Post-traumatic stress disorder - Emerging treatments

Topiramate

Two small randomised controlled trials (RCTs) have produced conflicting results regarding the efficacy of topiramate over placebo in PTSD. Two meta-analyses recommended its use as monotherapy.[75][87] However, these meta-analyses included a small augmentation study, where a mix of psychotropic medications were allowed across the experimental and placebo groups. When data from augmentation studies were excluded in another meta-analysis, topiramate showed no evidence of superiority over placebo, and therefore it cannot be recommended as an evidence-based monotherapy treatment for PTSD.[86] In general, there is insufficient evidence to recommend it as a treatment.[86][98][99] However, the American Academy of Sleep Medicine recommends topiramate for the treatment of PTSD-associated nightmares.[100]

Alternative therapies

Systematic reviews of acupuncture and mantram (mantra) repetition have shown promise, but the evidence is currently insufficient to recommend these interventions.[101]

Medical devices/software applications

The US Food and Drug Administration (FDA) has granted a smartphone app, NightWare®, breakthrough device designation for the treatment of nightmares in people with PTSD. During sleep, a smartwatch tracks body movement and heart rate to detect nightmares. The watch then vibrates, rousing the wearer enough to stop the nightmare but without waking them. In a small, sham-controlled RCT the group using NightWare® reported greater improvements in sleep at 30 days. Larger RCTs are ongoing.[102]

Internet-based cognitive and behavioural therapies

Results from a small number of trials suggest some beneficial effects of internet-based cognitive and behavioural therapies for PTSD. Further studies are in progress, and are required in order to establish non-inferiority to current first-line interventions.[103]

Virtual reality therapy

A small trial examining the use of audio-visual simulations of traumatic combat situations and post-disaster conditions to facilitate exposure-based psychological interventions showed promising results.[104] Two meta-analyses have subsequently concluded that virtual reality therapy may be useful as a form of exposure therapy when other treatments have failed.[105][106] Data from robust RCTs are needed to confirm the role of virtual reality therapy in this therapy area.

N-methyl-D-aspartate (NMDA) receptor agonists and antagonists

The use of NMDA receptor agonists (e.g., D-cycloserine) to enhance exposure-based psychological interventions has been reported in relation to obsessive-compulsive disorder, social phobia, and panic disorder. Guidelines have reported the potential for such agents to be used to augment psychotherapy in the treatment of PTSD.[44] However, evidence for D-cycloserine and other NMDA agonists in this indication remains inconclusive.[107][108] Another approach is to target and downregulate behavioural sensitisation through antagonism of the NMDA receptor. A phase 1 RCT investigated whether 3 infusions of NMDA receptor antagonist lanicemine affected behavioural sensitisation compared with placebo in people with PTSD. The study failed to meet its primary endpoint, which was change in anxiety-potentiated startle (APS) from baseline to end of third infusion. However, a single infusion had a more promising effect on APS, and lanicemine was generally well tolerated. It is likely that lanicemine will be pursued in further studies.[109]

3,4-methylendioxymethamphetamine (MDMA)-assisted psychotherapy

MDMA-assisted therapy has been investigated in numerous phase 3 RCTs, primarily led by the not-for-profit group Multidisciplinary Association of Psychedelic Studies (MAPS). In a systematic review of drug-assisted therapies for PTSD, MDMA-assisted therapy was the only intervention that showed superiority to placebo.[110] MDMA-assisted therapy demonstrated a large effect size, with clinically and statistically significant gains versus active and inactive placebo-assisted therapy. In the US, the FDA granted breakthrough therapy designation for MDMA-assisted therapy in 2017, with an expanded access programme agreed in 2019. FDA approval is likely to follow given the positive results of the phase 3 studies.

Eszopiclone

Two small RCTs have investigated eszopiclone for the treatment of PTSD and associated insomnia. Neither study found significant improvements in sleep compared with placebo.[111][112] A study by the US Department of Veterans Affairs is underway to compare the effect of eszopiclone alongside trazodone and gabapentin in veterans diagnosed with PTSD and insomnia.[113]