Dose Timing of D-Cycloserine to Augment CBT for Social Anxiety Disorder
Phase: EARLY_PHASE1
Conditions: Social Anxiety Disorder
Sponsor: University of Texas at Austin

 
 
 
Dose Timing of D-Cycloserine to Augment Cognitive Behavioral Therapy for Social Anxiety 
Disorder 
 
 
Trials Registration: 
ClinicalTrials.gov identifier: NCT02066792  
 
Date Revised: 
11/2/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Abstract 
The use of d-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive- behavioral 
therapy (CBT) represents a promising new translational research direction with the goal to accelerate and 
optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment 
extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS 
may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and 
design for an ongoing randomized controlled trial examining the relative efficacy of tailoring DCS 
administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for 
social anxiety disorder (n = 156). Specifically, tailored post-session DCS administration will be compared 
against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in 
social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a 
fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to 
receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this 
experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This 
study aims to serve as the first step toward developing an algorithm for the personalized use of DCS 
during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for 
anxiety disorders.  
 
 
Principal Investigator (1) 
Jasper A. J. Smits, Ph.D.  
Institute for Mental Health Research and Department of Psychology, The University of Texas at Austin 
Austin, TX, USA 
 
Principal Investigator (2) 
Mark H. Pollack, M.D. 
Department of Psychiatry, Rush University Medical Center 
Chicago, IL, USA 
 
Principal Investigator (3) 
Stefan G. Hofmann, Ph.D. 
Department of Psychological and Brain Sciences, Boston University 
Boston, MA, USA 
 
Funding: 
This study is funded as a multi-site linked R34 grant (R34MH099318) by the National Institute of Mental 
Health (Principal Investigators: Stefan G. Hofmann, Mark H. Pollack, and Jasper A. J. Smits)  
 
 
 
 
 
 

Introduction  
Whereas ample evidence supports the efficacy of cognitive behavioral therapy (CBT) for anxiety 
disorders, response rates leave considerable room for improvement.
1 Attempts to improve treatment 
response with combined CBT and anxiolytic pharmacotherapy have led to disappointing results.
2,3 One 
promising strategy for strengthening the effects of CBT has been the use of pharmacological agents that 
augment core learning processes in CBT. One important element in CBT for anxiety disorders is exposure 
procedures, which rely of extinction learning. Preclinical research has shown that extinction learning is 
blocked by antagonists at the glutametergic N-methyl-D-aspartate (NMDA) receptor, whereas d-
cycloserine (DCS), a partial NMDA agonist, augments such learning in animals.
4 
In clinical settings, a number of studies have shown that DCS also appears to augment the effects 
of exposure therapy.
5 In one of the first human trials, patients with social anxiety disorder (SAD) who 
received 50 mg of DCS one hour prior to each of five exposure sessions had greater reductions in social 
anxiety symptoms at post-treatment and one-month follow-up than those who received exposure therapy 
plus pill placebo.
6 Findings were replicated by Guastella and colleagues.
7 Similarly, promising results 
were reported in the treatment of height phobia
8 and panic disorder.
9 In contrast, a number of studies have 
found minimal to no benefits for DCS augmentation of exposure procedures for various clinical and 
subclinical anxiety problems.
10–14 In the largest DCS trial to date (n = 169),
12 patients with SAD showed a 
significantly faster rate of symptom improvement than those receiving placebo, but no differences were 
observed in the response or remission rates at post-treatment and 6-month follow-up. In addition to 
within-session changes, between session fear reduction also appears to be of importance, as shown in a 
recent trial with Iraq and Afghanistan veterans.
15 After six sessions of virtual reality exposure therapy, 
participants showed a greater reduction in PTSD symptoms with d-cycloserine augmentation when 
extinction learning was well achieved between sessions, which was quantified as the average decrease in 
peak subjective distress ratings across successive exposure sessions. This effect was not observed when 
the exposure sessions were combined with alprazolam or placebo.  
One possible explanation for these inconsistent findings is related to the extent to which 
extinction learning has occurred. Consistent with this hypothesis are the results of a re-analysis of the 
study by Hofmann and colleagues.
12 The results demonstrated that relative to placebo, patients receiving 
DCS showed greater symptom improvement at each session when self-reported fear levels were low at 
the end of the prior exposure session.
16 Conversely, patients who received DCS and whose end fear levels 
were high at the prior session showed less symptom improvement than those taking placebo. At post-
treatment, patients receiving DCS whose average fear level at the end of each exposure was low to 
moderate showed superior outcome to those receiving placebo. Similar results were found in another trial 
with height phobic patients in which DCS was administered post-session.
17  
It may then be best to selectively administer DCS only after exposures in which end fear levels 
are low, as DCS can make “good” exposures better and “bad” exposure worse.
18 This is based on findings 
from animal studies suggesting that NMDA antagonists impair reconsolidation of fear memories, whereas 
DCS appears to enhance reconsolidation of fear memory.
19 A critical condition determining whether DCS 
augments extinction learning or reconsolidation appears to be the length of memory reactivation and 
extinction training sessions. If the extinction session (and the period of stimulus re-exposure) is brief, 
reconsolidation processes are dominant, whereas extinction processes dominate in longer sessions.
19 
Therefore, if fear does not sufficiently decrease during exposure therapy, fear memory reconsolidation 
may occur and DCS can facilitate this counter-therapeutic process. To test the hypothesis that success of 
DCS depends on the level of fear experienced at the end of exposure, the present study will examine the 
effect of selectively administering DCS to patients after exposures in which end fear levels are low.  
 
