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 post-traumatic stress disorder (PTSD). Two meta-analyses recommended its use as monotherapy.[87][99] However, these meta-analyses included a small augmentation study, where a mix of psychotropic drugs 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.[98] In general, there is insufficient evidence to recommend it as a treatment.[98][111][112] However, the American Academy of Sleep Medicine recommends topiramate for the treatment of PTSD-associated nightmares.[113]

Alternative therapies

Systematic reviews of acupuncture and mantram (mantra) repetition have shown promise, but the evidence is currently insufficient to recommend these interventions.[114]

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.[115]

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. One randomized controlled trial (RCT) found that guided internet-based cognitive behavioural therapy (CBT) with a trauma focus was non-inferior to individual face-to-face CBT for treatment of mild to moderate PTSD.[116] Another RCT found that internet-based CBT with a trauma focus was superior to internet-based stress management therapy for PTSD.[117] Further studies are in progress, and are required in order to establish non-inferiority to current first-line interventions.[118]

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.[119] Two meta-analyses have subsequently concluded that virtual reality therapy may be useful as a form of exposure therapy when other treatments have failed.[120][121] 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.[4] However, evidence for D-cycloserine and other NMDA agonists in this indication remains inconclusive.[122][123] 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.[124]There is also emerging evidence that the NMDA receptor antagonist ketamine rapidly reduces PTSD symptoms in combination with psychotherapy.[125][126][127] Further investigation of the benefits of ketamine-assisted psychotherapy for PTSD is needed.

3,4-methylendioxymethamphetamine (MDMA)-assisted psychotherapy

MDMA-assisted therapy has been investigated in numerous phase 3 randomised controlled trial (RCTs), primarily led by the not-for-profit group Multidisciplinary Association of Psychedelic Studies (MAPS). In the first phase 3 RCT of MDMA-assisted psychotherapy in people with severe PTSD (MAPP1), 67% of those in the MDMA group no longer met diagnostic criteria for PTSD, compared with 32% of those in the placebo group, after three sessions (18 weeks).[128]In a second phase 3 RCT of MDMA-assisted psychotherapy in people with moderate or severe PTSD (MAPP2), 71% of those in the MDMA group no longer met diagnostic criteria for PTSD, compared with 47.6% of those in the placebo group, after three sessions (18 weeks).[129] In one systematic review of drug-assisted therapies for PTSD, MDMA-assisted therapy was the only intervention that showed superiority to placebo.[130] 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.