This double-blind, placebo-controlled crossover trial (n=18) investigated the effects of intravenous ketamine (35 mg/70 kg) in adults with social anxiety disorder. It finds that ketamine resulted in a significantly greater reduction in anxiety symptoms compared with placebo on clinician-rated measures, although self-reported anxiety scores did not show a significant difference.
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.
Social anxiety disorder (SAD) is common and causes substantial functional impairment, yet roughly one-third to one-half of patients do not achieve meaningful symptom relief with current evidence-based treatments such as selective serotonin reuptake inhibitors (SSRIs), venlafaxine, or cognitive behavioural therapy. Converging neuroimaging, spectroscopy, and preclinical data implicate glutamatergic abnormalities in SAD, including elevated glutamate or glutamine in regions such as the anterior cingulate and thalamus. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that modulates glutamate signalling, has produced rapid antidepressant and anxiolytic effects in prior controlled studies of depression and preliminary work in obsessive-compulsive disorder and post-traumatic stress disorder. Taylor and colleagues therefore designed a proof-of-concept, double-blind, randomised, placebo-controlled crossover trial to test whether a single intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) reduces social anxiety symptoms in adults meeting DSM-5 criteria for SAD. The trial aimed to characterise the time course of effects over two weeks post-infusion and to compare clinician-rated and self-reported anxiety measures, recognising uncertainty about durability and the optimal outcome measures for ketamine's anxiolytic effects.
Design and participants: The study was a double-blind, randomised, placebo-controlled crossover trial conducted at Yale University from 2014–2016. Eighteen adults aged 18–65 meeting DSM-5 criteria for SAD by structured interview were enrolled. Inclusion required a baseline Liebowitz Social Anxiety Scale (LSAS) score indicative of at least moderate social anxiety. Comorbid anxiety and mood disorders were permitted; other lifetime Axis I diagnoses were excluded. Participants on psychiatric medication were eligible if doses had been stable for at least one month and for SSRIs/SNRIs/clomipramine at least two months. Substance use disorders (other than tobacco) and positive drug screens were exclusionary. Recruitment sources included clinicaltrials.gov and community outreach. Intervention and procedure: Each participant received two infusions in random order: ketamine 0.5 mg/kg IV over 40 minutes and matched placebo (normal saline), separated by a 28-day washout. Randomisation was performed by the investigational drug service and concealed from study investigators. Blinded raters conducted clinician-rated assessments but were not present during infusions; separate raters at the infusion assessed dissociative/psychotomimetic effects. Participants were asked not to discuss infusion experiences with blinded raters to reduce inadvertent unblinding. Outcomes and timing: Assessments occurred pre-infusion, 3 hours post-infusion, and on days 1, 2, 3, 5, 7, 10 and 14 post-infusion. The primary clinician-rated outcome was the LSAS (0–144). The primary self-report outcome was a visual analogue scale for anxiety (VAS-Anxiety, 0–100). Secondary measures included the State-Trait Anxiety Inventory—State subscale (STAI-S) and the Hamilton Depression Rating Scale (HDRS-17) for depressive symptoms; dissociative effects were measured with the Clinician Administered Dissociative States Scale (CADSS). The LSAS was modified to ask about symptoms since the previous assessment. Statistical analysis: Analyses used SAS 9.4. Normality of continuous outcomes was confirmed by Shapiro–Wilk tests. The investigators tested for carryover effects by comparing baseline ratings between sequence groups (ketamine-first versus placebo-first) using paired t-tests; evidence of carryover for a given outcome led to analysing only data from the first phase for that outcome. For outcomes without carryover, mixed-effects linear models included treatment, infusion order, time, and relevant interactions; non-significant order terms were removed. Restricted maximum likelihood estimation with an autoregressive covariance structure was used. Cohen's d with confidence intervals was reported for treatment effects at each time point. Treatment response definitions followed prior literature: >35% reduction in LSAS and >50% reduction in VAS from baseline at any point ≥24 hours post-infusion. The Wilcoxon signed-rank test compared responder proportions. Alpha was set at 0.05. The extracted text indicates that depression analyses included only participants above an HDRS-17 threshold suggestive of mild to moderate depression, but the exact cutoff symbol was not clearly extracted.
