Before the exposures, the therapist helps patients identify situations they avoid as well as subtle behaviors (ie, safety behaviors) in which they engage to ease their distress. It is generally believed that individuals develop specific fears due to conditioning that occurs in a particular context; in turn, these generalize to other contexts. The individual tends to avoid the feared situation due to the false belief that situation is dangerous or unmanageable. Avoidance is assumed to maintain the fear as well as this false belief. During exposure therapy, patients systematically enter anxiety-provoking situations until there is a significant reduction in the anxiety response due to extinction learning.4 In addition, exposures serve as behavioral experiments aimed at testing the validity of maladaptive cognitions and feared outcomes. By modifying these maladaptive cognitions, emotional distress and engagement in maladaptive behaviors will decrease, and the individual can learn a new safe memory associated with the previously feared stimulus or context.
Despite the superior efficacy of CBT, there is still considerable room for improvement.5 Researchers have supplemented CBT with anxiety-reducing pharmacotherapies, as some individuals do not improve—or improve sufficiently—with exposure alone. However, augmenting exposure with anxiolytic drugs has resulted in minor success. Furthermore, these augmentation strategies may result in less successful treatment outcomes, as individuals may attribute treatment gains to medication rather than to their own effort, thereby undermining self-efficacy. More recent approaches have focused on strengthening CBT education, utilizing pharmacotherapy that affects the neurobiology implicated in the fear extinction processes.6 This approach aims at enhancing the memory processes underlying extinction.
D-Cycloserine as Treatment Adjunct
Fear extinction is a prime area of research in the anxiety literature, as researchers continue to investigate novel and effective ways to reduce the salience of distressing memories and replace these with more neutral memories. One such pathway, the N-methyl-D-aspartate (NMDA) receptor in the basolateral amygdala, is known to play an important role in controlling neural plasticity and memory. Recent research suggests that NMDA activity mediates fear extinction.7 As such, a compound known as d-cycloserine (DCS) has been demonstrated to augment extinction learning by serving as a partial NMDA agonist.8
Because DCS has long been used as an antibiotic medication for treating tuberculosis at high dosing for an extended period of time, it can be safely administered as a cognitive enhancer in exposure therapies for anxiety disorders at much lower dosing for a much shorter period of time. Accordingly, a vast body of research focuses on translating preclinical basic neuroscience findings about DCS into clinical trials with humans diagnosed with a large range of anxiety disorders.3
Efficacy of DCS
The first human trial of DCS as an augmentation strategy for exposure in patients with anxiety yielded promising results.9 The effects of a single dose of DCS taken prior to exposure sessions by patients with acrophobia were examined. Results revealed that DCS significantly enhanced extinction learning after the 2 sessions of acute treatment and at 3 months follow-up. Patients randomly assigned to the DCS condition subsequently reported less avoidance of heights in their daily activities after study completion. Therefore, DCS appeared to enhance the memory of successful exposure experiences and influence subsequent willingness to confront fearful situations. This promising study led to a further line of research that aimed to elucidate the possible enhancing effects of DCS on various anxiety disorders.
Subsequent studies from our group on social anxiety disorder and panic disorder found similarly successful results for DCS as an augmentation strategy.10 Other studies, however, presented null effects.11 Of particular interest and concern was 1 trial with posttraumatic stress disorder (PTSD). It found that patients who received DCS reported more symptoms at posttreatment than those who received placebo.12 As will be discussed further in this article, this study suggests that DCS might also augment fear memory reconsolidation and, therefore, might produce counter-therapeutic effects under certain circumstances.
These studies revealed the complex therapeutic and counter-therapeutic effects of DCS. The 3 main literature findings should be carefully considered when using DCS in exposure therapy: (1) Effect of dose and timing of administration; (2) DCS as an accelerator of early treatment response; (3) Specific conditions in which DCS can lead to fear reconsolidation and worsen symptoms.
Effect of Dose and Timing of Administration
DCS Dosing and dose timing could explain the inconsistent findings from previous studies. The results from several animal and human studies suggest that DCS only shows the extinction augmentation effect when administered in low (eg, 50 mg) and isolated (ie, acute) dosing, but not when administered chronically (ie, repeatedly over an extended period of time).7
Timing is another important issue. Peak blood levels of DCS typically are evident 4 to 6 hours after ingestion. Extinction learning processes usually happen at the end of an exposure session. Therefore, DCS is likely to be most effective when administered within 1 to 2 hours before an exposure session. Indeed, studies demonstrated that DCS administration 1 to 2 hours before exposure achieved greater effects than studies DCS administration multiple hours before exposure.13 These results hint at a rather narrow therapeutic window of DCS, as it appears DCS needs to be administered acutely and in small doses approximately 1 to 2 hours before exposures.
