如果抑郁症并非血清素导致，那究竟因何导致？
Serotonin may not explain depression, but research on other brain pathways may provide answers.
血清素可能无法解释抑郁症，但关于其他脑部回路的研究可能会给出答案。
The wiring and rewiring of our brains (neuroplasticity) is influenced by our lifestyle and may affect depression.
大脑的塑造与重塑（神经可塑性）受到我们生活方式的影响，而且可能会影响到抑郁症。
Our inflammatory state is affected by things like diet quality and sleep quantity, and has been linked to depression.
炎症状态受到饮食质量和睡眠量的影响，而且已被认为与抑郁症有关。
The gut-brain connection and our hormonal state are influenced by lifestyle choices, and are connected to brain health and depression.
肠-脑连接与我们的荷尔蒙状态均受到我们生活方式的影响，而且被认为与大脑健康和抑郁症有关。
For the last half-century, the dominant explanation for depression has centered on serotonin. The basic idea: low levels of brain serotonin or serotonin activity leads to symptoms of depression. This theory, which is known as the “serotonin hypothesis,” is based on several data points, including animal research and the effects of antidepressants that are supposed to work by increasing brain serotonin levels. But, in the last several decades, a number of researchers have challenged the idea that serotonin plays a principal or even major role in depression.
在过去半个世纪中，关于抑郁症的主流解释一直围绕着血清素展开。其基本理论是：低血清素水平或血清素的低活跃性导致了抑郁症症状产生。该理论被称之为“血清素假说”，基于多种数据，其中包括动物研究、血清素水平提升型抗抑郁药的效果等。但在过去数十年中，大量研究人员都对“血清素在抑郁症中扮演着主要甚至最关键角色”的这一理论提出了挑质疑。
In recent days, the serotonin hypothesis of depression has been explicitly challenged by a number of scientific publications. Most notable (at the time of this writing), a paper published in Nature Molecular Psychiatry reviewed several lines of evidence on the subject of the serotonin-depression connection and concluded that “the main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”
近来，关于抑郁症的这一血清素假说已经被众多科学文章明确质疑。其中（在本文创作之时）最值得关注的，是出版于自然出版集团《分子精神病学》杂志中的一篇文章。该文章综述了关于血清素-抑郁症联系的多组证据，得出结论：在关于血清素的主要研究活动中，并无证据能充分证明血清素与抑郁症之间的关系，也无证据支持“抑郁症由低血清素活跃性或低血清素浓度导致”这一假说。
Datapoints like this recent study point to a major question: if serotonin isn’t driving depression, what does explain the brain state of the hundreds of millions of people living with it? While there are many potential explanations, here are four major systems that may prove more important to the brains of people with depression, and some ways we may be able to target them.
这类研究所提供的数据都指向了一个更大的问题：如果抑郁症并非因血清素导致，那么究竟该如何解释这种见诸数以亿计患者的大脑状态呢？尽管有很多潜在的可能，以下是可能会被证明对抑郁症患者大脑有更大影响的四种主要系统，以及我们针对这些系统可采取的应对措施。
NO.01
Brain Rewiring (Neuroplasticity)
大脑重塑（神经可塑性）
One of the most empowering results of neuroscience research is the idea that our brains are constantly being rewired. Specifically, our neurons are actively changing the number and strength of their connections to other neurons and to non-neuron brain cells called “glia.” This is a process called “neuroplasticity,” and it’s increasingly thought to play a role in mood disorders like depression.
神经科学研究的最具赋能意义的成果之一，是“我们的大脑在不断被重塑”这一观点。具体而言，神经元在不断改变它们与其他神经元和非神经元脑细胞（被称为胶质细胞）之间的连接数量与强度。这一过程即”神经可塑性“，越来越多的人认为这一过程在诸如抑郁症等情绪障碍中扮演着特定的作用。
Supporting factors for the neuroplasticity-depression connection include imaging findings, cell study research, and measurements connected to the rewiring process. The basic idea is that in depression, there may be issues with the quality, number, and type of connections our neurons make, and this may help explain depression symptoms. Importantly, research is showing that we may be able to positively affect neuroplasticity through lifestyle factors like exercise, learning new things, and, potentially, certain dietary modifications. There is also data showing that conventional antidepressants, as well as psychedelics, may positively influence neuroplasticity.
