https://joannamoncrieff.com/2020/10/06/how-little-we-really-know-about-psychiatric-drugs/

How little we really know about psychiatric drugs

joannamoncrieff / October 6, 2020

我们对精神病药物知之甚少

joannamoncrieff/2020年10月6日

In this blog I reflect on what has and has not changed in the field of psychiatric drug treatment in the years between the first and newly published second edition of the Straight Talking Introduction to Psychiatric Drugs.

The second edition of my Straight Talking Introduction to Psychiatric Drugshas just been published 11 years after the first. Some progress has been made in that time. Services for people with early psychosis now routinely prescribe low doses of antipsychotics and frequently support people to come off them.  The UK government funded the RADAR trial that is evaluating a gradual programme of antipsychotic reduction and discontinuation in people with long-term psychotic disorders or ‘schizophrenia’ and several other trials of this sort are going on around the world involving people with a first episode of psychosis. This research is being conducted by psychiatric researchers who recognise that psychiatric drugs can be harmful, and that their use needs to be minimised. From my experience, most psychiatrists are now aware of the evidence that long-term antipsychotic treatment causes brain shrinkage (although many are also enamoured with the misleading studies on antipsychotics and mortality produced by the Finnish group, which have been helpfully deconstructed in this blog by Robert Whitaker). The fact that antidepressants can cause severe and prolonged withdrawal effects has now been widely recognised, although not without the concerted efforts of those who have suffered these problems.   

在这个博客中，我回顾了在《精神病药物直言不讳入门》第一版和新出版的第二版之间的几年里，精神病药物治疗领域发生了什么变化，也没有发生什么变化。

我的《精神病药物直言不讳入门》第二版距离第一版出版已经有11年。在这段时间里取得了一些进展。为早期精神病患者提供的服务现在通常会开出低剂量的抗精神病药物，并经常支持患者停止服用。英国政府资助了这项RADAR 试验，该试验正在评估长期精神病性疾病或“精神分裂症”患者的抗精神病药物逐渐减少和停用方案，世界各地正在进行其他几项此类试验，涉及首次发作精神病患者。这项研究是由精神病研究人员进行的，他们认识到精神病药物可能有害，需要尽量减少使用。根据我的经验，大多数精神病医生现在都意识到长期抗精神病药物治疗会导致大脑萎缩的证据（尽管许多人也迷恋芬兰研究小组关于抗精神病药物和死亡率的误导性研究，罗伯特·惠特克在本博客中对这些研究进行了有益的解构）。抗抑郁药可能导致严重和长期的戒断效应这一事实现在已经得到广泛承认，尽管并非没有那些遭受这些问题的人的共同努力。

The drug-centred model of drug action (the idea that psychiatric drugs change normal brain functions and mental states, and that these changes inevitably interact with the ‘symptoms’ of mental disorders) is now established in some circles. It is recommended in the Power Threat Meaning framework and other convention-challenging texts and textbooks. I know many psychiatrists who feel that, as well as making sense of the evidence, it provides a useful guide for a cautious and collaborative approach to the use of psychiatric drugs. Yet mainstream psychiatry has ignored it and presses on with business as usual. Prescriptions for antidepressants continue to rise and money is still poured into research trying to locate the specific brain abnormality that produces disorder X or Y. Despite the failure of this research to provide any conclusive findings, clinicians and much of the general public remain bedazzled by the disease-centred model of drug action – the idea that drugs work by tweaking some underlying brain abnormality, sometimes specified as an imbalance or ‘dysregulation’ of particular brain chemicals.  

