Overview

We conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with SAD and compared the effects of intravenous ketamine (dosed 0.5 mg/kg over 40 min) on social anxiety symptoms compared to placebo (normal saline). A power analysis based on ketamine’s antidepressant effects was used to determine the sample size of 18 (Murrough et al, 2013a; Zarate et al, 2006). All participants met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for SAD. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. That is, each participant received either ketamine or placebo infusion on Day 0; then on Day 28 the participant received whichever infusion they did not get on Day 0. The study was conducted from 2014 to 2016 at Yale University in New Haven, CT. Randomization was conducted by the Yale Investigational Drug Service and kept separate from any other investigators involved in the trial. All procedures were approved by the Yale Human Investigation Committee.

Inclusion Criteria and Recruitment

Inclusion criteria were: (1) Male or female (post-menopausal, surgically sterile or negative pregnancy test at screening and agreement to utilize an established birth control including complete abstinence during the testing period) between the ages of 18 and 65 years old; (2) Meet DSM-5 criteria for SAD by structured clinical interview for DSM-5 (SCID) and have a Liebowitz Social Anxiety Score (LSAS) score>60 (Heimberg et al, 1999; Liebowitz, 1987; Mennin et al, 2002), which are typically seen in patients with at least moderate social anxiety. No other lifetime DSM-5 Axis I diagnoses by SCID were allowed, with the exception of comorbid anxiety and mood disorders; (3) Stable psychiatric medications. Patients must have had stable doses of all psychiatric medications for the month prior to treatment and have been on stable doses of SSRIs, SNRIs, and clomipramine for at least 2 months prior to study enrollment. Medications prescribed ‘as needed’ for anxiety (ie not taken regularly) were discontinued for the duration of the trial; (4) Not currently receiving cognitive behavioral therapy; (5) Medically and neurologically healthy. Individuals with stable medical problems and medications (eg, oral hypoglycemics) were included if their medications had not been adjusted in the month prior to entry; (6) No current substance use disorder diagnoses by SCID (excluding tobacco) and urine toxicology screen negative for drugs of abuse; (7) Able to provide written informed consent according to the Yale Human Investigation Committee guidelines.

Patients were recruited through clinicaltrials.gov, outreach to local anxiety peer support groups, and word of mouth. Participants were assessed for eligibility using a phone screen and a subsequent in-person medical and psychiatric evaluation.

Assessments

Assessments were conducted pre-infusion, 3-h post-infusion, and days 1, 2, 3, 5, 7, 10 and 14 post-infusion. The primary self-report outcome of the trial was self-rated anxiety on a visual analog scale (VAS) scored 0 (‘not at all anxious’)–100 (‘as anxious as you could possibly be’) (Aitken, 1969). Subjects also completed the State-Trait Anxiety Inventory State Subscale (STAI-S) (Barnes et al, 2002; Spielberger, 1983). The primary clinician-rated outcome was LSAS, scored 0–144, to measure social anxiety at each assessment point. The LSAS (Heimberg et al, 1999; Mennin et al, 2002), VAS (Cella and Perry, 1986; Davey et al, 2007; Williams et al, 2010), and STAI-S (Spielberger, 1983) have demonstrated reliability and validity. LSAS scores>60 suggest moderate social anxiety and scores>90 suggest severe social anxiety (Heimberg et al, 1999). LSAS typically assesses symptoms during the prior week; however, the scale was modified so that participants were asked about their symptoms during the time since previous assessment. Blinded raters used the 17-item Hamilton Depression Rating Scale (HDRS-17) to measure depression (Hamilton, 1960). Blinded raters were not present for the 3 h following infusions and conducted assessments at a site different from the clinical unit where the infusion took place. Also, participants were instructed to not discuss any aspects of the infusion with blinded raters in order to avoid inadvertent unblinding by the patient discussing dissociative symptoms that frequently occurred during ketamine infusions. Separate raters present at the infusion conducted assessments regarding potential dissociative and psychotomimetic side-effects of the infusions including the Clinician Administered Dissociative States Scale (CADSS) (Bremner et al, 1998).

Statistical Analyses

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 (Heimberg et al, 1999).

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 non-significant 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-17>15 (suggestive of mild to moderate depression) (Zimmerman et al, 2013) 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 score (Bloch et al, 2012) based on the ~34% LSAS reduction seen after SSRI treatment (Liebowitz et al, 2003) and (2) greater than 50% improvement in VAS score from baseline at any point at least 24 h following infusion (Williams et al, 2010). For all primary and secondary outcomes alpha was set at 0.05.