Early in the COVID-19 pandemic, repurposing some already-approved drugs was proposed for reducing the morbidity and mortality risk of those who were infected. For example, the UK RECOVERY trial demonstrated the benefits of dexamethasone for severe respiratory illness, leading to its widespread adoption by mid-2020. Many psychiatric drugs have antiviral and immune modulatory effects, and are candidates for repurposing for COVID-19 and other non-psychiatric conditions.

Fluvoxamine is a potent activator of the sigma-1 receptor (S1R), dampening cellular stress responses and leading to anti-inflammatory effects¹. In 2020, we conducted a randomized placebo-controlled trial which demonstrated that fluvoxamine prevented clinical deterioration from COVID-19². These findings were replicated in a larger study, the TOGETHER trial, which randomized 1,497 patients to fluvoxamine 100 mg twice daily or placebo for 10 days. The trial found a 32% reduction in risk for severe disease progression with fluvoxamine. Among patients who were compliant with their treatment regimen, taking at least 80% of their pills, there was a 66% reduction in risk for hospitalization with fluvoxamine, and only one death in the fluvoxamine group compared to 12 in the placebo group³. Fluvoxamine has now been recommended for use by several organizations, including the Ontario province in Canada. Two ongoing trials are testing fluvoxamine at a lower dose of 50 mg twice daily: the ACTIV-6 trial and the COVID OUT trial.

Based on this growing scientific evidence, as well as its safety profile and availability, we believe that fluvoxamine should be used in COVID-19 for outpatients at high risk for morbidity and mortality from complications of the infection. The recommended dose is 100 mg twice daily for 10-15 days, which can be adjusted based on tolerability. No laboratory monitoring is needed, but co-prescribed drugs should be evaluated for potential interactions, because of fluvoxamine’s inhibition of cytochromes P450 (CYP) 1A2 and 2C19. Patients taking theophylline, clozapine, olanzapine and tizanidine, which are CYP1A2 substrates, should not be administered fluvoxamine in most cases. Caffeine, a CYP­1A2 substrate, should be eliminated or greatly reduced during fluvoxamine treatment. Also, for patients already taking a serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), we would discourage adding fluvoxamine or switching to it for COVID-19 treatment.

Other potential mechanisms have been suggested for the effects of SSRIs, beyond fluvoxamine alone, including inhibition of hypercoagulable states or excess serotonin release by platelets, and functional inhibition of acid sphingomyelinase, leading to inhibition of entry and propagation of SARS-CoV-2 into cells¹. For example, a study of adults hospitalized for severe COVID-19 found that those who were taking a medication which was a functional inhibitor of acid sphingomyelinase (including all SSRIs) were less likely to be intubated or die⁴.

A study of psychiatric inpatients in New York state during the first wave of the pandemic in 2020 found that SSRIs and SNRIs, and specifically fluoxetine, showed a protective effect against COVID-19 infection⁵. Also, a study of 83,584 patients found that those who were taking SSRIs, and in particular those who were on fluoxetine or fluvoxamine, had a reduced mortality⁶.

Given the time and costs of conducting large randomized con­trolled trials, it is tempting to use the data from these observational studies as sufficient evidence for drug repurposing. Yet, observational studies are known to suffer from biases, including confounding by indication. Although techniques exist to reduce these biases, it remains controversial to assert a drug’s benefit for a new indication based purely on observational data. For example, a drug or drug class might appear to be protective against COVID-19, yet be a proxy for some other patient characteristic or behavior (e.g., social isolation because of depression). Thus, promising observational study findings will still require corroboration in randomized trials, and accomplishments such as the UK RECOVERY trial show that rapid clinical innovations are possi­ble.

SSRIs and other antidepressants might also help with the long­er-term neuropsychiatric manifestations of COVID-19. “Neuro­psychiatric long COVID” refers to the fact that cognitive and psy­chiatric symptoms are a large proportion of the constellation of post-acute COVID-19 symptoms that are either chronic or intermittent, and are bothersome, painful and disabling. For example, the Patient-Led Research Collaborative assessed the prevalence of symptoms in 3,762 persons over 7 months post-COVID⁷. They found a preponderance of neuropsychiatric symptoms, particularly memory and cognitive dysfunction, which were experienced by over 85% of respondents, with negative impacts on daily functioning. Other common neuropsychiatric symptoms were insomnia, anxiety, depression, and occasionally hallucinations (olfactory and other).