以药物为中心的药物作用模式（精神病药物改变正常的大脑功能和精神状态，这些变化不可避免地与精神障碍的“症状”相互作用的观点）现在在一些圈子里已经确立。在《权力威胁意义框架》和其他具有挑战性的公约文本和教科书中建议使用。我认识许多精神科医生，他们认为，在理解证据的同时，它为谨慎和合作地使用精神科药物提供了有用的指南。然而，主流精神病学忽视了这一点，照常行事。抗抑郁药的处方不断增加，资金仍在投入研究，试图找出导致X或Y障碍的特定大脑异常。尽管这项研究未能提供任何结论性发现，临床医生和大部分公众仍然被以疾病为中心的药物作用模式所迷惑——药物通过调整某些潜在的大脑异常（有时被指定为特定大脑化学物质的失衡或“失调”）而发挥作用。

The few psychiatrists who have engaged with ideas about models of drug action take different positions. As I discussed in a previous blog, some leading academic psychiatrists have re-asserted the disease-centred view (though sometimes denying that this is what they are doing). Others argue that most psychiatrists have an ‘outcome-based’ understanding of drug action. This means they prescribe drugs because research has shown that they can be helpful, with no commitment to an explanation of why that might be. We do not ingest a drug or recommend others do so without having beliefs about what it might do, however, and if psychiatrists provide no other explanation, then they are implicitly endorsing the disease-centred model of drug action. This is how they are generally understood nowadays, at any rate.

The drug-centred model obviously touches a nerve among mainstream psychiatrists. This is because it suggests that the way drugs ‘work’ when prescribed for mental health problems is different from what drugs are doing in other areas of medicine. Those who oppose it are keen to defend the medical identity of psychiatry. It is ironic that the drug-centred model demands a much fuller understanding of the action of drugs on every aspect of physical functioning, mental states and behaviour, compared to the blinkered approach of the disease-centred model that focuses primarily on the site of the presumed disease or abnormality. The drug-centred model is, therefore, a much better basis for a properly scientific, medical training.

为数不多的对药物作用模式有想法的精神病学家采取了不同的立场。正如我在上一篇博客中所讨论的那样，一些著名的学术精神病学家重新提出了以疾病为中心的观点（尽管有时否认这是他们正在做的事情）。其他人则认为，大多数精神病医生对药物作用有“基于结果”的理解。这意味着他们开药是因为研究表明它们是有帮助的，而没有承诺解释为什么会这样。然而，如果精神科医生没有提供其他解释，那么他们就是在暗中支持以疾病为中心的药物作用模式。无论如何，这就是如今人们普遍理解它们的方式。

以药物为中心的模式显然触动了主流精神病医生的神经。这是因为它表明，当为心理健康问题开处方时，药物的“作用”方式与药物在其他医学领域的作用不同。反对它的人热衷于捍卫精神病学的医学身份。具有讽刺意味的是，与以疾病为中心的模式的狭隘方法相比，以药物为中心的模式要求更全面地了解药物对身体机能、精神状态和行为的各个方面的作用，而以疾病为中心的模式主要关注假定疾病或异常的部位。因此，以药物为中心的模式是进行适当科学、医学培训的更好基础。

Some important research has been published since I wrote the first edition. Further follow-up studies show that people who take long-term antipsychotic treatment for psychotic episodes have worse outcomes than those who do not (e.g. Moilanen et al 2016; Wils et al, 2017). Most importantly the follow-up of participants in the Dutch randomised trial confirmed that this is not simply a reflection of the more severe profile of those who end up on long-term treatment, but likely to be due to the drugs themselves (Wunderink et al, 2013). More recently, a small, but well-conducted study from Australia showed that antipsychotics had no advantage over placebo in people experiencing a first episode of psychosis who were receiving high quality psychosocial support (Francey et al, 2020). These studies fundamentally change the way we should approach the use of antipsychotics. Combined with the mounting evidence that these drugs cause serious effects on the brain and other body systems, they underline the need to use antipsychotics as sparingly as possible, and to try to help people come off them where possible. Certainly some psychiatrists have taken this on board.

