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Published Online: 1 October 2014

Starting From Something: Augmenting Exposure Therapy and Methods of Inquiry

In this issue of the Journal, Telch et al. (1) examine the ability of methylene blue to augment extinction learning in individuals with claustrophobic fear. The authors studied 42 individuals randomly assigned to double-blind administration of 260 mg of methylene blue or placebo following multiple extinction trials in an enclosed chamber over the course of one clinical session. The primary outcome is self-rated peak fear (scale: 0–100 points) upon re-entry into a similar enclosed chamber a month later. The authors correctly hypothesize extinction augmentation only for those who report low end-state fear subsequent to extinction training; the primary interaction and follow-up analysis effects are large and statistically significant. Marginally supportive evidence is also found for a hypothesized deleterious effect of the medication on those with high end-state fear subsequent to extinction training. The authors include a free-recall contextual learning test to examine the impact of medication on learning in general and find positive hypothesized effects. In other words, methylene blue improved recall of nonfear-related stimuli for the entire medication group but only improved outcomes for those with low end-state fear after exposure. The take-home message is that methylene blue is related to enhanced contextual learning in general. Accordingly, learning is enhanced regarding whatever takes place; if exposures are successful, the successful learning is enhanced, if unsuccessful, learning related to the negative experience is enhanced.
Telch et al. offer a rigorous study that builds on the literature with a highly controlled exposure paradigm, well-specified a priori hypotheses, and appropriate means to address those hypotheses. The study is not without limitations, which the authors adequately identify. I have been asked to comment, more generally, on the relative importance of extinction augmentation research, and Telch et al. provide a solid sounding board to do so.
In the past 5 years, over 20 studies have been published regarding pharmacological enhancement of extinction in humans, and there are at least 15 similar studies in the active-recruitment phase on clinicaltrials.gov. This growing body of research provides optimized environments to noninvasively investigate mechanisms of pathological anxiety and treatment in humans. The translational nature of extinction enhancement research necessitates investigation of interactions among pharmacological agents, human behavior, and psychotherapy protocols. Accordingly, translating animal extinction paradigms into appropriate analogs of exposure therapy for humans calls for, perhaps, more exacting methods than are typically employed in standard psychotherapy outcome studies. As a result, research related to exposure enhancement is significant not only because of the very real potential to improve evidence-based treatments for anxiety spectrum disorders but also because such research is spurring on the application and development of measurement paradigms and specified research designs that are healthy for and beneficial to the larger field of clinical research regarding evidence-based treatments.
Given an augmentation effect, detecting it can be challenging for a number of reasons, including already robust effect sizes for exposure-oriented interventions. Meta-analyses indicate effects for exposure therapies close to or over 1 standard deviation for specific phobias (2), social phobias (3), obsessive-compulsive disorder (4), and posttraumatic stress disorder (PTSD) (5), which the balance of scientific evidence supports as an anxiety spectrum disorder. Moreover, effect sizes for individuals who complete treatment are often close to or over 2 standard deviations (6, 7). Comparatively, a meta-analysis of antidepressants for major depressive disorder evidenced a 0.20 standard deviation effect size (8). In other words, variations of exposure therapy for anxiety are associated with effects arguably five to 10 times larger than those of antidepressants for depression, the most widely accepted standard of care for the disorder. Of course, there is much room for improvement; dropout rates are substantial (although normative compared with other psychotherapies), and posttreatment diagnosis rates tell a more somber tale than effect sizes. However, casting the size of exposure effects in this comparative light underscores the importance of specificity in augmentation trials. For example, it may be difficult for augmentation trials to broadly improve posttreatment effects for treatment completers, as significant gains for completers in both conditions may wash out