Acquisition, extinction, and return of fear in veterans in intensive outpatient prolonged exposure therapy: A fear-potentiated startle study.

Prolonged exposure (PE) therapy is a first-line treatment for posttraumatic stress disorder (PTSD) and involves repeated presentation of trauma-related cues without aversive outcomes. A primary learning mechanism of PE is fear extinction (new learning that a dangerous cue is now safe) and its retention (maintaining this new learning over time). Extant research suggests extinction is impaired in PTSD patients. In this study, we employed an established fear-potentiated startle-based paradigm to examine fear acquisition, extinction learning and retention before and after completion of intensive outpatient treatment. First, PTSD patients undergoing PE (n = 55) were compared to trauma-exposed patients without PTSD (n = 57). We identified excessive fear in PTSD patients during acquisition and extinction before treatment compared to non-PTSD patients. At post-treatment, we examined the return of fear after extinction in PTSD patients showing high or low treatment response to PE (≥50% change in PTSD symptom severity vs. < 50%). High PE responders maintained fear extinction learning whereas low PE responders showed significant return of fear at post-treatment. These results replicate and extend previous findings of impaired extinction in PTSD and provide support for the proposed theoretical link between fear extinction and PE response.

A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults.

BACKGROUND: Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention. AIMS: This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans. METHODS: The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21-55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants (N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events. RESULTS: Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007). CONCLUSION: Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention.Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9.

When translational neuroscience fails in the clinic: Dexamethasone prior to virtual reality exposure therapy increases drop-out rates.

Posttraumatic stress disorder (PTSD) is characterized by exaggerated expression of fear responses to danger and safety cues. Translational research suggests that dexamethasone facilitates fear extinction in animal and human fear conditioning models. For this randomized, placebo-controlled trial (N = 27), we aimed to translate these findings to the clinic by using virtual reality exposure (VRE) therapy for OEF/OIF/OND veterans with PTSD to determine whether dexamethasone will increase the efficacy of exposure therapy for VRE relative to placebo. VRE sessions involved imaginal exposure to the most traumatic war memories while viewing a computer-generated view of virtual Iraq or Afghanistan with multisensory stimulus options used to match patient's description of the trauma. VRE was effective in reducing PTSD symptoms but there was no interaction with dexamethasone. Drop-out rate was significantly higher in the dexamethasone group, with 10 of 13 (76.9%) participants in this group discontinuing, compared to only 4 of 14 (28.5%) in the placebo group, χ2 = 6.31, p = 0.02. Results indicate that the dexamethasone group may have experienced an increase in PTSD symptoms, particularly re-experiencing, at session 2 following first drug administration. Contrary to study hypotheses, dexamethasone did not enhance exposure therapy outcomes and was associated with increased drop-out. This demonstrates potential pitfalls in translating neuroscience models to the clinic; future research carefully examining glucocorticoid mechanisms involved in therapy augmentation is warranted.