 

Methods 
Study Design and Objectives 
The primary objective of this study is to optimize the application of DCS to augment exposure 
therapy. We will examine the relative efficacy of tailoring post-session administration of DCS based on 
end fear levels during a five-session exposure therapy protocol for SAD. Tailored post-session DCS 
administration will be compared to the most common application of DCS in prior research, which is 
unselective DCS administration before exposure sessions, as well as unselective post-session DCS 
administration in order to determine whether post-session DCS administration needs to be tailored. We 
will also include a placebo condition. We hypothesize that selectively administering DCS when fear 
levels are low at the end of exposures will lead to greater reductions in social anxiety symptoms at post- 
treatment and follow-up compared to placebo, unselective pre-session DCS administration, and 
unselective post-session DCS administration.  
A secondary aim is to examine whether DCS enhances fear extinction retention in a laboratory 
setting. Doing so will allow us to make inferences about the mechanism of action through which DCS 
enhances outcomes (i.e. whether its effects are due to increased fear extinction retention), and to better 
interpret any possible null results of the clinical trial (e.g. DCS may work in an experimental paradigm 
but not in a clinical setting). To examine the effect of DCS on fear extinction retention, a subset of 
participants will complete a computerized protocol involving a fear conditioning procedure, fear 
extinction training, and fear extinction retention testing on three separate days, while receiving DCS or 
pill placebo prior to extinction training. We hypothesize that participants receiving DCS will show greater 
fear extinction retention in the laboratory experiment than those receiving placebo.  
 
Participants 
Our sample will consist of 156 participants for the clinical trial portion of the study, with a subset 
of 96 participants completing the optional laboratory-based fear extinction paradigm. Recruitment will be 
split amongst the three study sites: Boston University, University of Texas at Austin, and Rush University 
Medical Center. Inclusion and exclusion criteria are listed in Table 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Screening and Randomization 
Individuals interested in the study will undergo a psychiatric evaluation to evaluate psychiatric 
inclusion and exclusion criteria. Participants will be medically cleared by a study physician.  
Participants in the optional fear extinction retention experiment will be randomized to receive 
either DCS or placebo prior to fear extinction procedures. For the clinical trial portion of the study, 
participants will be randomized to one of four conditions: 1) tailored post-session DCS, 2) unselective 
pre-session DCS, 3) unselective post-session DCS, or 4) pill placebo. The conditions of the fear 
extinction experiment will be equally distributed across the four clinical trial conditions such that 
participants will be equally likely to receive any combination of fear extinction condition and trial 
condition. Randomization will occur by site using variable-sized permuted block randomization (block 
sizes varying from 4 to 12). Randomization tables will be created before the first subject is run and sent to 
the study pharmacist to make the appropriate medication kits. The statistician will check the balance of 
randomization to control for any unbalanced factors.  
 
