In a particular success of translational research (Anderson & Insel, 2006
), the application of DCS as an augmentation strategy was the product of animal research on the brain circuits underlying extinction learning (for a review, see Davis, Ressler, Rothbaum, & Richardson, 2006
). Extinction learning appears to be modulated by activity of the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor in the amygdala. Inhibitors of this activity appear to block the retention of extinction learning (Falls, Misrendino, & Davis, 1992
), and likewise, partial agonists, like DCS, enhance this learning (Walker, Ressler, Lu, & Davis, 2002
). Specifically, it appears that DCS enhances the consolidation of the new learning that occurs during extinction learning; augmentation effects continue to be present when DCS is administered within several hours after extinction learning (see Richardson, Ledgerwood, & Cranney, 2004
). Hence, DCS appears to act as a memory enhancer, aiding the consolidation of what was learned during extinction learning. Indeed, only animals that show effective learning during extinction training display the benefits of memory enhancement in subsequent tests (Bouton, Vurbic, & Woods, 2008
These exciting findings from the animal laboratory were extended to the clinic in a placebo controlled trial by Ressler et al. (2004)
. Height phobic patients were given a single dose of study medication prior to each of two exposure sessions. Exposure was conducted using a virtual reality apparatus, and the use of only two exposure sessions mirrored animal study designs; e.g., an enhancement effect is easier to observe when an inadequate number of extinction sessions are given (cf., Walker et al., 2002
). Ressler et al. (2004)
found that DCS given prior to exposure significantly enhanced extinction learning, and this effect was evident at both 1–2 weeks and 3 months after the treatment sessions. Moreover, patients who received DCS reported more exposure to heights in life, consistent with the notion that DCS may have enhanced the memory of successful exposure experiences in the virtual reality environment and hence influenced the willingness to continue such exposure.
The successful trial by Ressler and associates (2004)
was followed by a number of other successful studies, starting with the application of DCS augmentation to social anxiety disorder (Hofmann et al., 2006
). In that study, we randomized 27 patients with social phobia to 50 mg DCS or pill placebo. DCS was administered one hour during the final four of a five session protocol of weekly treatment. During these four sessions, patients completed social exposure exercises. Patients who had received DCS achieved significantly more benefit as evaluated at acute and one-month follow-up evaluations. This small study was subsequently replicated by Guastella et al. (2008)
with a larger (N = 56) sample size; similar benefit for DCS administration was found. We have reported similar positive findings for the application of DCS to the treatment of panic disorder (Otto et al., 2009
). In that trial, DCS or pill placebo was administered to 31 patients with panic disorder during the final 3 of a 5-session protocol. In addition to targeting patients with panic disorder, this trial was unique for relying on exposure to feared internal sensations (interoceptive exposure) as the key extinction procedure. The majority of participants (87%) had failed to respond to previous pharmacologic interventions; nonetheless, strong DCS effects (reflecting a large effect size) were found relative to placebo. Larger scale, federally funded trials are now underway to confirm these results for social anxiety disorder and panic disorder in separate, large, multisite trials. Furthermore, federally funded controlled trials are currently underway to examine the efficacy of DCS as an augmentation strategy of exposure therapy for PTSD.
As compared to augmentation of exposure-based CBT for social anxiety disorder and panic disorder, applications of DCS to obsessive compulsive disorder (OCD) have been less positive (Kushner et al., 2007
; Wilhelm et al., 2008
; Storch et al., 2010
). These studies are marked by more intensive scheduling of exposure sessions (twice weekly) and/or a greater number of doses of DCS across treatment. The studies by Kushner et al. (2007)
and Wilhelm et al. (2008)
showed an initial DCS augmentation effect that weakened with continuous administration. This suggests that DCS might enhance the speed of recovery when administered acutely during CBT and thereby reduce dropouts. The only trial in which DCS did not show an augmentation effect is the study by Storch et al. (2010)
. Patients in this trial received 250 mg of DCS 4 hours before each of 12 CBT sessions. As discussed below, these differences in the frequency, amount, and dosing schedule of DCS may be one source of the inconsistent results in some of the studies.
1.1. Limits of DCS Augmentation: Dosing and Learning Issues
Dose response studies have not been conducted for determining the optimal dose of DCS for the enhancement of extinction learning. Ressler et al. (2004)
applied single doses of either 50 mg or 500 mg DCS, and found no differences between them. Subsequent studies have applied single doses of 50, 100, and 125 mg DCS, and have found this dose adequate for enhancement of exposure therapy (Guastella et al., 2008
; Kushner et al., 2007
; Hofmann et al., 2006
; Otto et al., 2009
; Wilhelm et al., 2008
). In our own studies, we in part chose 50 mg because of a desire to avoid side effects, as well as concerns about the rapid tolerance to DCS. Concerning side effects, we have observed few across our clinical and nonclinical trials, suggesting to us that patients are unlikely to be able to discriminate DCS from placebo when 50 mg doses are used. Concerning tolerance, animal research suggests that tolerance to DCS may be reached rapidly with repeated dosing (for review see Hofmann, Pollack, & Otto, 2006
). For that reason, we have sought to use DCS sparingly, applying it in single doses before therapy sessions arranged one week apart. Weaker results have been found when DCS has been applied twice a week for more extended periods and using larger doses (cf. Kushner et al., 2007
, Storch et al., 2010
; Wilhelm et al., 2008
), but there are enough design differences between studies that attribution of these effects to dosing cannot be made reliably.