The etiological factors involved in neuropsychiatric long COVID may include persistent SARS-CoV-2 infection and a prolonged hyper-inflammatory state, compounded by psychosocial stress. Unfortunately, there is little research to-date on the treatment of neuropsychiatric long COVID. One recent report in post-COVID depressive illness⁸ found that 55/60 (92%) patients showed a clinical response after 4 weeks of SSRI treatment. This strong antidepressant benefit was seen irrespective of gender, previous psychiatric history, and SSRI type. The authors speculated that this rapid response to SSRIs could be due to their direct action on neuroinflammation, in addition to their typical antidepressant mechanisms (which remain unclear). This was a single-site, open-label study, and more research is needed regarding the efficacy of various treatments. But this study also shows an important role for psychiatrists in managing, and supervising, the long-term neuropsychiatric effects of COVID-19.

With the pandemic continuing to evolve, it will be critical to keep on answering key questions about the role of SSRIs in the treatment of acute COVID-19 illness. What is the best dose and timing of fluvoxamine, and how effective is it in combination with other treatments against COVID-19 (such as monoclonal antibodies)? Is fluoxetine, which has lower S1R affinity compared to fluvoxamine but has shown promise in preclinical and observational studies, also an effective treatment, considering that it is more widely available and easier to use? And what are the best treatments for neuropsychiatric manifestations of long COVID, and in which patients?

Given that many psychotropics are now appreciated to have widespread molecular, cellular and physiological effects, in­cluding anti-inflammatory, neuroprotective and cardioprotective, and antiproliferative, we can expect that lessons learned in testing these medications for COVID-19 will be important for other drug repurposing efforts, ranging from infectious and inflammatory diseases, to neurodegenerative diseases such as Alzheimer’s disease, and cancer⁹.

在 COVID-19 大流行初期，有人提议重新利用一些已获批准的药物，以降低感染者的发病率和死亡风险。例如，英国的 RECOVERY 试验证明了地塞米松对严重呼吸道疾病的益处，导致其在 2020 年中期得到广泛采用。许多精神科药物具有抗病毒和免疫调节作用，是重新用于 COVID-19 和其他非精神疾病的候选药物。

氟伏沙明是 sigma-1 受体 (S1R) 的有效激活剂，可抑制细胞应激反应并产生抗炎作用¹。2020 年，我们进行了一项随机安慰剂对照试验，该试验证明氟伏沙明可预防 COVID-19 ²的临床恶化。这些发现在一项更大的研究 TOGETHER 试验中得到了复制，该试验将 1,497 名患者随机分配到氟伏沙明 100 毫克每天两次或安慰剂组 10 天。该试验发现氟伏沙明可降低 32% 的严重疾病进展风险。在遵守治疗方案且服用至少 80% 药片的患者中，使用氟伏沙明住院的风险降低了 66%，氟伏沙明组只有 1 人死亡，而安慰剂组有 12 人死亡³ . 氟伏沙明现已被包括加拿大安大略省在内的多个组织推荐使用。两项正在进行的试验正在以每天两次 50 毫克的较低剂量测试氟伏沙明：ACTIV-6 试验和 COVID OUT 试验。

基于这一不断增长的科学证据，以及其安全性和可用性，我们认为氟伏沙明应用于 COVID-19 用于感染并发症发病率和死亡率高的门诊患者。推荐剂量为 100 毫克，每日两次，持续 10-15 天，可根据耐受性进行调整。无需实验室监测，但应评估共同处方药物的潜在相互作用，因为氟伏沙明可抑制细胞色素 P450 (CYP) 1A2 和 2C19。在大多数情况下，服用茶碱、氯氮平、奥氮平和替扎尼定（它们是 CYP1A2 底物）的患者不应服用氟伏沙明。咖啡因是一种 CYP1A2 底物，在氟伏沙明治疗期间应消除或大大减少。还，