the ability to measure incremental benefits of a novel strategy. Regardless of the reason, a significant number of trials evidence an early augmentation benefit that diminishes with more treatment (913). In this context, initial slope of response over time is emerging as an important primary outcome (14). Accordingly, it is notable that Telch et al. utilize multiple exposures within just one session in their experiment. Providing multiple sessions may have obscured a positive/important finding. Under-dosing exposures might efficiently reveal how enhancing agents can be incorporated into a course of treatment and/or replace the need for additional sessions. Although the one-session claustrophobia protocol has been shown to be quite effective, a recent investigation of d-cycloserine for PTSD purposely under dosed the number of exposures to avoid ceiling effects for responders (15). This less-is-more strategy may be particularly helpful in translating animal-to-human effects, as unknowns regarding optimal timing and level of dosing for drugs imbedded within specific therapies render the task of isolating effects even more difficult.
Augmentation studies also require careful thought about who the novel effects are meant to target. Extinction augmentation is not necessarily the same as treatment augmentation. In general terms, treatment augmentation may refer to reducing dropout, improving treatment efficiency, bolstering effects for responders, or bolstering effects for partial and nonresponders. These are four separate, not necessarily related, goals aimed at distinct populations of patients undergoing exposure therapy. Along these lines, Telch et al. build on the literature by demonstrating augmentation effects for subjects with “successful” exposures and poor effects for those with “unsuccessful” exposures. This finding, noted in previous d-cycloserine (16) and yohimbine (17) trials, represents an increasingly popular design strategy. Such designs move the field toward focusing stratified research questions on ideographic patient factors, therapy-specific reactions, and phenotypes, rather than on broad demographic stratifications, taxonomies (i.e., co-occurring diagnoses), or baseline severity of self-reported symptoms, which traditionally have yielded modest scientific progress regarding the explanation of variance in outcomes to exposure protocols.
A related point is that augmentation trials often identify outcomes that are more specified than standard patient-reported clinician interviews, which, for good or bad, have come to dominate the field. The translational nature of the research encourages testing mechanisms as one goes and differentiating subjects with measures that are dynamically relevant to their ongoing treatment. For example, Telch et al. use specific fear in response to a stimulus as the primary outcome, rather than a diagnostic interview. Data related to inhibitory learning models provide robust support for measuring decreases in exposure-related arousal as meaningful markers of future symptom decline (18), with predictive validity centering on between-exposure declines, rather than on within-exposure habituation. Objective measures, such as cortisol, startle, heart rate, and skin conductance, have also been employed (19, 20) and can be more sensitive to augmentation manipulations than subjective outcomes (15). Overall, there is a trend toward validating biological and physiological measures implicated in preclinical/laboratory-based anxiety studies as dynamic indices of effective exposure therapy (21). Establishing the predictive validity of objective measures in multiple exposure contexts not only assists in the identification of novel exposure/drug combinations but also builds an evidence base to enable future preselection of individuals with specific exposure-related response styles. Thus, augmentation research is playing multiple roles, not only in seeking to improve evidence-based treatments in general but also in helping to identify for whom and under what circumstances evidence-based treatments will be effective.
In summary, the translational nature of extinction augmentation research and the necessity of understanding individualized responses create the need for specificity and complexity in clinical trials. Yet the level of appropriate complexity is not prohibitive; rather, it is readily attainable with current and developing measurement paradigms and research designs. This literature has the potential to address crucial knowledge traditionally deemed as peripheral to the development of evidence-based treatments. Whether or not specific agents are eventually proven to be helpful, the augmentation literature on a whole is focusing on aspects of the clinical canvass that have often been out of the frame, and perhaps for too long.

