Pharmacological memory modulation to augment trauma-focused psychotherapy for PTSD: a systematic review of randomised controlled trials

Trauma-focused psychotherapy (tf-PT) is the first-line treatment for posttraumatic stress disorder (PTSD). Tf-PT focuses on processing and modulating trauma memories. Not all patients benefit, however, and there is room for improvement of efficacy. Pharmacologically augmenting trauma memory modulation in the context of tf-PT may help optimise treatment outcome. To systematically review effects of pharmacologically augmented memory modulation in the context of tf-PT for PTSD (PROSPERO preregistration ID: CRD42021230623). We conducted a systematic review of randomised controlled trials of psychotherapy treatment for PTSD. We included placebo-controlled studies that augmented at least one treatment session pharmacologically targeting memory extinction or reconsolidation. We calculated post-treatment between group (pharmacological augmentation vs placebo control) effect sizes of PTSD symptom severity. We included 13 RCTs. There was large heterogeneity in augmentation procedure and methodological quality. Four studies showed significantly greater PTSD symptom reduction in the pharmacological augmentation group (propranolol, hydrocortisone, dexamethasone, D-cycloserine) compared to placebo. Seven studies showed no significant effect of pharmacological augmentation compared to placebo (D-cycloserine, rapamycin, mifepristone, propranolol, mifepristone combined with D-cycloserine, methylene blue). Two studies showed significantly smaller PTSD symptom reduction in the pharmacological augmentation group (D-cycloserine, dexamethasone) compared to placebo. Results of pharmacological augmentation were mixed overall and heterogenous for the pharmacological agents tested in more than one study. Additional studies and replications are needed to identify which pharmacological agents work, in which combination and to identify patient groups that benefit most to tailor PTSD treatment.