Metacognition in psychosis: a renewed path to understanding of core disturbances and recovery‐oriented treatment

Abstract

359 and tocilizumab and, equally importantly, the lack of benefits of hydroxychloroquine, lopinavir-ritonavir and azithromycin in patients hospitalized with COVID-19. The speed and power of the results obtained from a trial of extreme simplicity, with a singleminded dedication to maximizing recruitment across a health system, are impressive. By radical simplification of procedures to minimize patient and clinician burden, RECOVERY has provided an example of a sustainable rolling trial platform which allows the sequential evaluation of multiple agents. The simplicity and speed of RECOVERY did not come at the cost of sacrificing quality or the short-cutting of ethical or regulatory oversight. Instead, the RECOVERY investigators worked closely with both the ethics committees and the UK regulator in parallel with setting up the trial, achieving a hitherto unimagined speed of trial set-up. I believe that we urgently need to apply the lessons learned from RECOVERY in mental health trials. We have previously identified the potential for large, streamlined trials in mental health, although this approach remains unusual. One exception is the BALANCE trial comparing long-term treatments in bipolar disorder. In this trial, we did radically simplify procedures and achieved a reasonably sized sample with a clear primary outcome. Building on the example of RECOVERY, we now need to scale up trials such as BALANCE by an order of magnitude to allow multiple arms and deliver strong evidence of modest (but worthwhile) treatment effects. There is no shortage of important clinical questions that need answering via large-scale, streamlined, directly randomized studies. As with RECOVERY, we should initially focus on comparative efficacy of existing, licensed interventions, adding more innovative treatments once the platform is up-and-running. A prime illustrative example is the comparative efficacy of antidepressant drugs. A network meta-analysis reported that there are potentially clinically important differences between 21 available antidepressants, but that nearly all the comparative data are indirect and based on pre-regulatory approval trials. This is a major gap in the evidence base and a substantial barrier to knowing which antidepressant might be most likely to be effective for any specific patient – the goal of precision psychiatry. Large-scale, streamlined trials should be designed in partnership with a broad range of stakeholders, including patients, regulators and industry, and recruiting a broad range of patients from routine clinical settings. Large-scale recruitment can be facilitated by using electronic health records. Progressing this idea using the momentum and learning from RECOVERY seems to be an outstanding opportunity for mental health clinicians, researchers and patients, and needs to be supported by funders. Finally, the COVID pandemic helps to clarify the relative strengths of randomized and observational studies. Early on, considerable publicity was given to small, uncontrolled reports of the potential benefits of hydroxychloroquine. A report of routinely collected observational data seemed to confirm this, only to be quickly retracted. RECOVERY found no benefit of hydroxycholoquine in severely ill patients, although there remains the possibility that it might be effective in very early or mild cases. This demonstrates the danger of retrospective analyses of data of uncertain provenance as well as the power of large simple randomized controlled trials. On the other hand, observational data of infection rates following vaccinations were hugely reassuring, given the remaining uncertainties around vaccine efficacy in specific patient subgroups. Observational data can extend and confirm the results of randomized trials, which will always remain smaller and less representative. These data are increasingly available via electronic care records and, although susceptible to residual confounding even after multivariate propensity score matching, may be very valuable for post-marketing safety surveillance and confirmation of treatment effects in larger, more representative datasets. In conclusion, despite the human tragedy and suffering, the COVID-19 pandemic has inspired some outstandingly creative responses from the international research community. We need to capture this and apply it to the major global challenge of mental illness, building on the developing international collaborative efforts. We should draw inspiration from just how much can be achieved so quickly with a clearly defined objective and common sense of purpose and urgency.