Background: Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves inhibitory learning where the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and might have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown.Methods: We used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. In a double-blind parallel design, healthy volunteers were randomly assigned to single-dose losartan (50mg) (N=28) versus placebo (N=25). Participants then performed a reinforcement learning task which simultaneously probes appetitive and aversive learning. Participant choice behaviour was analysed using both a standard reinforcement learning model and analysis of choice switching behaviour.Results: Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behaviour. Conclusion:This study shows that losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations.

Dysfunctional appraisals are a key factor suggested to be involved in the development and maintenance of PTSD. Research has shown that experimental induction of a positive or negative appraisal style following a laboratory stressor affects analogue posttraumatic stress symptoms. This supports a causal role of appraisal in the development of traumatic stress symptoms and the therapeutic promise of modifying appraisals to reduce PTSD symptoms. The present study aimed to extend previous findings by investigating the effects of experimentally induced appraisals on reactions to a naturally occurring analogue trauma and by examining effects on both explicit and implicit appraisals. Participants who had experienced a distressing life event were asked to imagine themselves in the most distressing moment of that event and then received either a positive or negative Cognitive Bias Modification training targeting appraisals (CBM-App). The CBM-App training induced training-congruent appraisals, but group differences in changes in appraisal over training were only seen for explicit and not implicit appraisals. However, participants trained positively reported less intrusion distress over the subsequent week than those trained negatively, and lower levels of overall posttraumatic stress symptoms. These data support the causal relationship between appraisals and trauma distress, and further illuminate the mechanisms linking the two.

Introduction: Dysfunctional appraisals about traumatic events and their sequelae are a key mechanism in posttraumatic stress disorder (PTSD). Experimental studies have shown that a computerized cognitive training, cognitive bias modification for appraisals (CBM-APP), can modify dysfunctional appraisals and reduce analogue trauma symptoms amongst healthy and subclinical volunteers. Objective: We aimed to test whether CBM-APP could reduce dysfunctional appraisals related to trauma reactions in PTSD patients, and whether this would lead to improvements in PTSD symptoms. Methods: We compared CBM-APP to sham training in a parallel-arm proof-of-principle double-blind randomized controlled trial amongst 80 PTSD patients admitted to an inpatient clinic. Both arms comprised a training schedule of 8 sessions over a 2-week period and were completed as an adjunct to the standard treatment programme. Results: In intention-to-treat analyses, participants receiving CBM-APP showed a greater reduction in dysfunctional appraisals on a scenario task from pre- to posttraining (primary outcome) assessments, compared to those receiving sham training (d = 1.30, 95% CI 0.82–1.80), with between-group differences also found on the Posttraumatic Cognitions Inventory (PTCI; d = 0.85, 95% CI 0.39–1.32) and the PTSD Checklist for DSM-5 (PCL-5; d = 0.68, 95% CI 0.23–1.14), but not for long-term cortisol concentrations (d = 0.25, 95% CI –0.28 to 0.78). Reductions in dysfunctional appraisals assessed via the scenario task correlated with reductions on the PTCI, PCL-5, and hair cortisol concentrations from pre- to posttraining time points. Conclusions: Results support dysfunctional appraisals as a modifiable cognitive mechanism, and that their proximal modification transfers to downstream PTSD symptoms. These findings could open new avenues for improving present therapeutic approaches.

The angiotensin-II antagonist losartan is a promising candidate that has enhanced extinction in a post-traumatic stress disorder (PTSD) animal model and was related to reducing PTSD symptom development in humans. Here, we investigate the neurocognitive mechanisms underlying these results, testing the effect of losartan on data-driven and contextual processing of traumatic material, mechanisms proposed to be relevant for PTSD development. In a double-blind between-subject design, 40 healthy participants were randomized to a single oral dose of losartan (50mg) or placebo, 1 hr before being exposed to distressing films as a trauma analogue while heart rate (HR) was measured. Peritraumatic processing was investigated using blurry picture stimuli from the films, which transformed into clear images. Data-driven processing was measured by the level of blurriness at which contents were recognized. Contextual processing was measured as the amount of context information retrieved when describing the pictures' contents. Negative-matched control images were used to test perceptual processing of peripheral trauma-cues. Post-traumatic stress symptoms were assessed via self-report questionnaires after analogue trauma and an intrusion diary completed over 4 days following the experiment. Compared to placebo, losartan facilitated contextual processing and enhanced detail perception in the negativematch pictures. During the films, the losartan group recorded lower HR and higher HR variability, reflecting lower autonomic stress responses. We discuss potential mechanisms of losartan in preventing PTSD symptomatology, including the role of reduced arousal and increased contextual processing during trauma exposure, as well as increased threat-safety differentiation when encountering peripheral trauma-cues in the aftermaths of traumatic events.