Fear Extinction Retention Experiment  
The fear extinction retention experiment will occur on three separate days prior to treatment. 
Participants will undergo conditioning procedures on Day 1, extinction learning on Day 2, and extinction 
recall and fear renewal on Day 3. Day 1 and Day 3 sessions will take place no more than seven days 
apart. DCS or placebo will be administered immediately prior to the Day 2 procedures to examine 
whether DCS enhances extinction recall and reduces fear renewal on Day 3.  
Experiment procedures are based on a previously validated fear conditioning and extinction 
paradigm.
22 During each portion of the experiment, recording electrodes will be attached to the palm of 
the participant’s left hand to measure skin conductance response (SCR), and stimulating electrodes will 
be connected to two fingers of the participant’s right hand to deliver an electric shock. SCR will be 
measured through a 9-mm (sensor diameter) Sensor Medics Ag/AgCl electrodes. For each trial, 
participants will view a computer monitor with an image of one of two different rooms containing an unlit 
lamp for 6 seconds. The lamp will then be “switched on” to one of two colors for 12 seconds, which will 
serve as the conditioned stimulus (CS). One of the two colors will be paired with an electric shock (the 
unconditioned stimulus, or US), while the other color will not. The shock will have been previously 
selected by the participant to be “highly annoying but not painful” and delivered for 500 millisecond 
through electrodes attached to the second and third finger of the right hand. The inter-trial interval will 
last an average of 15 seconds. The stimulating electrodes will remain attached to the fingertips throughout 
the experiment, but the US will be administered only during the Conditioning session on Day 1.  
On Day 1, the to-be CS+ and the to-be CS− (four trials of each) will be presented within each 
room in a counterbalanced manner without presentation of the US (Habituation phase). The Conditioning 
phase will follow with five CS+ trials that will be immediately followed by the US (100% reinforcement), 
and five CS− trials (i.e., not followed by shock). All conditioning trials will use the same context (one of 
the two rooms). On Day 2 (Extinction phase), five CS+ trials and five CS− trials will be presented within 
the extinction context (the room not used during conditioning) with no US presentation. Day 3 consists of 
the Extinction Recall phase and the Renewal phase. Extinction Recall is identical to the Extinction phase 
on day 2, while Renewal is identical to the Conditioning phase except without presentation of the US.  
For each trial, SCR will be calculated by taking the difference between the highest skin 
conductance level (SCL) during each 12-second CS+/CS− presentation and the mean SCL during the 2 
seconds immediately preceding that trial. The SCR for the CS− will be subtracted from the SCR for the 
CS+ to create a differential SCR. Performance during Extinction Training and Recall will be assessed by 
comparing SCR during CS+ trials on Day 2 and 3 with the maximum SCR during the Conditioning phase. 
Our main outcome of interest will be Extinction Retention, for which we will calculate an extinction 
retention index based on the ratio of the mean SCR during the first two trials of the Extinction Recall 
phase to the largest SCR during the Day 1 Conditioning phase. This ratio will be multiplied by 100 to 

yield a percentage of the maximum conditioned response, and this value will be subtracted from 100% to 
yield the extinction retention index.  
 
Therapy Procedures  
Consistent with prior clinical trials,
6,7 we will use a 5-session group CBT protocol emphasizing 
repeated exposure practice. Each group will consist of 4–6 patients and 2 therapists, who will be PhDs or 
advanced, trained doctoral students supervised by the PIs. In the first session (60 minutes), patients will 
be introduced to the cognitive-behavioral model of SAD and provided a rationale for treatment with 
exposure therapy. Sessions 2–5 (90 minutes each) will consist of increasingly difficult public speaking 
exposure tasks in which each participant in the group will give an impromptu speech on a topic chosen by 
the therapist in front of the other group members, confederates and a video camera. Video recordings of 
each exposure will then be reviewed, and participants will compare pre-exposure predictions about their 
behavior and appearance during the speech task with their actual performance. Participants will be 
encouraged to apply home-practice strategies.  
 