Sample and retention: Of 18 randomised participants, 17 (94%) completed both infusion phases; one participant missed the second (placebo) infusion for non-study reasons. All ketamine infusions were completed without reported serious adverse outcomes in the extracted text. Carryover effects: A significant carryover effect was detected for the LSAS: participants who received ketamine in the first period had lower LSAS baselines before the second period than those who received placebo first (mean difference 15.35, t = 2.84, df = 15, p = 0.012). No significant carryover was detected for VAS-Anxiety, HDRS-17, or STAI-S. Clinician-rated social anxiety (LSAS): Restricting to phase 1 for the LSAS due to carryover, mixed-model analyses showed a significant Time effect (F 8,124 = 3.0, p = 0.004) and a significant Time × Treatment interaction (F 9,115 = 2.6, p = 0.01), favouring ketamine over saline. Significant between-group mean differences (ketamine minus placebo) occurred at day 2 (diff = 22.67 ± 7.28, effect size (ES) = 1.10, F = 4.9, p = 0.04), day 5 (diff = 22.33 ± 7.28, ES = 1.09, F = 4.7, p = 0.04), and day 10 (diff = 28.72 ± 7.36, ES = 1.37, F = 7.6, p = 0.01). Six of 18 subjects (33.33%) met the predefined LSAS responder criterion (>35% reduction) after ketamine versus 0 of 17 after placebo (Wilcoxon z = 2.24, p = 0.025). Subscale analyses indicated significant Time and Time × Treatment effects for LSAS Fear and Avoidance subscales, and for Social Anxiety and Social Avoidance subscales; Performance Anxiety and Performance Avoidance subscales did not show significant Time × Treatment interactions. Maximum CADSS score and age at SAD onset did not significantly moderate LSAS effects. Self-reported anxiety (VAS, STAI-S): On the VAS, time alone was significant (F 10,141 = 5.8, p < 0.001) but the Time × Treatment interaction was not (F 10,141 = 0.4, p = 0.95) and the treatment main effect approached but did not reach conventional significance (F 1,27.4 = 3.4, p = 0.07). No individual time point showed a significant ketamine advantage on VAS. Nevertheless, responder analysis found 16 of 18 (88.89%) achieved >50% VAS reduction after ketamine versus 9 of 17 (52.94%) after placebo (Wilcoxon z = 2.12, p = 0.034). STAI-S scores showed significant treatment effects: Time (F 7,167 = 5.4, p < 0.001) and Treatment (F 1,47 = 8.2, p = 0.006); between-group differences favouring ketamine were observed at days 1 (diff = 7.76 ± 2.30, ES = 0.83, F = 5.7, p = 0.02), 7 (diff = 8.53 ± 2.28, ES = 0.92, F = 7.0, p = 0.01) and 10 (diff = 8.39 ± 2.64, ES = 0.78, F = 5.0, p = 0.03). Sensitivity analyses restricted to phase 1 produced similar STAI-S findings. Depressive symptoms: Among 12 participants with comorbid depressive symptoms at baseline (HDRS-17 mean = 22, SD = 5), ketamine did not produce significant reductions in HDRS-17 scores in either the full crossover analysis or phase 1–only analyses (time and interaction terms not significant). The authors note few participants met criteria for major depressive disorder and the study was underpowered for depression outcomes. Safety and tolerability: Ketamine was generally well tolerated. Common adverse effects reported in the extracted text included paresthesias and numbness (n = 9), feeling disconnected from reality (n = 7), visual changes (n = 6), and confusion or difficulty thinking (n = 6); the text breaks off during a list that included dizziness, so the full adverse-event list is not completely available in the extraction.
Taylor and colleagues interpret their findings as initial, proof-of-concept evidence that a single ketamine infusion reduces clinician-rated social anxiety symptoms in adults with SAD over the short term, while effects on self-reported momentary anxiety (VAS) were not observed in mixed-model analyses. The study also found higher proportions of treatment responders after ketamine on both clinician-rated (LSAS) and self-reported (VAS) definitions, and significant improvements on the STAI-S at several post-infusion time points. The authors situate these results within prior literature showing ketamine's rapid anxiolytic effects in depression and preliminary benefits in obsessive-compulsive disorder and post-traumatic stress disorder. They note that, despite statistically significant reductions, the overall sample on average continued to exhibit moderate social anxiety after ketamine and that some individual responders still retained moderate symptoms shortly after infusion. Ketamine did not significantly reduce depressive symptoms in this sample, a null result the investigators attribute to the small number of participants with current major depressive disorder, generally milder depressive severity in the cohort, and limited statistical power. Key limitations acknowledged by the study team include inadequate blinding using saline—17 of 18 participants correctly identified when they had received ketamine—which may bias self-report and even blinded clinician ratings. The LSAS showed carryover effects through 28 days, prompting reliance on first-period data for that outcome; the authors suggest ketamine's anxiolytic effects may have enabled behavioural activation (increased social exposure), which could have sustained benefit but was not systematically measured. Other limitations include the small sample size and the crossover design given apparently durable anxiolytic effects. For future research the authors recommend larger, parallel-group trials using an active comparator such as midazolam to improve blinding, prioritising blinded clinician ratings over single-item VAS measures, incorporating physiological anxiety measures (for example skin conductance), exploring optimal dosing and repeated administration schedules, and examining potential genetic moderators (for example BDNF rs6265). They caution that these results are preliminary and should not be taken as definitive evidence for long-term use of ketamine in anxiety disorders, but suggest that ketamine-like glutamatergic compounds merit further investigation for SAD and other anxiety disorders.
