In both the ICD-11 and the DSM-5, the core symptoms of depression are reported to be depressed mood (e.g., feeling sad, down or hopeless) and markedly diminished interest or pleasure in activities. However, in the ICD-10 diagnostic guidelines, a third core symptom was also identified: “fatigue or low energy”. In two regions of the world (Latin America and East Asia), “fatigue” is the most commonly experienced depressive symptom¹. In a third region (Southeast Asia), “issues with the heart” are the most commonly reported depressive symptoms, along with depressed mood¹. Do people in these regions just “somatize” what is primarily a “psychological” experience? Do “somatic” symptoms just represent a “mask”, as implied some decades ago by the concept of “masked depression”²?

An alternative view may be that the core of the depressive syndrome, at least in part of the cases of this heterogeneous condition, is neither only “psychic” nor only “somatic”, but consists of an actual “depression” of the individual's psychic/physical tone, energy, drive and/or response to rewarding stimuli (partially captured by the constructs of depressed mood, fatigue, and diminished interest or pleasure), along with an overwhelming feeling of psychic/physical pain (which has a complex and probably variable relationship to the cognitive component of the syndrome). The way these core phenomena are perceived, elaborated and verbalized by the affected person likely depends upon how that person generally functions and appraises her functioning (e.g., how rich and articulated her cognitive life is, or how much she is focused on her body and its functioning), upon the influence of the cultural environment in which she is immersed, and upon the pattern of predisposing and precipitating factors at work in that individual case.

Feelings involving the heart (“heavy heart”, “heart pain”; chest tightness, weakness or excessive tension; palpitations) do not appear in textbook descriptions of depression, but are more frequently experienced by depressed individuals than we use to believe¹. Ordinary people sometimes refer to depression as “broken heart”, and we tend to regard this as a metaphor. But, the acute “broken heart syndrome” – which has the same precipitating factors as depression and, similarly to the heart involvement in depression, is ascribed to a sympathetic overactivation – is now a recognized clinical entity³. An intrinsic cardiac nervous system (“a brain in the heart”) has been recently described⁴, including a multitude of nervous ganglions consisting not only of neurons receiving sympathetic and parasympathetic input, but also of intracardiac interneurons which act as processors of information. Indeed, the heart conveys to the brain more information than the brain sends to the heart, and ascending fibres in the vagus nerve are more numerous than descending ones. Could the above dynamics be an under-recognized factor contributing to the frequent coexistence (“comorbidity”) and complex interaction between depression and heart disease?

That many patients with a diagnosis of depression do not respond adequately to two subsequent antidepressant medications (“treatment resistance”) is not surprising. Clinical trials of both medications and psychotherapies for depression have aimed during the past few decades to document the “equivalence” of any new experimental intervention to an already consolidated one, while “differences” in the profiles of action of those interventions have usually not been a focus of attention. Consequently, antidepressants and evidence-based psychotherapies for depression are regarded by treatment guidelines as essentially all “equivalent” to each other. It is only recently that secondary analyses of large trial databases, conducted using innovative methodologies, have started to focus again on the “differences” between the various antidepressants, and between antidepressants and evidence-based psychotherapies, with respect to their profiles of action^{5, 6}. On the other hand, it is not common in ordinary practice that a patient with a diagnosis of depression receives a detailed clinical characterization beyond that diagnosis, guiding the choice of treatment. It is therefore understandable that a person may receive two or more antidepressants that, although validated for depression tout court, are not among the most appropriate for her specific case, and consequently may not elicit an adequate response. Furthermore, medications do not work in a vacuum: a variety of “aspecific” factors (e.g., the therapeutic relationship, family dynamics, the socio-cultural context) may affect the outcome of an intrinsically efficacious intervention. The concept of “pseudo-resistance” does not adequately consider at the moment these factors (not to mention problems with the definition of what is an “adequate response” to an antidepressant, difficulties in ascertaining the adherence to the antidepressant regimens that have been used, and the basic incongruence of defining a case as “treatment-resistant” when one group of therapies currently regarded as first-line in the treatment of depression, i.e. psychotherapies, have not been tried).