Evidence for a potential dose effect comes from a study of DCS enhancement outside of an extinction paradigm. First, we found no beneficial effects for augmentation of the learning of verbal and nonverbal stimuli. Specifically, we found that single dose applications of 50 mg DCS vs. placebo prior to weekly trials of learning complex verbal (a detailed narrative) and nonverbal (complex figures) stimuli had no effects on immediate or delayed recall in healthy participants (Otto et al., 2009
). Furthermore, only limited and inconsistent positive findings of a single-dose application of 50 mg DCS was found for memory tasks in individuals with schizophrenia (Goff et al., 2008
). In contrast, Onur et al. (2010)
found that 250 mg DCS did offer augmentation for declarative learning (specifically, item category associative learning), reducing the number of trial repetitions needed to attain improved learning. Onur and associates linked this DCS effect to enhanced activity in the hippocampus. Accordingly, given the failure to achieve a similar effect with 50 mg by Otto et al. (2009)
, Onur et al. proposed that whereas 50 mg DCS may be sufficient for amygdala-dependent learning such as extinction, a higher dose may be necessary for learning more specific to hippocampal processes. Further research is needed to confirm this hypothesis. Given concerns regarding tolerance to DCS (see Hofmann, Pollack, & Otto, 2006
), it is important to consider in this work the possibility that the dose-response relationship may take on a quadratic function.
Another concern about the clinical application of DCS augmentation concerns the potential for sensitization of negative memories, for example should a patient have a sensitizing experience (e.g., a car accident or a poor exposure session) after taking DCS. It would be preferable to administer DCS after completion of the exposure session, so that the memory enhancing effects of DCS could be targeted toward only the sessions judged to be successful by the clinician, but the time course of orally given DCS is such that peak doses are achieved 4 to 6 hours after ingestion. For this reason, even though the targeted activity for DCS is to be after the session, DCS is typically given one hour prior to the session, so that it is likely to be active during the hours after the session (e.g., with a 90 minute session, starting 150 minutes after the pill was taken). Despite potential limitations of this time course, testing of post-session oral administration of DCS is underway. Nonetheless, sensitizing experiences could occur after the session. In response to this issue, Davis et al. (2006)
have reasoned that under fear conditioning experiences, the NMDA receptors may already be saturated, and that because DCS is a partial agonist, it may have relative inhibitory effects at times of fear. Specifically, Davis et al. (2006
, p. 272) argue, “if the site on the NMDA receptors involved in fear conditioning is fully saturated, DCS might actually reduce the activity of the receptors by displacing the more effective endogenous chemicals. This could explain why DCS seems to actually inhibit fear conditioning in some situations.” Recent evidence that DCS facilitation of extinction learning can be disrupted by the occurrence of a stressor (e.g., footshock) prior to DCS administration (Langton & Richardson, in press
) provides support for this hypothesis. In humans, testing of the relative effects of DCS vs. placebo on positive and negative emotional stimuli is currently underway, allowing the evaluation of aspects of this hypothesis. Similarly, a number of studies are underway to examine the optimal timing of administration of DCS, providing data that has important clinical and theoretical implications.
In summary, clinical studies provide strong evidence for a role of DCS in augmenting exposure therapy for the anxiety disorders, with evidence of a medium effect size (d = .60) for clinical populations (Norberg et al., 2008
). Additional and ongoing examination of DCS will provide more information of the limits of this strategy and whether the very promising effects can be replicated across large samples. If so, DCS may emerge as a clinical strategy for three purposes. First, it can be applied as a strategy for reducing the number of sessions needed for treatment, a strategy of particular value in practice settings where access to CBT providers may be limited. For example, in primary care settings where limited numbers of sessions have been offered (Roy-Byrne et al., 2005
), DCS augmentation may help more patients enter remission from treatment. Second, it can be applied to patients who have failed to respond adequately to standard CBT strategies, to see if additional retention of session material can aid outcome. Third, it can be applied in a targeted way to patients who are likely to have difficulty retaining the benefits of exposure therapy. For example, deficits in extinction retention have been found in schizophrenia (Holt et al., 2009
), and animal studies suggests that DCS may help overcome specific extinction retention deficits, at least those that occur developmentally (e.g., McCallum, Kim & Richardson, 2010
). All of these applications hold promise for decreasing the burden of anxiety disorders on affected patients. Finally, one value that successful studies of DCS augmentation offer is encouragement for further study of memory enhancement strategies to empirically-supported psychosocial treatments for anxiety. In the following sections, we review a number of candidates for these additional augmentation efforts.