All analyses were conducted in SAS version 9.4. All continuous outcomes (LSAS, VAS, HDRS-17, STAI-S) were sufficiently normally distributed as evidenced by the Shapiro-Wilk Test (p-values = 0.28, 0.13, 0.23, 0.21). To investigate possible carryover effects in our trial, we used a paired t-test to compare the difference between baseline ratings in the first and second phase of the trial between different infusion order (ketamine first, placebo second or placebo first, ketamine second) for all continuous outcomes (LSAS, VAS, HDRS-17, STAI-S). When there exists a significant difference between baseline ratings based on the sequence of treatments, there is evidence of carryover effects in a crossover trial, and it is standard to analyze data from the first phase of the trial. When no significant carryover effects were present, we analyzed data from both phases of the crossover trial and present data from the first phase only as a sensitivity analysis. Carryover effects were demonstrated for the LSAS but not for other outcomes in this trial (VAS, HDRS-17, STAI-S), and thus data from the first phase of the trial were analyzed for the LSAS and its subscales. Analysis of outcomes with carryover effects. When evidence of carryover effects was present, we restricted analysis to phase 1 data in the trial (up to day 14). We used SAS to construct a mixed-effects linear model with time and time-by-treatment interaction as included terms in the model. The restricted maximal likelihood method was used with an autoregressive covariance structure. We used this analysis for the LSAS as well as the analysis of LSAS subscale measures-specifically (1) the LSAS Fear and Avoidance factors and (2) the LSAS Social Anxiety and Social Avoidance and LSAS Performance Anxiety and Performance Avoidance factors. Analysis of outcomes with no evidence of carryover effects. We used SAS to construct mixed-effects linear models for each continuous outcome with treatment, infusion order, time, and interactions between treatment and time as well as treatment and infusion order. Infusion order and interaction between treatment and infusion order were initially included in the models to additionally examine possible carryover effects. If these terms were both nonsignificant they were dropped from the final model as is standard in mixed-effects modeling of crossover trials. For all analyses, time, treatment, and infusion order were included as within-subject factors. The restricted maximal likelihood method was used with an autoregressive covariance structure. We used this method of analysis for the VAS-anxiety, HDRS-17, and STAI-S. As part of a sensitivity analysis, we additionally present results for all outcomes with data restricted to phase 1 of the trial given that some evidence of carryover effects was present in the trial. This analysis was identical to that outlined in the previous paragraph. For all outcomes of continuous measures, we also present Cohen's d with confidence intervals for least mean square estimates of treatment effects at each time point. For our primary outcomes, the VAS-anxiety and LSAS, we report data on all subjects (as well as secondary analyses involving STAI-S and CADSS). In our analysis of depression outcomes, only individuals with HDRS-17415 (suggestive of mild to moderate depression)at baseline were included. We also examined the proportion of treatment responders using the Wilcoxon signed-rank test. Like prior studies, treatment response was defined by (1) a greater than 35% improvement in LSAS scorebased on the ~34% LSAS reduction seen after SSRI treatmentand () greater than 50% improvement in VAS score from baseline at any point at least 24 h following infusion. For all primary and secondary outcomes alpha was set at 0.05.