除了氟伏沙明以外，SSRIs 的作用还有其他潜在机制，包括抑制血小板的高凝状态或过量血清素释放，以及酸性鞘磷脂酶的功能抑制，从而抑制 SARS-CoV-2 进入和传播到细胞中¹ . 例如，一项针对因严重 COVID-19 住院的成年人的研究发现，服用酸性鞘磷脂酶功能性抑制剂（包括所有 SSRI）药物的人插管或死亡的可能性较小⁴。

一项针对 2020 年第一波大流行期间纽约州精神科住院患者的研究发现，SSRI 和 SNRI，特别是氟西汀，对 COVID-19 感染具有保护作用⁵。此外，一项针对 83,584 名患者的研究发现，服用 SSRIs 的患者，尤其是服用氟西汀或氟伏沙明的患者死亡率降低⁶。

鉴于进行大型随机对照试验的时间和成本，很容易将这些观察性研究的数据用作药物再利用的充分证据。然而，众所周知，观察性研究存在偏见，包括因适应症而造成的混淆。尽管存在减少这些偏差的技术，但纯粹基于观察数据断言药物对新适应症的益处仍然存在争议。例如，一种药物或药物类别可能看起来对 COVID-19 具有保护作用，但可以代表其他一些患者特征或行为（例如，由于抑郁症而导致的社会孤立）。因此，有希望的观察性研究结果仍需要在随机试验中得到证实，而英国 RECOVERY 试验等成就表明，快速的临床创新是可能的。

SSRI 和其他抗抑郁药也可能有助于缓解 COVID-19 的长期神经精神症状。“神经精神病学长期 COVID”是指认知和精神症状在 COVID-19 急性后症状群中占很大比例，这些症状要么是慢性的，要么是间歇性的，并且令人烦恼、痛苦和致残。例如，以患者为主导的研究合作组织在 COVID ^{7后 7 个月内评估了 3,762 人的症状流行率}. 他们发现神经精神症状占优势，特别是记忆和认知功能障碍，超过 85% 的受访者经历了这些症状，对日常功能产生负面影响。其他常见的神经精神症状是失眠、焦虑、抑郁，偶尔还会出现幻觉（嗅觉和其他）。

神经精神长期 COVID 的病因可能包括持续的 SARS-CoV-2 感染和长期的高炎症状态，再加上社会心理压力。不幸的是，迄今为止，关于神经精神长期 COVID 治疗的研究很少。最近一份关于 COVID 后抑郁症的报告⁸发现 55/60 (92%) 的患者在 SSRI 治疗 4 周后表现出临床反应。无论性别、既往精神病史和 SSRI 类型如何，都可以看到这种强大的抗抑郁药益处。作者推测，这种对 SSRI 的快速反应可能是由于它们对神经炎症的直接作用，以及它们典型的抗抑郁机制（尚不清楚）。这是一项单中心、开放标签的研究，需要更多关于各种治疗效果的研究。但这项研究也表明，精神科医生在管理和监督 COVID-19 的长期神经精神影响方面发挥着重要作用。

随着大流行的继续发展，继续回答有关 SSRI 在治疗急性 COVID-19 疾病中的作用的关键问题至关重要。氟伏沙明的最佳剂量和时间是多少，它与其他针对 COVID-19 的治疗（如单克隆抗体）联合使用的效果如何？与氟伏沙明相比，氟西汀的 S1R 亲和力较低，但在临床前和观察性研究中显示出前景，氟西汀是否也是一种有效的治疗方法，考虑到它更广泛可用且更易于使用？对于长期 COVID 的神经精神症状，最好的治疗方法是什么？在哪些患者中？

鉴于许多精神药物现在被认为具有广泛的分子、细胞和生理作用，包括抗炎、神经保护和心脏保护以及抗增殖作用，我们可以预期，在测试这些药物的 COVID-19 时吸取的经验教训对于其他药物再利用很重要努力，从传染病和炎症性疾病，到神经退行性疾病，如阿尔茨海默病和癌症⁹。