Retrieval-dependent Nitrous Oxide Therapy (R-NOT): A novel treatment for Post-traumatic Stress Disorder (PTSD)

The context and challenge: Posttraumatic stress disorder (PTSD) is a prevalent, debilitating and persistent psychiatric condition that causes severe social and occupational impairment. The lifetime prevalence rate is 7-8%, although some occupational groups (e.g. first responders) and communities (e.g. asylum seekers) are especially vulnerable to stress-related disorders. Without effective treatment, PTSD follows a chronic course and contributes to numerous physical and psychiatric comorbidities.

Existing therapies for PTSD are resource-intensive yet ineffective in many patients. In well-controlled clinical trials, <60% of patients are classified as recovered at the end of treatment. Real-world data on first-line treatments suggests a more pessimistic outlook, with recovery rates of <40%.

Although new treatments are being developed, few have well-defined mechanistic targets, so their efficacy and durability may be suboptimal. However, recent advances in cognitive neuroscience and experimental psychopathology suggest that novel therapies that target a single, mechanistically 'central' symptom of PTSD - intrusive memories (IMs) - might produce rapid, generalised and sustained reductions in symptoms.

Simultaneously, research on pharmacological treatments suggests that, in addition to rapid antidepressant effects, NMDA receptor antagonists (NMDA-RAnts) may have rapid symptom-suppressing effects in PTSD.

Aims/objectives: Acknowledging the critical role of distressing IMs in the persistence of PTSD, we propose using the ketamine-like NMDA-RAnt, nitrous oxide (N2O) in a new way to weaken or 'overwrite' traumatic memory networks that underlie IMs in people with PTSD. Like subanaesthetic ketamine, 50%-N2O is a rapidly-acting antidepressant that may also rapidly suppress PTSD symptoms.

While these effects would be clinically significant in their own right, their short-lived nature may limit N2O's utility as a scalable treatment for PTSD. Our solution, therefore, combines N2O with a procedure for activating the 'retrieval-dependent plasticity' of specific traumatic memories. We predict that this combination will persistently reduce IMs and, hence, produce long-lasting and generalised reductions in PTSD symptoms.

We aim to test this novel approach in the current project. Firstly, in two small-scale open-label studies, we will design and refine a prototype of Retrieval-dependent Nitrous Oxide Therapy (R-NOT) to ensure it is feasible, safe and acceptable to patients. We will then conduct an RCT of multi-session R-NOT in people with PTSD awaiting psychotherapy.

Participants receiving R-NOT will undergo a memory retrieval procedure to activate plasticity in targeted trauma memory networks and then receive 50%-N2O gas to disrupt these temporarily 'malleable' networks. Two control conditions - retrieval-plus-placebo (medical air) and N2O-without-prior-retrieval (retrieval occurs after recovery from N2O) - will allow us to test the hypothesis that rapid reductions in PTSD symptoms following 50%-N2O treatment will only be sustained at follow-up in those receiving prior memory retrieval (R-NOT).

Potential applications and benefits: We hypothesise that unlike existing treatments (and most novel competing solutions), R-NOT will be rapidly acting and disease-modifying, producing lasting symptom improvement and protection against recurrence/relapse. Due to its brief nature and modest requirements for service adaptations and clinician training, R-NOT should find application in a range of NHS settings, including primary and secondary care mental health services where PTSD is typically treated.

Notably, the target symptom - IMs - is common to numerous psychological disorders (depression, anxiety and substance use disorders). A proof-of-concept demonstration of R-NOT's efficacy in PTSD would, therefore, serve as a springboard for the development of an array of similar interventions adapted to these other common psychological disorders.