关于神经可塑性与抑郁症之间的联系，证据包括大脑图像、细胞研究，以及与重塑过程相关的测量结果等。其基本概念是：在抑郁症中，神经元所建立的连接的质量、数量和类型可能存在问题，这可能是抑郁症状的原因所在。重要的是，研究显示，我们可能能够通过生活方式来对神经可塑性产生积极影响，比如锻炼、学习新事物，以及或者实施特定的饮食调整等。另外还有数据表明传统抗抑郁药以及致幻剂都可能对神经可塑性产生积极影响。
NO.02
Inflammation
炎症
The planet had a wake-up call to the significance of immune health in the context of the pandemic. But immune health is linked to far more than just risk for infectious disease. In the world of neuroscience and affective disorders, immune activation, and especially inflammation, is thought to be a risk factor for the development of conditions like depression. Higher levels of inflammation in our bloodstream have been shown this, and more broadly, has been linked to worse brain function.
在当前疫情背景下，我们的星球为人类自身免疫系统的重要性敲响了警钟。但健康免疫系统并不仅仅只是与传染型疾病有关。在神经科学和情感障碍的世界，免疫激活，尤其是炎症，被认为是导致抑郁症形成的风险因素之一。血液系统中较严重的炎症已被显示会产生此作用，而且更宽泛来说，已经被与大脑机能下降联系在一起。
When excess or chronic inflammation is present in the brain, it appears to influence a number of pathways involved in depression. First, it may impair the healthy function of neurons by physically damaging them. Inflammation also may block healthy neuroplasticity, while leading to the generation of toxic breakdown molecules like quinolinic acid that could further damage neuron health and contribute to depressive pathology. Within the brain, research shows that unique immune cells called microglia may be key to sustaining inflammation. So how is our inflammatory status regulated? It appears to be sensitive to the quality of our diet, sleep, exercise, stress-lowering interventions, and potentially even nature exposure.
当大脑中存在严重或长期炎症，似乎会影响到与抑郁症相关的众多回路。首先，炎症可能会通过生理破坏的方式损害神经元的健康机能。另外，炎症也可能阻滞健康的神经可塑性，同时导致毒性分解分子，比如喹啉酸的生成，这类分子可能会进一步破坏神经元的健康机能，促使抑郁病症的形成。在大脑中，研究显示某种被称为小胶质细胞的独特免疫细胞（过度活跃）可能是炎症持续存在的关键原因所在。那么，我们的炎症状态是如何被管控的呢？这似乎与我们的饮食质量、睡眠质量、锻炼质量、降压力干预活动或者甚至是与大自然接触程度密切相关。
NO.03
The Gut-Brain Connection
肠脑连接
The gut is home to trillions of bacteria and the majority of our immune cells, making it a major hub for information transfer. A wide range of research now suggests that the gut and the brain are in constant communication, and it’s been proposed that this data exchange may have an effect on everything from our cognitive state to our mood. Researchers have proposed that the state of our gut health (e.g., the leakiness of our gut lining, the immune cells in the gut, and the diversity of the microbes that live in our gut) plays a major role in our mental health and may significantly influence depression symptomatology.
肠道中生存着数以千亿计的细菌以及我们的大部分免疫细胞，这就让我们的肠道成为了一个主要的信息传递中枢。大量研究如今显示肠道与大脑是在不断交流的，而且有理论认为这一数据交流可能对我们有着全方位的影响，从我们的认知状态，到我们的情绪等。也有研究人员提出：我们的肠道健康程度（肠道衬里的渗透性、肠道中的免疫细胞、生存在肠道中的微生物多元性）对我们的精神健康扮演着重要影响，而且可能会对抑郁症症状存在显著影响。
One of the most impressive aspects of our gut is the quantity and diversity of microbes that call it home. These bacteria make up the gut microbiome. Alterations in the bacteria that live in the gut microbiome have been linked to depression. It’s thought that these bacteria may influence brain function through their effects on the vagus nerve (which runs from the gut to the brain), their impact on the immune system (e.g., by affecting levels of inflammation), and through tiny molecules they create (e.g., short-chain fatty acids) which may reach the brain by way of the bloodstream.
