Response

Many individuals feel markedly anxious before and during performance tasks such as speaking in public, and ‘performance anxiety’ is a key symptom domain in individuals with social anxiety disorder. Unfortunately practice does not always make perfect, despite applying techniques drawn from cognitive-behaviour theories, and avoidance of performance and other social activities can sometimes become troublesome: beta-blockers or benzodiazepines may be taken in anticipation of performance challenges, despite limited evidence to support their use in those situations. Hence, there is scope for the development of novel psychological or pharmacological approaches to reduce the psychological distress and physical symptoms associated with performance tasks. In this issue, He et al describe the potential efficacy and tolerability of a double-blind, randomised, placebo-controlled trial of an investigational compound with a novel mechanism of action (‘VQW-765’, previously designated ‘AQW051’), in individuals with public speaking anxiety, of whom approximately 80% had moderate to severe social anxiety symptoms. ^{Reference He, Polymeropoulos, Mohrman, Truslow, Xiao and Wu1}

Preclinical studies suggest that the alpha-7 nicotinic acetylcholine receptor (α7-nAChR) is important in neurotransmitter release (its activation reduces glutamatergic and increases GABAergic neurotransmission), cognitive functioning and the acute stress response. ^{Reference Lee and Hung2} VQW-765 was found to increase social behaviour in rodents, similarly to the benzodiazepine chlordiazepoxide, with an inverted U-shaped dose–response relationship, ^{Reference Feuerbach, Pezous, Weiss, Shakeri-Nejad, Lingenhoehl and Hoyer3} and another α7-nAChR negative-allosteric modulator (‘BNC210’) has shown anxiolytic effects across some anxiety-related disorders. ^{Reference Hampsey, Perkins and Young4} He et al report that, when compared with placebo, a single dose of compound VQW-765 was associated with significantly lower levels of psychological subjective distress during performance of the Trier Social Stress Test (TSST) in female participants, with evidence of an inverted U-shaped plasma level–response relationship. ^{Reference He, Polymeropoulos, Mohrman, Truslow, Xiao and Wu1}

There are limitations relating to trial design and description: as examples, critics will note that all authors are/were employees of the pharmaceutical company responsible for development of the compound; that exclusion criteria resulted in a study population substantially different to treatment-seeking subjects; that the task of preparing a 5-min speech for a mock job interview in the TSST might have variable ecological applicability; and that some previous investigations have indicated that the TSST may be a suboptimal experimental paradigm for inducing performance anxiety in male participants. ^{Reference Labuschagne, Grace, Rendell, Terrett and Heinrichs5} We recently developed an online social interaction challenge for social anxiety disorder ^{Reference Huneke, Rowlatt, Hyde, McEwan, Maryan and Baldwin6} that addresses some of these limitations; this challenge involves ‘getting to know’ another person for 5 min (improved ecological validity) while participants are ‘observed’ by 3 judges (in reality, ‘dummy’ accounts). We found that anxiety during the challenge was predicted specifically by trait social anxiety symptoms rather than by other anxiety disorders, ^{Reference Huneke, Rowlatt, Hyde, McEwan, Maryan and Baldwin6} suggesting potential utility in testing novel treatments for social anxiety disorder. Furthermore, while the authors suggest that the compound could be developed as an ‘on-demand’ treatment for acute symptoms in social anxiety disorder, the study population was recruited on the basis of a history of public speaking anxiety rather than the diagnosis of a specific anxiety disorder.

The study report contains several intriguing findings that have some bearing on future trial design and drug development. First, the investigation was conducted during the second year of the Covid-19 pandemic, and the vast majority (95%) of participants wore a face mask during the study procedures. Previous studies have indicated that mask wearing might reduce symptom severity when interacting or performing in social situations in individuals with social anxiety disorder, ^{Reference Saint and Moscovitch7} and an exploratory comparison of the findings of this investigation with a similar study suggests that mask wearing might reduce emergent psychological distress in placebo-administered participants, thereby reducing the ability to detect drug–placebo differences. Second, the rather nuanced plasma level–response relationship, if replicated in further investigations, implies that it would first be necessary to ascertain the achieved plasma level following single drug administration on a personalised medicine basis, to determine the optimal dosage subsequently to be taken by an individual patient when anticipating distressing anxiety during a public performance task. Third, the recorded effects of study medication on a measure of heart rate variability (HRV) in a subsample of study participants – in which VQW-765 was associated with a more rapid and greater decline in HRV in response to the TSST, compared with the decline seen with placebo – are somewhat hard to interpret.

Meta-analysis indicates that the normal physiological phenomenon of variability in heart rate during respiration is altered in anxiety disorders or post-traumatic stress disorder, with individuals showing evidence of lower resting HRV when compared with controls ^{Reference von Majewski, Kraus, Rhein, Lieb, Erim and Rohleder8}  (although, interestingly, there is an apparently blunted response in HRV reactivity to physical or psychological challenge), and reduced HRV could be a potential marker of anxiety-related disorders. ^{Reference Tomasi, Zai, Pouget, Tiwari and Kennedy9} The HRV measure employed by He et al (root mean square of successive differences between heartbeats) may not be optimal, but the observation that VQW-765 administration was associated with a steady increase in HRV during the performance phase of the TSST is novel and worthy of repeated evaluation.

Should further studies support the finding that administration of a compound with this mechanism of action can reduce psychological distress during a performance challenge, and if other investigations attest to its safety and tolerability, there will need to be careful consideration about the potential benefits and risks of its use in ‘real-world’ situations. Might individuals with unsettling anxiety and troublesome avoidance be helped to overcome their difficulties, to reach their full potential at work and in social situations? Or could a developing reliance on a pharmaceutical ‘quick fix’ for reducing distress inhibit the steady acquisition of self-confidence and presentational skills that might otherwise be achieved by determined practice and psychotherapeutic support? Furthermore, might there be an additional hazard, of ‘cosmetic psychopharmacology’, that such medication could also be taken by psychologically robust individuals striving to gain an advantage in competitive employment? Drug development programmes for novel psychotropics should be mindful of such hazards when evaluating the probable effectiveness, acceptability and safety of potential novel anxiolytics.