Pill Administration  
Following prior research demonstrating DCS to augment exposure therapy,
6–9 DCS will be 
administered in 50 mg doses. Administration of DCS at such a dose has been shown to have a benign side 
effect profile,
23,24 and increasing the dose to as high as 500 mg has not shown additive effect in enhancing 
exposure-based treatment.
8 DCS and placebo capsules will be identical in appearance and administered by 
staff blind to study condition and not involved in the assessment or treatment of participants. Participants 
in the fear extinction retention experiment will take one study pill (i.e.,50 mg DCS or placebo) 
immediately before Day 2 of the experiment.  
The pharmacist will fill three bottles (with one pill type in each) for each patient for each 
exposure session according to the schedule in Table 2. Patient, therapist, and staff will be blind to the 
drug condition (DSC vs. placebo) at pre- exposure; and therapists and patients will be blind to the drug 
condition at post-exposure. Regardless of study condition, research staff will administer a pill (Pill 1) to 
each participant one-hour before the exposure session and administer a second pill (Pill 2) immediately 
after the exposure session. In the tailored administration condition, the selection of Pill 2 will be guided 
by the end fear level. Specifically, DCS will be administered if the end fear is ≤40 (of 100) on the 
Subjective Units of Distress Scale (SUDS), whereas placebo will be selected if the end fear is >40. A 
cutoff of 40 and below was selected based on results of our prior clinical trial, which demonstrated that 
when end SUDS ratings were 
below 47, DCS showed an 
advantage over placebo.
16 Two 
prior studies using the same 5- 
session CBT protocol found that 
mean end SUDS ratings were 
49.5 (SD = 19.2)
12 and 39.1 (SD 
= 17.7).
25 In the latter study, 
85% of patients had at least one 
end SUDS rating of 40 or 
below, and 67.5% had at least 2 
end SUDS ratings of 40 or 
below, demonstrating that there 
is sufficient variability in end fear ratings to justify the examination of tailored and non-tailored post-
session DCS administration.  
 
 

Outcome Measures  
The administration of assessments is detailed in Table 3.  
Data Analysis  
We will assess the equivalence of the treatment groups on key baseline variables and any 
variables that differ among groups will be used as covariates in the final analyses. We will examine 
missing data patterns, dropout rates, and distributional properties of measures and use transformations to 
improve distributions if necessary. We will use pattern mixture modeling to assess the effect of missing 
data.
26 We will rerun our analyses coding for various missing data patterns (no missing data, sporadic 

missing, dropouts, etc.) to determine 1) if missingness impacts our findings and 2) how the differences 
between treatment conditions depends on the missing data pattern.  
We will use multilevel modeling (MLM) to evaluate the effect of condition on our continuous 
outcome measures (LSAS, SPD-SC severity, MADRS, QLES-Q) and generalized linear mixed modeling 
(GLMM, which is MLM with a logistic linking function) to examine DCS’s effect on the dichotomous 
outcomes (“response” and “remission,” explained below). MLM is the recommended method for 
analyzing longitudinal psychiatric data,
27 easily accommodates missing data, and allows inclusion of all 
subjects in the analysis even if they drop out. In our MLM analyses, the repeated assessments over time 
will be nested within individuals, which will be nested within treatment cohort, thereby appropriately 
accounting for correlated scores within cohorts. We will use a piecewise growth curve model, separately 
modeling change over time during treatment and follow-up. We will test for quadratic trends and include 
them if significant. Other non-linear models (e.g., exponential models) will be also be tested, and the 
model that best fits the data (based on AIC and BIC) will be used. Our “time” variable in these models 
will be coded as “assessment week” and will reflect the number of weeks since baseline. Using this 
model, we can test differences between tailored DCS administration and the 3 comparison groups (pre-
session DCS, post-session DCS, and placebo) by including 3 dummy coded variables as predictors of the 
growth curve parameters. Each dummy variable will contrast tailored DCS to each of the other 3 
conditions.  
 
Definition of Treatment Response and Remission  
Treatment “response” is based on the SPD-SC and is defined by an overall change score of 2 
(much improved) or 1 (very much improved) as compared to the pre- treatment assessment. “Remission” 
is defined as an SPD-SC of 2 or 1 and an LSAS total score of < 30. This LSAS cutoff score is supported 
by a study of 364 patients that used receiver-operating characteristics in diagnosing SAD,
28 and has 
generally been adopted as the boundary between remitted and symptomatic patients.
29 It should be noted 
that the goal of this study is to determine effect size estimates for these gold-standard response and 
remission outcomes. Detecting differences on these dichotomous outcomes would require a very large 
sample size, and thus these estimates will be used to evaluate whether a larger- scale trial is warranted.  
 