关于我们的肠道，最令人震撼的一点，就是生存于其中的微生物的数量与种类。这些细菌构成了肠道微生物组。肠道微生物组中细菌的变化已被提出与抑郁症相关。有观点认为这些细菌可能会影响到迷走神经（从肠道直至大脑）、影响免疫系统（比如，通过影响炎症程度来实现）、或生成可能会被血流带入大脑的微小分子（短链脂肪酸），从而最终影响大脑机能。
NO.04
Endocrine (Hormonal) Changes
内分泌（荷尔蒙）变化
When it comes to the regulation of brain function, a wide range of hormone pathways are thought to play important roles. This research extends to depression. And while certain hormonal changes can be hard to reverse, there’s also much we can do to help improve aspects of our endocrine signaling pathways.
在大脑机能管理方面，大量荷尔蒙回路被认为发挥着重要作用，这类研究也涉及到了抑郁症。尽管某些荷尔蒙变化很难被逆转，但我们依旧有很多方式去改善我们的内分泌信号传递回路。
Likely the strongest endocrine-depression connection, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (a.k.a. the stress system) is thought to significantly increase risk for depression. For example, people with an episode of major depression are 2.5 times more likely to have experienced a stressful event prior, and a single high-stress event has been found to increase risk for a depressive episode by 1.4 times. Issues with HPA system balance may contribute to depression by negatively impacting the hippocampus, increasing inflammation, damaging neuroplasticity and even killing off neurons. A number of strategies have been shown to be successful in regulating HPA function ranging from daily meditation to regular exercise to time in nature.
下丘脑-垂体-肾上腺（HPA）轴（也被称为应激系统/压力系统）可能是内分泌与抑郁症之间的最强关联所在。这一系统的失调被认为能够显著增加抑郁症患病风险。例如，严重抑郁症发作的患者在发作前经历过高应激事件的几率是无抑郁症发作人群的2.5倍。单一高应激事件会将抑郁发作的几率提高1.4倍。HPA系统失衡，会对海马体产生负面影响、恶化炎症、破坏神经可塑性，甚至杀死神经元，可能因此就会催生抑郁症。很多策略都被证实可有效调节HPA机能，比如日常冥想、在定期在大自然中运动等。
Another important link between hormones and depression relates to estrogen. This hormone is thought to have a number of brain-protective roles, including enhancing neuroplasticity. It has been proposed that declining levels of estrogen and related hormones during and after menopause may help explain the higher rates of depression seen by women in this period. While some research suggests that estrogen replacement therapies may present an interesting treatment strategy, there’s still considerable debate around the safety of this practice.
荷尔蒙与抑郁症的另外一个重要关联，与雌激素有关。雌激素被认为具有很多大脑保护功能，其中包括提升神经可塑性。也有理论认为，在更年期期间与之后，雌激素与相关荷尔蒙的降低，可能与这一时期女性抑郁症发病率增加有关。尽管一些研究显示雌激素替换疗法可能会是一种值得关注的治疗方式，但关于这种疗法的安全性依旧存在巨大争议。
Insulin is a key metabolic hormone that facilitates the uptake of glucose by cells throughout the body. In the brain, insulin is thought to regulate blood sugar as well as influence memory and behavior. Insulin resistance is an increasingly common condition of metabolic dysfunction, where our bodies have trouble sensing insulin and using glucose, and it’s now been linked to a substantially higher risk of developing depression. A wide range of techniques can help improve insulin resistance in most people, especially those related to dietary modification and exercise.
胰岛素是一种关键的新陈代谢荷尔蒙，它可以促进全身细胞对葡萄糖的摄取。在大脑中，胰岛素被认为可以调节血糖并影响记忆和行为。胰岛素抵抗是一种越来越普遍的新陈代谢失调病症，这种病症下，我们的身体难以发现胰岛素，从而难以利用葡萄糖。现在这一病症也被认为会导致抑郁症患病风险显著提高。有很多方法可以用于改善大多数人的胰岛素抗性，尤其是关于饮食结构改变和运动的方法。
Does this mean antidepressants don’t work?
这是否意味着抗抑郁药无效？
No. The current best evidence says that antidepressants, including SSRIs, do work to treat people who have depression. This study isn’t a reason to stop taking antidepressants. Instead, it suggests that we don’t understand how antidepressants work as well as we thought.
并非如此，当前最有力证据表明：抗抑郁药，其中包括SSRI，的确是对抑郁症患者有效的。新研究结果并非意味着我们需要停止服用抗抑郁药，而是表明我们还并未充分了解抗抑郁药的工作原理。
SSRI medications operate on neurons, which communicate via neurotransmitters. Serotonin is one of these neurotransmitters, which is released by a neuron and then travels to and binds to other neurons. After serotonin has been released by one cell and then communicated with another cell, it gets taken back up to await the next time it needs to be released. SSRIs block that reuptake, meaning the serotonin stays floating between cells for longer and potentially relays its message multiple times before being taken back up.