I have learnt a lot in the last 11 years – much of it from people who have had the courage to share their experiences of using psychiatric drugs and thereby publicise effects that official research has barely tried to address. Perhaps most importantly I have come to appreciate how little we really know and understand about what psychiatric drugs do, especially in the long-term, and the terrible consequences this ignorance can have.

自从我写第一版以来，一些重要的研究已经发表了。进一步的随访研究表明，因精神病发作而接受长期抗精神病药物治疗的人的预后比不接受治疗的人差（例如Moilanen等人2016年；Wils等人2017年）。最重要的是，荷兰随机试验参与者的随访证实，这不仅反映了那些最终接受长期治疗的患者更严重的情况，而且可能是由于药物本身（Wunderink等人，2013年）。最近，来自澳大利亚的一项小型但实施良好的研究表明，抗精神病药物在经历第一次精神病发作并接受高质量心理社会支持的人群中没有优于安慰剂（Francey et al，2020）。这些研究从根本上改变了我们使用抗精神病药物的方式。结合越来越多的证据表明这些药物会对大脑和其他身体系统造成严重影响，他们强调需要尽可能少地使用抗精神病药物，并尽可能帮助人们戒掉这些药物。当然，一些精神科医生已经接受了这一点。

在过去的11年里，我学到了很多东西——其中大部分是从那些有勇气分享他们使用精神病药物的经验，从而宣传官方研究几乎没有试图解决的效果的人身上学到的。也许最重要的是，我开始意识到，我们对精神病药物的作用，特别是长期作用，以及这种无知可能带来的可怕后果知之甚少。

Take the example of benzodiazepines. We understand the mechanism of action of benzodiazepines better than most drugs. They produce their relaxing effects through modifying the actions of the natural neurotransmitter known as GABA. But we do not know exactly how they affect the GABA system, nor how these or other actions produce the range of disabling withdrawal effects that can occur. We also do not understand the mechanisms underlying the cognitive impairment that benzodiazepines appear to cause both during and after withdrawal from long-term use (Crowe & Stranks, 2017). Most worryingly, as I highlighted in a previous blog, we have known since at least the early 1990s that some people develop new medical conditions or symptoms while coming off the drugs (including tinnitus and restless legs, for example). These can last for months afterwards, possibly longer, suggesting the drugs have permanently altered the brain in some way. Yet we have no idea what benzodiazepines are doing to the brain that might result in these persistent and often disabling symptoms.

Unfortunately, neither this data, nor the evidence that antipsychotics can cause permanent neurological damage (tardive dyskinesia), seem to have made us any more wary of launching new drugs without good data on their long-term effects.

以苯二氮卓类药物为例。我们比大多数药物更了解苯二氮卓类药物的作用机制。它们通过调节天然神经递质GABA的作用产生放松效果。但我们不知道它们是如何影响GABA系统的，也不知道这些或其他行为是如何产生可能发生的停用戒断效应的。我们也不了解苯二氮卓类药物在长期停用期间和停用后引起认知损害的机制（Crowe&Stranks，2017）。最令人担忧的是，正如我在上一篇博客中强调的那样，至少从20世纪90年代初开始，我们就知道一些人在停药后会出现新的疾病或症状（例如耳鸣和不宁腿）。这些药物可能会持续数月，甚至更长时间，这表明这些药物在某种程度上永久性地改变了大脑。然而，我们不知道苯二氮卓类药物对大脑的作用可能会导致这些持续的、常常是致残的症状。

不幸的是，无论是这些数据，还是抗精神病药物可能导致永久性神经损伤（迟发性运动障碍）的证据，似乎都没有让我们在没有关于其长期影响的良好数据的情况下，更加警惕地推出新药。

The SSRI ‘antidepressants’ flooded onto the market in the 1990s. At first they seemed relatively innocuous. They are certainly safer in overdose and far less sedating than their predecessors, the tricyclic antidepressants. But then, as I described in my previous blog, withdrawal effects started to come to light, and more recently persistent sexual dysfunction.  These effects suggest these drugs too are changing the brain in significant ways that we do not understand, and that may take a long time to normalise when the drugs are stopped.