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Ketamine resulted in a significantly greater reduction in anxiety when compared to placebo as assessed by blinded ratings on the LSAS but not on self-reported VAS-anxiety measures. Ketamine also demonstrated significantly greater number of treatment responders as assessed by both LSAS and VAS ratings. Our findings provide evidence for the potential use of ketamine-like compounds for reducing symptoms in SAD. To our knowledge, this is the first placebo-controlled study to investigate ketamine's efficacy in patients with a DSM-5 anxiety disorder. The results of the study are consistent with previous work suggesting that ketamine has anxiolytic effects in patients with major depression. Prior work has also found that ketamine reduced OCD symptoms. For example, Rodriguez et al, 2013 found post-infusion ratings were lower 1 week post-infusion on the Yale-Brown Obsessive Compulsive Scale (YBOCS). Furthermore, a 2017 study of 12 adults with generalized anxiety disorder and/or social anxiety found ketamine reduced anxiety symptoms; however, the study was open label and there was no placebo control. Of note, in our study the overall sample continued to have moderate social anxiety symptoms post-ketamine despite reductions in symptoms. Two of the six ketamine responders, as measured by the LSAS, continued to have moderate social anxiety symptoms 24 h after ketamine infusion. Additionally, in our study ketamine did not significantly improve depressive symptoms. Several studies have demonstrated the efficacy of ketamine for treatment-resistant depression. The lack of efficacy in our trial is likely due the fact that in our study most patients had mild to moderate depression as opposed to the more severe treatment-resistant major depression studied in ketamine clinical trials. In fact, only three patients in this trial met criteria for current major depressive disorder. Furthermore, our study was under-powered to detect a change in depression ratings. More research is needed to determine whether ketamine is effective in moderate depression. A significant limitation of our study was that 17 of 18 patients correctly identified when they received ketamine, suggesting that the use of saline as a placebo control for ketamine led to inadequate blinding. This inadequate blinding was not unique to our study and has been quite typical in previous saline-controlled ketamine studies. This functional unblinding may affect self-report measures (eg VAS) as well as lead to possible reporting bias even on ratings conducted by blinded raters (eg LSAS, HDRS-17). Further larger, randomized, midazolam-controlled trialsshould be performed to confirm the benefits of ketamine for SAD as well as debilitating anxiety in general. A midazolam-controlled trial would not fully eliminate the issue of functional unblinding with ketamine but may reduce the issue somewhat. We would suggest that these future trials should (1) employ a parallel rather than crossover design as there seems to be more durable effects of ketamine on anxiety as compared to depression (leading to an increased likelihood of carryover effects) and an active control, even though blinding with active controls like midazolam is suboptimal (and giving subjects both medications exacerbates this issue); (2) use blinded, clinical-ratings of anxiety rather than the VAS as these gestalt ratings, even though theoretically more sensitive to change, appear particularly sensitive to momentary or situational anxiety; and (3) consider additional physiological measures of anxiety (eg skin conductance) to capture the effects of ketamine. Future studies should also explore several other aspects of administration including the optimal dosing of ketamine for anxiety and the effects of repeated ketamine dosing on anxiety symptoms. Future studies should also include genotyping, specifically for the brainderived neurotrophic factor (BDNF) allele at rs6265because the Val/Val BDNF allele at rs6265 has been associated with greater ketamine antidepressant effects relative to the effects seen in Met carriers. Our trial is meant to demonstrate proof-of-concept for the potential use of ketamine-like compounds for reducing symptoms of anxiety. Overall, ketamine appeared to be effective in alleviating social anxiety symptoms over the short term. The overall improvement of anxiety symptoms after This table displays the individual characteristics for the participants in the trial listed in order of trial enrollment. Pre/post ketamine and saline results are indicative of scores received on Day 0 prior to the infusion and on Day 1 (24 h after the infusion), respectively. Response could occur at any point during the 14 days following infusion (ie some patients responded after Day 1). ketamine infusion seemed possibly more modest in scale (effect size varied from 0.2 to 0.6 on the VAS to 0.74 -1.38 on the LSAS during the first 2 weeks following infusion) but perhaps more durable than that observed in previous depression studies. The LSAS measures demonstrated significant carryover effects 28 days following infusion with an effect size = 0.93 at 14 days. A possible explanation for the carryover effects of ketamine is that when a subject's social anxiety was reduced, the subject participated in more social activities. Increased exposure to social activities is a treatment for SAD (eg CBT)and may have maintained ketamine's anxiolytic effects. Several participants reported increased social engagement in the days following ketamine infusion; however, we did not systematically track social exposure, and further research is needed to substantiate this hypothesis. These findings should not be used as definitive evidence for the use of ketamine as a long-term treatment for anxiety as this is a small, proof-ofconcept study that did not show significant benefit on all outcome measures. Several ketamine-like glutamate modulators, including AXS-05 and esketamine, are under investigation by pharmaceutical companies and in Clinical Trial phases II and III for depression. Our findings suggest ketamine-like compounds may also be effective in SAD and could be investigated for other anxiety disorders.