SSRI药物作用于神经元，神经元通过神经递质互相交流。血清素是其中一种神经递质，由神经元释放，之后前往其他神经元并与这些神经元结合。在血清素被一个细胞释放，然后与另外一个细胞交流后，会被收回，等待下次被释放。SSRI阻碍这种”再回收“过程，这样，血清素就能够在细胞之间浮动更长时间，就有可能在被收回之前多次重复传递信息。
We know that SSRIs improve depression, and we know that one thing SSRIs do is allow serotonin receptors to be stimulated more often. So a simple model of depression would suggest that depressed people just don’t have enough serotonin. Maybe the reason SSRIs work is that they increase serotonin levels when they are too low. This is a reasonable first hypothesis about how depression works. The new review, however, suggests that this simple explanation isn’t right. When you measure people’s serotonin levels, it doesn’t tell you whether they are depressed or not.
我们知道SSRI可以改善抑郁症，而且我们也知道SSRI的作用之一是让血清素受体被更频繁刺激。因此，如果从简单的抑郁症模型来看，就会得出抑郁症患者血清素不足的结论。可能SSRI之所以奏效，是在血清素水平较低时提高血清素水平。这一假设听起来的确是合理的。但文首的这一研究却显示这一假说并不正确。血清素水平并无法表明是否抑郁。
The authors of the new study also raise a counterintuitive possibility: In the long term, SSRIs might actually reduce the amount of serotonin levels in the brain. This would be due to the brain—which is plastic and can change over time—adjusting to the presence of the SSRIs. Some studies have found that people who take SSRIs over a long period of time actually have lower levels of serotonin, suggesting that taking the medication might lead the brain to produce less serotonin naturally. Taking this into account would mean developing an explanation for how antidepressants work that operates on two different time scales. In the short term, they might increase serotonin levels. Longer term, they might reduce them.
这一新研究的作者们也提出了一种听起来并不合理的可能性：长期而言，SSRI可能实际上是减少大脑中的血清素水平。这可能是因为面对SSRI，大脑自动调整适应，毕竟大脑是可塑的，会随时间而改变的。一些研究也发现，长期服用SSRI的患者实际上血清素水平更低，这反映出，服用这一药物可能会导致大脑自然降低血清素分泌量。如果将这一理论考虑进来，就意味着在研究抗抑郁药工作原理时，需要纳入两个不同的时间段。短期而言，药物可能会提升血清素水平，但长期而言，可能反而会降低血清素水平。
So why do antidepressants work?
那么为什么抗抑郁药奏效呢？
The next logical question to ask is why antidepressants do seem to work. The frequently taught “chemical imbalance” model—at least where serotonin is concerned—may not be true. Serotonin is not just a “depression chemical” but may be involved in more complicated systems or reactions. Or antidepressants might work by changing other aspects of brain chemistry.
这自然而然就引出下一个问题：为什么抗抑郁药的确似乎是奏效的呢？课堂上常常教的”化学物质失衡“模型——至少在血清素相关方面——可能并不正确。血清素不仅仅只是一种抑郁化学物质，它可能还参与一些更复杂的系统或反应。或者，抗抑郁药之所以奏效，是因为它们改变了大脑化学状态的其他方面。
One recent article argues that the fact that antidepressants typically take approximately two weeks to start working means their most important effects might be in changing neuroplasticity—that is, altering the way the brain functions over time. They cite some evidence that SSRIs may increase neuroplasticity or cause stress to have less harmful effects on neuroplasticity. These sorts of alternative explanations should be taken more seriously now, as scientists move to a deeper understanding of what does—and doesn’t—cause depression.
一篇近期发布的文章认为，抗抑郁药通常会在两周后才开始发挥作用，这意味着它们的最重要作用可能是在于改变神经可塑性，即，逐渐改变大脑运作方式。文章作者引用了一些证据，这些证据表明SSRI可能会提升神经可塑性，或降低压力对神经可塑性的损害。现在来看，科学家们对抑郁症致病原因和非致病原因的理解已经向更深入的方向发展，我们对与上面类似的各种不同的解释理论应该更认真对待。
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