The past two decades have seen an increasing recognition of the contribution of mental disorders to global disease burden. There has also been an awareness that therapeutic innovation based on sound understanding of disease mechanisms has evaded single companies working within a conventional competitive market-based model. Governments, charities and philanthropists are increasingly willing to fund research programmes, and several collaborative initiatives and networks have emerged in recent years. For example, we soon expect the launch of the Health Brains Global Initiative (https://www.hbgi.org), which aims to “address market failures by galvanizing new science and new finance to enable new life trajectories”.

Those of us involved in brain health research have a responsibility to take this opportunity, but we need to identify clear objectives and priorities to ensure that we deliver real advances. Inspiration and exemplars can be drawn from many areas of collaborative science. An example is the global response to the COVID-19 pandemic, where, alongside the dreadful death toll and enormous human suffering, we have observed the extraordinary acceleration in research success that is possible when researchers and funders collaborate with shared purpose, and prioritize and coordinate their efforts.

The extraordinary response to COVID-19 has not emerged out of the blue. The global research community had learned from previous inadequate responses to infectious disease outbreaks and created the partnerships and platforms to ensure a state of preparedness for emerging epidemics. The International Severe Acute Respiratory and emerging Infection Consortium (https://isaric.tghn.org) was funded in 2011 to ensure a rapid clinical research response to epidemics. The Coalition for Epidemic Preparedness Innovations (https://cepi.net) was launched in 2017 with a mission to “stimulate and accelerate the development of vaccines against emerging infectious diseases and enable access to these vaccines for people during outbreaks”.

What are the key areas in trial design and conduct that have delivered the vaccines? A key area has been the standardization of early phase clinical trials. Vaccine development is not alone here – the critical contribution of phase II trials in providing crucial go-no-go evidence at earlier phases of development (rather than waiting to discover lack of efficacy in highly costly phase III trials) has been recognized for almost two decades¹. This is most effective when illness mechanism is understood and biomarkers/interim outcomes can be reliably linked to clinical outcomes. Hence, phase II vaccine trials assess immune response rather than clinical outcomes².

Pathogenetic understanding of mental disorders is still limited, but the tactic of reverse translation, investigating the effects of treatments of known efficacy on biomarkers, has been productive. For example, antidepressant drugs have rapid effects on emotional bias, and this is a useful experimental measure of potential longer-term therapeutic effect³. Emotional bias is now used frequently in early phase studies as an indicator of longer-term clinical benefit of putative antidepressants.

An additional striking feature of the COVID-19 vaccine development has been the disruption of the standard linear sequential approach. Phase II/III trials have been planned and set up – using efficient combination designs – while preliminary studies were just getting underway. We have previously suggested that a non-linear, iterative approach might also be of benefit in drug development in psychiatry⁴.

The COVID-19 pandemic also provides an excellent example of the power of embedding a highly simplified, randomized trial platform comparing available and licensed medicines in real world settings. The RECOVERY trial was rapidly designed and set up in March 2020⁵. It randomized over 35,000 patients by February 2021. By that time, it had demonstrated the benefits of dexamethasone 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 single-minded 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 health⁶, although this approach remains unusual. One exception is the BALANCE trial comparing long-term treatments in bipolar disorder⁷. 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 trials⁸. 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 psychiatry⁹.

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.

过去二十年，人们越来越认识到精神障碍对全球疾病负担的影响。人们还认识到，基于对疾病机制的充分理解的治疗创新已经避开了在传统的竞争性市场模式下运作的单一公司。政府、慈善机构和慈善家越来越愿意资助研究项目，近年来出现了一些合作倡议和网络。例如，我们很快就会推出“健康大脑全球计划”(https://www.hbgi.org)，该计划旨在“通过激发新科学和新金融来解决市场失灵问题，从而实现新的生活轨迹”。

我们这些参与大脑健康研究的人有责任抓住这个机会，但我们需要确定明确的目标和优先事项，以确保我们取得真正的进展。合作科学的许多领域都可以汲取灵感和范例。一个例子是全球对 COVID-19 大流行的反应，除了可怕的死亡人数和巨大的人类痛苦之外，我们还观察到，当研究人员和资助者本着共同目标进行合作，并优先考虑和协调时，研究成功的速度可能会显着加快。他们的努力。

对 COVID-19 的非凡反应并不是突然出现的。全球研究界从之前对传染病爆发的不充分反应中吸取了教训，并建立了伙伴关系和平台，以确保对新出现的流行病做好准备。国际严重急性呼吸系统和新发感染联盟 (https://isaric.tghn.org) 于 2011 年获得资助，以确保对流行病做出快速临床研究反应。流行病防范创新联盟 (https://cepi.net) 于 2017 年成立，其使命是“刺激和加速新发传染病疫苗的开发，并使人们在疫情爆发期间能够获得这些疫苗”。