DCS as an Accelerator of Early Treatment Respons
Rather than directly targeting anxiolysis, DCS is used to enhance consolidation of the therapeutic learning offered by CBT. As DCS is a cognitive enhancer, it was reasonable to expect that DCS would strengthen the benefits of CBT through faster learning. Studies that examined the application of DCS for obsessive-compulsive disorder (OCD) revealed that DCS had an effect that attenuated with subsequent administrations.14 These results provided the first hints that DCS primarily acts by accelerating treatment response in the early part of therapy.
Furthermore, with repeated exposure sessions, studies have revealed that exposure alone can eventually show similar effects to the initial DCS augmentation effects. This apparent catch-up effect has also been shown in animal models and human trials for social anxiety disorder, agoraphobia, and panic disorder.15 Although these studies did not show an advantage at the end of treatment in terms of response or remission rates for DCS, faster treatment response can have far-reaching effects. For example, a rapid reduction in distress and disability is linked with a lower dropout rate, as treatment gains are realized more quickly.11,14
Possible Fear Reconsolidation
The mixed results of the efficacy of DCS may be partially explained by the fact that DCS might not only augment fear extinction learning, but also fear memory reconsolidation, or the stabilization of a fear-related memory after initial fear acquisition.16,17 For example, we found in one study that DCS can actually worsen symptoms by enhancing reconsolidation of fear memory when treatment ends with the individual in a high state of fear.6 Since DCS has the capacity to consolidate both extinction and reconsolidation processes, it may be vital to ensure that extinction learning is the predominant process occurring during DCS-augmented sessions.
Post-session DCS administration augmented exposure sessions only when exposure sessions were deemed successful and ended with low levels of fear.18 Accordingly, administering DCS post-extinction learning and judiciously (only after sessions wherein extinction learning is evident) may prevent potentially deleterious effects of DCS. Furthermore, posttreatment fear (rather than a change in fear) should be used as an index for predicting DCS augmentation effects.
Evidence for DCS as an augmentation strategy for CBT for anxiety disorders has been promising, thanks to small placebo-controlled trials across the anxiety disorders. Yet, as research on DCS augmentation has progressed to more diverse protocols and large multicenter trials, the effect size for its benefit has started to falter.6 Subsequent studies and closer examination of the existing data shed light on the mechanism of DCS as a cognitive enhancer in exposure therapy. These studies have revealed important moderators for the use of DCS and guidance for accurate and effective use. There is ongoing research to determine if DCS can be applied to CBT that does not rely solely on exposure interventions. These types of treatments include cue exposure for substance use disorders,19 exposure to feared foods and weight restoration in eating disorders, cognitive restructuring for depression, and imaginary re-scripting therapy for PTSD. Future studies are needed to confirm augmentation effects and to explore whether, like the application of DCS to anxiety disorders, judicious use of DCS is warranted.
A recent individual participant level meta-analysis shed additional light on the use of DCS for exposure-based cognitive behavior therapy.8 Mataix-Cols et al meta-analysis revealed that DCS had a small but significant augmentation effect at posttreatment, with mixed support for the maintenance of its effects at follow up. Importantly, results revealed significant decrease in the augmentation effect of DCS across the time frame covered by the meta-analysis (21 studies published across a 14-year period). In a reanalysis of this meta-analysis, Rosenfield et al.20 examined potential explanations of the apparent declining effect and provided important concrete suggestions for dosing and dose timing.20 Data indicated that participants might benefit most from about 9 doses of DCS, and from administering the doses more than 60 minutes prior to exposure. Additionally, the recommended dose is 50 mg, as the data did not support improved effectivity for greater than 50 mg dosage. Optimizing DCS administration might achieve substantial improved treatment outcomes.
Beyond the important clinical implications of DCS literature, it is an excellent example of translational research from neuroscience to clinical science that directly translates findings from animal studies to clinical trials in humans. We hope that rather than simply combining treatment strategies, which aim for a cumulative effect, future research will continue to focus on elucidating the specific circumstances in which clinical applications (novel and traditional) may (or may not) be successful. This might allow clinicians to tailor treatments accurately to achieve the best possible results for their patients.
Ms Moskow is a clinical extern at McLean Hospital/Harvard Medical School Psychology and a third-year doctoral student at Boston University. Dr Snir is a clinical psychologist and postdoctoral research fellow at Boston University. Dr Hofmann is a professor of psychology at the Department of Psychology at Boston University, where he directs the Psychotherapy and Emotion Research Laboratory. Dr Hofmann receives financial support from the Alexander von Humboldt Foundation (as part of the Humboldt Prize), NIH/NCCIH (R01AT007257), NIH/NIMH (R01MH099021, U01MH108168), and the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition – Special Initiative. He receives compensation for his work as editor from SpringerNature and the Association for Psychological Science, and as an advisor from the Palo Alto Health Sciences Otsuka Pharmaceuticals, and for his work as a Subject Matter Expert from John Wiley Sons, Inc. and SilverCloud Health, Inc. He also receives royalties and payments for his editorial work from various publishers.
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