Outcome Analysis  
In order to evaluate whether tailored DCS administration produces superior outcomes to pre- 
session DCS, post-session DCS, and placebo, we will examine if the dummy variable contrasting tailored 
DCS to the relevant comparison condition is a significant predictor of the intercept. We will alternately 
“center” the “assessment week” variable at either posttreatment, 1-mo FU, or 3-mo FU to test for 
significant differences between conditions at each of these time points.
30  
We will also examine a number of possible moderators of the potential superiority of tailored 
DCS over the comparison conditions (and, secondarily, of the superiority of pre-and post-DCS 
administration over PBO). We will use the Fournier approach
31 to identify important moderators. This 
approach uses an algorithmic method to select significant predictors and moderators within each group of 
potential moderators (e.g., demographics, clinical and personality characteristics). These selected 
moderators are then combined in a final analysis, which identifies moderators that are significant over and 
above the other potential moderators. This approach strikes a balance between testing each moderator 
separately (which substantially increases Type I error due to the multiple tests) and testing all moderators 
simultaneously (which may substantially increase the likelihood of Type II error). 
 
 
Power analysis  
This study is not powered to detect small differences between treatment conditions, nor is it 
powered to detect differences on our dichotomous outcomes. We performed power analyses only for our 
primary outcomes, which were continuous measures of LSAS and SPD-SC. MLM allows the inclusion of 
all subjects with at least one data point, regardless of missing data and regardless of whether they drop 

out. Thus, we based our power analysis on 156 participants and conservatively assumed that, on average, 
we will obtain 5 out of the 7 total assessments from each subject. The power analyses were calculated 
using the program PinT 2.12 (Power in Two Level Models).
32 
For our main outcome analysis, we used our similarly sized DCS trial
12 to estimate the variances 
and covariances required by PinT, and calculated detectable effect sizes for both LSAS and SPD-SC. 
PinT indicated we would have a power of .80 to detect an effect size as low as d=.296, between a small 
(d=.20) and a medium (d=.50) effect size. This translates into a difference of 6.59 points on the LSAS and 
.42 points on the SPD-SC (at post- treatment, 1-month follow-up, or 3-month follow-up). For the Fournier 
moderator analysis, we assumed five simultaneous moderators in each group, and included their 15 
interactions with the 3 dummy variable contrasts. Moderators were modeled as predictors of both the 
intercept and slope. Using our prior DCS study to calculate the variances and covariances required by 
PiNT, we found that, with .80 power, we could detect an effect size of d=.466, slightly smaller than a 
medium effect size.  
 
Data and Safety Monitoring Board (DSMB) 
A Data and Safety Monitoring Board (DSMB) will be created to ensure that the safety of study 
subjects is protected, and the scientific goals of the study are being met. The DSMB will review any 
proposed amendments to the study protocol, perform expedited monitoring of all serious adverse events, 
perform ongoing monitoring of drop-outs and non-serious adverse events, determine whether study 
procedures should be changed or the study should be halted for reasons related to the safety of study 
subjects, and perform periodic review of the completeness and validity of data to be used for analysis of 
safety and efficacy. The DSMB will ensure subject privacy and research data confidentiality. 
 
Collection and Reporting of AEs and SAEs 
AE information will be obtained by questioning subjects. All new complaints must be recorded. 
Pre-existing complaints or symptoms that increased in intensity/frequency after having signed the 
Informed Consent Form must be recorded. All AEs must be characterized in terms of their start/stop 
dates, start/stop times, intensity, action taken on Intervention, relationship to Intervention, subject 
outcome and whether or not the AE led to a Serious Adverse Event (SAE). Clinically relevant changes to 
the intensity/frequency of a reported AE requires a separate entry on the AE Form.  
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that: 
• 
Results in death; 
• 
Is life-threatening;  
• 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect. 
 
All serious events occurring between signing of the Informed Consent Form by the subject and 
signing of the End of Trial Form by the investigator, except those pre-specified in the protocol, must be 
reported as soon as practical (within 24 hours of awareness) to the IRB and the DSMB.  
 
 
 
 
 
 
 
 
 
 

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