交付疫苗的试验设计和实施的关键领域有哪些？一个关键领域是早期临床试验的标准化。疫苗开发并不孤单——II 期试验在开发早期阶段提供关键的“不予通过”证据（而不是等待在成本高昂的 III 期试验中发现缺乏疗效）的关键贡献已被近两个国家认可。几十年¹ .当了解疾病机制并且生物标志物/中期结果可以与临床结果可靠地联系起来时，这是最有效的。因此，II 期疫苗试验评估的是免疫反应而不是临床结果² 。

对精神疾病的发病机制的了解仍然有限，但逆向翻译的策略，即研究已知疗效的治疗对生物标志物的影响，已经取得了成效。例如，抗抑郁药物对情绪偏见具有快速作用，这是潜在长期治疗效果的有用实验措施³ 。情绪偏见现在在早期研究中经常被用作假定抗抑郁药长期临床益处的指标。

COVID-19 疫苗开发的另一个显着特点是对标准线性序贯方法的破坏。 II/III 期试验已经计划和建立——使用有效的组合设计——而初步研究刚刚开始。我们之前曾提出，非线性迭代方法也可能对精神病学药物开发有益⁴ 。

COVID-19 大流行还提供了一个很好的例子，展示了嵌入高度简化的随机试验平台的力量，该平台可以比较现实世界中可用和许可的药物。 RECOVERY 试验于 2020 年 3 月迅速设计并启动⁵ 。截至 2021 年 2 月，它对 35,000 多名患者进行了随机分组。到那时，它已经证明了地塞米松和托珠单抗的益处，同样重要的是，羟氯喹、洛匹那韦-利托那韦和阿奇霉素对住院的 COVID-19 患者缺乏益处。通过极其简单的试验以及一心一意地致力于最大限度地扩大整个卫生系统的招募所获得的结果的速度和力量令人印象深刻。

通过彻底简化程序以最大程度地减少患者和临床医生的负担，RECOVERY 提供了可持续滚动试验平台的示例，该平台允许对多种药物进行连续评估。 RECOVERY 的简单性和速度并没有以牺牲质量或走捷径的道德或监管监督为代价。相反，RECOVERY 研究人员在启动试验的同时与伦理委员会和英国监管机构密切合作，实现了迄今为止难以想象的试验启动速度。

我认为我们迫切需要将“康复”中吸取的经验教训应用到心理健康试验中。我们之前已经发现了在心理健康领域进行大规模、简化试验的潜力⁶ ，尽管这种方法仍然不寻常。一个例外是比较双相情感障碍长期治疗的 BALANCE 试验⁷ 。在这次试验中，我们从根本上简化了程序，并获得了合理大小的样本和明确的主要结果。以 RECOVERY 为例，我们现在需要将 BALANCE 等试验规模扩大一个数量级，以允许使用多个试验组，并提供有力的证据来证明适度（但有价值）的治疗效果。

不乏需要通过大规模、简化、直接随机研究来回答的重要临床问题。与 RECOVERY 一样，我们首先应该关注现有许可干预措施的比较疗效，一旦平台启动并运行，就添加更多创新治疗方法。一个主要的说明性例子是抗抑郁药物的功效比较。一项网络荟萃分析报告称，21 种可用的抗抑郁药之间存在潜在的临床重要差异，但几乎所有比较数据都是间接的，并且基于监管批准前的试验⁸ 。这是证据基础上的一个重大空白，也是了解哪种抗抑郁药最有可能对任何特定患者有效的重大障碍——精准精神病学的目标⁹ 。

大规模、简化的试验应与广泛的利益相关者（包括患者、监管机构和行业）合作设计，并从常规临床环境中招募广泛的患者。使用电子健康记录可以促进大规模招募。利用“恢复”的动力和学习来推进这一想法对于心理健康临床医生、研究人员和患者来说似乎是一个绝佳的机会，并且需要资助者的支持。

最后，新冠疫情有助于阐明随机研究和观察性研究的相对优势。早期，关于羟氯喹潜在益处的小规模、不受控制的报道得到了大量宣传。一份定期收集的观测数据报告似乎证实了这一点，但很快就被撤回了。 RECOVERY 发现羟基胆喹对重症患者没有益处，尽管它仍然有可能对非常早期或轻微的病例有效。这证明了对来源不确定的数据进行回顾性分析的危险以及大型简单随机对照试验的力量。

另一方面，鉴于疫苗在特定患者亚组中的功效仍存在不确定性，疫苗接种后感染率的观察数据非常令人放心。观察数据可以扩展和确认随机试验的结果，但随机试验的规模始终较小且代表性较差。这些数据越来越多地通过电子护理记录获得，尽管即使在多变量倾向评分匹配后也容易受到残留混杂的影响，但对于上市后安全监测和在更大、更具代表性的数据集中确认治疗效果可能非常有价值。

总之，尽管造成了人类悲剧和苦难，但 COVID-19 大流行还是激发了国际研究界一些非常有创意的反应。我们需要抓住这一点，并在不断发展的国际合作努力的基础上，将其应用于应对精神疾病这一全球重大挑战。我们应该从通过明确的目标以及共同的目的感和紧迫感能够如此迅速地取得成就中汲取灵感。