References

1.
Telch MJ, Bruchey AK, Rosenfield D, Cobb AR, Smits J, Pahl S, Gonzalez-Lima F: Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Am J Psychiatry 2014; 171:1091–1098
2.
Wolitzky-Taylor KB, Horowitz JD, Powers MB, Telch MJ: Psychological approaches in the treatment of specific phobias: a meta-analysis. Clin Psychol Rev 2008; 28:1021–1037
3.
Gould RA, et al.: Cognitive-behavioral and pharmacological treatment for social phobia: a meta-analysis. Clin Psychol Sci Pract 1997; 4:291–306
4.
Abramowitz JS, Whiteside SP, Deacon BJ: The effectiveness of treatment for pediatric obsessive-compulsive disorder: a meta-analysis. Behav Ther 2006; 36:55–63
5.
Powers MB, Halpern JM, Ferenschak MP, Gillihan SJ, Foa EB: A meta-analytic review of prolonged exposure for posttraumatic stress disorder. Clin Psychol Rev 2010; 30:635–641
6.
Abramowitz JS: Variants of exposure and response prevention in the treatment of obsessive-compulsive disorder: a meta-analysis. Behav Ther 1996; 27:583–600
7.
Foa EB, Hembree EA, Cahill SP, Rauch SAM, Riggs DS, Feeny NC, Yadin E: Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics. J Consult Clin Psychol 2005; 73:953–964
8.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, Fawcett J: Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303:47–53
9.
Smits JA, Rosenfield D, Davis ML, Julian K, Handelsman PR, Otto MW, Tuerk P, Shiekh M, Rosenfield B, Hofmann SG, Powers MB: Yohimbine enhancement of exposure therapy for social anxiety disorder: a randomized controlled trial. Biol Psychiatry 2014; 75:840–846
10.
Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, Cannistraro P, Jenike MA, Rauch SL: Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder. Am J Psychiatry 2008; 165:335–341, quiz 409
11.
Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW: Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Arch Gen Psychiatry 2006; 63:298–304
12.
Nave AM, Tolin DF, Stevens MC: Exposure therapy, d-cycloserine, and functional magnetic resonance imaging in patients with snake phobia: a randomized pilot study. J Clin Psychiatry 2012; 73:1179–1186
13.
Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, Cannistraro P, Jenike MA, Rauch SL: Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder. Am J Psychiatry 2008; 165:335–341, quiz 409
14.
Hofmann SG, Wu JQ, Boettcher H: D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders. Biol Mood Anxiety Disord 2013; 3:11
15.
Rothbaum BO, Price M, Jovanovic T, Norrholm SD, Gerardi M, Dunlop B, Davis M, Bradley B, Duncan EJ, Rizzo A, Ressler KJ: A randomized, double-blind evaluation of d-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans. Am J Psychiatry 2014; 171:640–648
16.
Smits JA, Rosenfield D, Otto MW, Powers MB, Hofmann SG, Telch MJ, Pollack MH, Tart CD: d-Cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia. Biol Psychiatry 2013; 73:1054–1058
17.
Smits JA, Rosenfield D, Davis ML, Julian K, Handelsman PR, Otto MW, Tuerk P, Shiekh M, Rosenfield B, Hofmann SG, Powers MB: Yohimbine enhancement of exposure therapy for social anxiety disorder: a randomized controlled trial. Biol Psychiatry 2014; 75:840–846
18.
Craske MG, Treanor M, Conway CC, Zbozinek T, Vervliet B: Maximizing exposure therapy: An inhibitory learning approach. Behav Res Ther 2014; 58:10–23
19.
Wangelin BC, Powers MB, Smits JA, Tuerk PW: Enhancing exposure therapy for PTSD with yohimbine HCL: protocol for a double-blind, randomized controlled study implementing subjective and objective measures of treatment outcome. Contemp Clin Trials 2013; 36:319–326
20.
Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M: Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry 2004; 61:1136–1144
21.
Rauch SAM, King AP, Abelson J, Tuerk PW, Smith E, Rothbaum BO, et al.: Biological and symptom changes in posttraumatic stress disorder treatment: a randomized clinical trial. Depress Anxiety (in press)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 1034 - 1037
PubMed: 25272341

History

Accepted: July 2014
Published online: 1 October 2014
Published in print: October 2014

Authors

Details

Peter W. Tuerk, Ph.D.
From the Ralph H. Johnson VA Medical Center, Veterans Health Administration, Charleston, S.C.; and the Department of Psychiatry and Behavioral Sciences, Military Sciences Division, Medical University of South Carolina, Charleston, S.C.

Notes

Address correspondence to Dr. Tuerk ([email protected]).

Competing Interests

Dr. Tuerk was supported by a research award from the Department of Veteran Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development (PI: Tuerk; NCT01031979). Dr. Freedman has reviewed this editorial and found no evidence of influence from this relationship.

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