the efficacy of pharmacological treatments for restricted and repetitive behaviors (RRB) in autism spectrum disorders (ASD). METHOD: We searched PubMed, Embase, and CENTRAL to identify all double-blind, randomized, placebo-controlled trials that examined the efficacy of pharmacological agents in the treatment of ASD and measured RRB as an outcome. Our primary outcome was the standardized mean difference in rating scales of RRB. RESULTS: We identified 64 randomized, placebo-controlled trials involving 3,499 participants with ASD. Antipsychotics significantly improved RRB outcomes compared to placebo (standardized mean difference [SMD] = 0.28, 95% CIs = 0.08-0.49), z = 2.77, p = .01) demonstrating a small effect size. Larger significant positive effects on RRB in ASD were seen in individual studies with fluvoxamine, buspirone, bumetanide, divalproex, guanfacine, and folinic acid that have not been replicated. Other frequently studied pharmacological treatments in ASD including oxytocin, omega-3 fatty acids, selective serotonin reuptake inhibitors (SSRI), and methylphenidate did not demonstrate significant benefit in reducing RRB compared to placebo (oxytocin: SMD = 0.23, 95% CI = -0.01 to 0.47, z = 1.85, p = .06; omega-3 fatty acids: SMD = 0.19, 95% CI = -0.05 to 0.43, z = 1.54, p = .12; SSRI: SMD = 0.09, 95% CI = -0.21 to 0.39, z = 0.60, p = .56; methylphenidate: SMD = 0.18, 95% CI = -0.11 to 0.46, z = 1.23, p = .22). CONCLUSION: The results of the present meta-analysis suggest that currently available pharmacological agents have at best only a modest benefit for the treatment of RRB in ASD, with the most evidence supporting antipsychotic medications. Additional randomized controlled trials with standardized study designs and consistent and specific assessment tools for RRB are needed to further understand how we can best help ameliorate these behaviors in individuals with ASD.

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of the potential role of glutamate neurotransmission in anxiety disorders and highlight specific glutamate receptors that are potential targets for novel anxiety disorder treatments. We also review clinical trials of medications targeting the glutamate system in DSM-5 anxiety disorders. Understanding the role of the glutamate system in the pathophysiology of anxiety disorder may aid in developing novel pharmacological agents that are effective in treating anxiety disorders.

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.

Meta-analysis of placebo group dropout in adult antidepressant trials.

BACKGROUND: Minimizing dropouts across antidepressant, placebo-controlled trials remains a major opportunity to improve the efficiency of trials. This meta-analysis investigated placebo dropout rate and its predictors in second generation antidepressant (SGA) for anxiety, depression and obsessive-compulsive disorder (OCD). METHODS: A random-effects meta-analysis was performed to examine placebo group dropout rate in SGA trials for depression, anxiety and OCD using Freeman - Tukey transformation. Stratified subgroup analysis by diagnostic indication was performed to examine the dropout rate across disorders. Meta-regression was performed to identify correlates between placebo dropout rate and trial and subject characteristics. RESULTS: Meta-analysis included 148 trials with 18,016 participants receiving placebo. Across antidepressant trials the overall placebo dropout rate was 25% (dropout rate ±â€¯standard error (SE) = 0.25 ±â€¯0.01, 95% CI: 0.23-0.27, z = 23.95, p < .001) and was similar across disorders (χ2 = 1.09, df = 2, p = .58). The placebo group dropout rate was 26% in depressive disorders, 25% in anxiety disorders and 22% in OCD. Across all diagnostic indications, earlier publication year, placebo lead-in, studies conducted in a single country (instead of internationally), longer trial duration, fewer study sites, more study visits and less baseline illness severity were associated with higher placebo dropout rate. Significant predictors of placebo dropout did not replicate across disorders. CONCLUSION: No significant difference was found in placebo dropout rate between internalizing disorders with overall dropout rate for placebo groups in antidepressant trials being around 25%. Placebo dropouts in trials can be minimized by reducing subject burden in trials, enrolling more severely affected subjects and foregoing placebo lead-in periods.

Meta-Analysis of Placebo Response in Adult Antidepressant Trials.

BACKGROUND: Roughly 80% of the symptom improvement experienced on antidepressants in clinical trials is also observed in the placebo comparison group. Understanding the correlates of placebo improvement and response is important to designing efficient and successful trials of future antidepressants. OBJECTIVE: The objective of this meta-analysis was to investigate the magnitude of placebo symptom improvement and placebo response rates in second-generation antidepressant trials of depression, anxiety, and obsessive-compulsive disorder. METHODS: We searched PubMed on 10 June, 2016, with no date or language limits, to identify randomized placebo-controlled trials of second-generation antidepressants in adults with depression, anxiety, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the magnitude of placebo symptom improvement using standardized mean difference and placebo response rate. Stratified subgroup analysis and meta-regression were utilized to examine the effect of diagnostic indication and correlates of placebo symptom improvement. RESULTS: The meta-analysis included 164 trials involving 19,591 participants. Magnitude of placebo improvement and placebo response rates varied significantly between diagnostic indications. The magnitude of placebo improvement was much lower in obsessive-compulsive disorder (standardized mean difference = 0.58, 95% confidence interval 0.36-0.79) than in depression (standardized mean difference = 1.22, 95% confidence interval 1.12-1.32) or anxiety (standardized mean difference = 1.01, 95% confidence interval 0.90-1.12) trials. There was a large amount of heterogeneity in placebo improvement between studies (Q = 899, df = 110, p < 0.001, I2 = 88%). A greater number of study sites and a later publication year were associated with a greater magnitude of placebo improvement and response rate. Presence of a placebo lead-in and absence of non-US sites were associated with a reduced magnitude of placebo improvement. Trial duration was positively associated with the magnitude of placebo improvement in depression trials but negatively associated with the magnitude of placebo improvement in anxiety and obsessive-compulsive disorder trials. CONCLUSIONS: Magnitude of placebo symptom improvement differed significantly based on diagnostic indication with improvement being significantly less in obsessive-compulsive disorder than anxiety and depression. Some trial characteristics were associated with a greater magnitude of placebo improvement in trials across disorders but others were disorder specific.

Trim the fat: the role of omega-3 fatty acids in psychopharmacology.

The American Psychiatric Association (APA) currently recommends the use of omega-3 fatty acid supplementation for depressive disorders, impulse-control disorders, and psychotic disorders in treatment guidelines. This review examines the evidence for efficacy of omega-3 fatty acids in depressive disorders, bipolar disorder, anxiety disorders, post-traumatic stress disorder (PTSD), and psychosis. Meta-analysis of randomized-controlled trials of omega-3 fatty acids for depression are inconclusive, with strong evidence of publication bias, sizable heterogeneity between included studies, and substantial methodological shortcomings in included trials. The large amount of heterogeneity in findings of RCTs of omega-3 fatty acids for unipolar depression is likely attributable to highly heterogeneous sample populations that are given different omega-3 supplements [which differ widely in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content, ratio, and dosage] as either adjunctive or monotherapy of other existing treatments, and then measure several different outcomes of depression symptomatology with likely incomplete blinding. Evidence of efficacy of omega-3 supplementation in treating psychosis, PTSD, anxiety, and bipolar mania is minimal. The current guidelines recommending the use of omega-3 fatty acids in adulthood psychiatric conditions should be revisited, especially given several recent negative studies examining the effects of omega-3 fatty acids for cardiovascular disease. Recommending likely ineffective treatment to patients, no matter how benign the side-effect profile, has opportunity cost (e.g. other more effective medications or therapies not being utilized) and likely affects patient compliance with other evidence-based treatments.

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.