Schrödinger's Cat and d-Cycloserine to Augment Exposure Therapy-Both Are Alive and Dead.

Pediatric obsessive-compulsive disorder (OCD) is treated effectivelywithcognitivebehavior therapy(CBT).However, there is clearly room for further improvement, and the exposure strategies used in this treatment are often distressing to patients. Therefore, it is desirable to improvetheefficacyof CBTor to accelerate the treatment response. Attempts to improve the efficacy of CBT with traditional anxiolytic pharmacological agents, such as selective serotonin reuptake inhibitors, have beendisappointing. Amore promising strategy to augment CBT might be with the use of a cognitive enhancer, which was the objective of the study by Storch and colleagues1 in this issue of JAMA Psychiatry. One important therapeutic strategy during CBT for anxiety disorders is repeated or prolonged exposure to threat cues, which is based on extinction learning.2 The results of preclinical studies suggest thatextinction learning ismodulatedbyactivityof theglutamatergic N-methyl-D-aspartate receptor in the amygdala. D-cycloserine (D-4-amino-3-isoxazolidinone), apartial agonist at the glycine recognition site of the glutamatergicN-methylD-aspartatereceptorpartialagonists,enhancesthis learningprocess (eg, see the study byWalker et al3). Therefore, clinical researchers have examined whether D-cycloserine might also enhance exposure procedures in humans. After the initial excitement fueledbypromisingpilot data fromD-cycloserine augmentation trials, a number ofmore recent and large-scale studies have since been conducted that revealed more disappointing results.4 In fact, a recent meta-analysis5 demonstrated that D-cycloserinedoesnot augment CBT for anxiety disorders, contradicting earlier metaanalyses and reviews. Some data suggested that adding D-cycloserine to exposure for patients might even worsen symptoms.6 In OCD research, 2 earlier studies with adult patients demonstrated no differences in improvement between D-cycloserine and placebo on anymain outcomemeasures at posttreatment and follow-up but showed some evidence of faster improvement and fewer dropouts in the D-cycloserine group.7,8Astudy9ofpediatricpatientswithsevereanddifficultto-treat OCD reported greater improvements (especially in obsessional severity) among patients who received D-cycloserine. In contrast, another study10 found no difference in degree or rate of improvement between pediatric patientswith OCDwho received D-cycloserine or placebo. However,a later trialby thesameinvestigative teamreportedasmall tomoderate (butnonsignificant)effect favoringD-cycloserine.11 Themain limitation of these early proof-of-concept trialswas the small sample sizes. Furthermore, these studies oftenused truncated CBT protocols, thereby limiting the internal and external validity of the study findings. Since then, a number of well-controlled and wellpowered clinical trials were conducted to examine whether D-cycloserine augments standard CBT for social anxiety disorder,12 posttraumatic stress disorder,13 and OCD.14 The sample sizes of these studies (ranging between 106 and 169) not only allowed for a clearer interpretation of the data but also gave investigators the opportunity to conduct additional post hoc analyses that revealed some interesting results that might explain some of the inconsistent findings in earlier studies. The results of the present study by Storch and colleagues1 are in line with these other well-powered studies in that they showednoclear D-cycloserine augmentation effect in the total sample. However, post hoc analyses of some of these studies demonstrated some notable findings. One of these trials12 found that patients with social anxiety disorder who received D-cycloserine plus CBT had a faster response earlier in treatment compared with those who received placebo plus CBT. Moreover, patients who reported low fear at the end of a CBT session showed a clear advantage for D-cycloserine vs placebo augmentation, andanoppositepatternemerged for thosewho reported high fear at the end of a CBT session. Similarly, the study13ofpatientswithposttraumaticstressdisorder foundthat D-cycloserine augmentation demonstrated a specific advantage for the stronger extinction learners within their sample. Theseresultssupport thehypothesis thatD-cycloserinenotonly makes“goodexposures”better (by facilitatingextinction learning) but also maymake “bad exposures” worse, based on evidence suggesting that D-cycloserine enhances reconsolidation of fear memory.15 Unfortunately, Storch and colleagues1 were unable to examine this effect in their trial due to limitations in the study design. Another post hoc analysis of a trial among adult patients with OCD revealed a significant interaction of D-cycloserine effects with antidepressantmedication.14 In the D-cycloserine group (but not the placebo group), a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up than antidepressantmedicated patients. Many youth received prior selective serotonin reuptake inhibitor treatment in the trial by Storch and colleagues,1 which might have interfered with the effect of D-cycloserine, as shown in the study by Andersson et al.14 Finally, it is also possible that D-cycloserine might simply work differently inpatientswithOCDthan inotherpopulationswith Related article page 779 Opinion