Esketamine is one of the latest chemicals to be aimed at people who are looking for relief from chronic misery. The story of how esketamine was licenced illustrates why we have so much propaganda and so little data on the safety of psychiatric drugs. The FDA and other drug regulatory agencies were easily persuaded by Janssen to relax their criteria for establishing efficacy and did not express particular concern about the natural deaths, driving accidents and suicides that occurred during or shortly after treatment. They had little curiosity about withdrawal effects and other long-term complications.  

SSRI“抗抑郁药”在20世纪90年代大量涌入市场。起初，它们似乎相对无害。与之前的三环类抗抑郁药相比，这些药物服用过量肯定更安全，镇静作用也少得多。但是，正如我在上一篇博客中所描述的那样，戒断效应开始显现，最近出现了持续性的性功能障碍。这些效应表明，这些药物也在以我们不了解的重要方式改变大脑，当药物停止使用时，这可能需要很长时间才能恢复正常。

Esketamine（艾氯胺酮）是最新的化学品之一，主要针对那些正在寻求缓解长期痛苦的人。关于艾氯胺酮如何获得许可证的故事说明了为什么我们对精神病药物的安全性有如此多的宣传，而数据却如此之少。杨森很容易说服FDA和其他药品监管机构放宽其确定疗效的标准，并且没有对治疗期间或治疗后不久发生的自然死亡、驾驶事故和自杀表示特别关注。他们对戒断效应和其他长期并发症几乎不感兴趣。

If drug regulatory agencies are not interested in data on immediate and long-term safety, then clearly there is no incentive for drug companies to produce it. Government funding agencies are also focused primarily on establishing the effectiveness of interventions, rather than exploring their harmful effects. Hence it is left to users themselves to highlight the adverse effects of drugs – some of which will only come to light after years of use and after thousands, maybe millions, of people have been exposed.

I am not opposed, in principle, to the use of psychiatric drugs. I believe, as I say in the book, that ‘some psychiatric drugs do help some people in some situations’. Having said this, I think it is likely that the vast majority of people who take psychiatric drugs derive little or no benefit from them, and yet are susceptible to all the harms they can induce. It is people’s right to know how little we really know about these drugs. People should be informed that the story they have been told, implicitly or explicitly, about having an underlying chemical imbalance that drugs can correct is just that – a story – with very little evidence to back it up. They need to know that these drugs are doing things to the brain that we do not understand properly, and people should be aware how little research there has been into the long-term effects of the drugs, and the difficulties of coming off them. I hope the second edition of a Straight Talking Introduction to Psychiatric Drugs will enable people to make better informed decisions about whether to start or continue these sort of drugs.

如果药品监管机构对即时和长期安全性数据不感兴趣，那么很明显，制药公司就没有动力生产这些数据。政府供资机构还主要侧重于确定干预措施的有效性，而不是探讨其有害影响。因此，让使用者自己来强调药物的副作用——其中一些副作用只有在使用数年后，以及在数千人，甚至数百万人接触药物后才会暴露出来。

原则上，我并不反对使用精神病药物。正如我在书中所说，我相信“一些精神病药物确实在某些情况下帮助了一些人”。话虽如此，我认为很可能绝大多数服用精神药物的人从中获益甚微或毫无益处，但却容易受到其可能带来的所有伤害的影响。人们有权知道我们对这些药物所知甚少。人们应该被告知，他们所听到的关于药物可以纠正的潜在化学失衡的故事，无论是含蓄的还是明确的，都只是一个没有什么证据支持的故事。他们需要知道这些药物对大脑的作用是我们无法正确理解的，人们应该意识到，对药物的长期作用以及摆脱药物的困难的研究是多么的少。我希望第二版《精神病药物的直言不讳介绍》能让人们对是否开始或继续使用这类药物做出更明智的决定。