In this issue of the journal, two papers and a Forum deal, respectively, with the lived experience of depression⁷, with its multiple “physical comorbidities”⁸, and (in a critical vein) with “treatment-resistant depression” and its management⁹. I think these contributions should be welcome by the scientific community, by people with depression and their families, and by the public at large.

A “depression” of the individual's psychic/physical tone, energy, drive and/or response to rewarding stimuli may be the outcome of repeated and inescapable adverse events, but also of a disruption of circadian rhythms, a non-psychiatric disease, or the use of certain medications. Or it may occur in the absence of any such evidence as far as the person is aware of, as often happens in bipolar disorder. Perhaps research should more actively focus on those core phenomena, building on the reports of experts by experience and exploring their biological correlates, without any prejudice about whether they are primarily or essentially psychic or physical in nature.

The effects of the various antidepressant medications could perhaps be explored – beyond current stereotypes – in the same light (are they psychophysical “tonics”?; do they have energizing or disinhibiting properties?; do they affect reward responsiveness?; do they impact psychic/physical pain?), through a more in-depth and nuanced reconstruction of patients’ experiences of “response” to those agents, and a more targeted investigation of their biological correlates. The same may apply to the effects of other interventions, from physical exercise and behavioural activation to neurostimulation techniques. Neuroscientific explorations of depression should probably look at the autonomic as well as the central nervous system (and at their interactions with the cardiovascular and gastrointestinal systems in addition to the immune and endocrine ones). Finally (or first of all), some more psychopathological sophistication should perhaps be added to the current conceptualization and description of “depression”.

在ICD-11和DSM-5中，据报道抑郁症的核心症状是情绪低落（例如感到悲伤、沮丧或绝望）以及对活动的兴趣或乐趣明显减少。然而，在ICD-10诊断指南中，还确定了第三个核心症状：“疲劳或精力不足”。在世界两个地区（拉丁美洲和东亚），“疲劳”是最常见的抑郁症状¹。在第三个地区（东南亚），“心脏问题”以及抑郁情绪是最常报告的抑郁症状¹。这些地区的人们是否只是将主要是“心理”的体验“躯体化”？^{“躯体”症状是否只是代表“面具”，正如几十年前“面具抑郁症” 2}的概念所暗示的那样？

另一种观点可能是，抑郁综合症的核心，至少在这种异质病症的部分病例中，不仅是“精神上的”，也不仅仅是“躯体上的”，而是由个人精神上的实际“抑郁”组成。身体张力、能量、驱动力和/或对奖励刺激的反应（部分由抑郁情绪、疲劳和兴趣或快乐减少的结构捕获），以及压倒性的精神/身体疼痛感（其具有复杂且可能可变的感觉）与该综合征的认知成分的关系）。受影响的人感知、阐述和表达这些核心现象的方式可能取决于该人通常如何运作和评价她的功能（例如，她的认知生活有多丰富和清晰，或者她对自己的身体及其身体的关注程度）。功能），取决于她所处的文化环境的影响，以及在该个案中发挥作用的诱发和促成因素的模式。

涉及心脏的感觉（“心脏沉重”、“心痛”、胸闷、虚弱或过度紧张、心悸）并未出现在抑郁症的教科书描述中，但抑郁症患者所经历的频率比我们想象的要高¹。普通人有时将抑郁症称为“破碎的心”，我们倾向于将此视为一个隐喻。但是，急性“心碎综合征”——与抑郁症具有相同的诱发因素，并且与抑郁症中的心脏受累类似，被归因于交感神经过度激活——现已成为公认的临床实体³。最近描述了一种内在的心脏神经系统（“心脏中的大脑”）⁴，包括多个神经节，这些神经节不仅由接收交感神经和副交感神经输入的神经元组成，而且还由充当信息处理器的心内中间神经元组成。事实上，心脏向大脑传递的信息比大脑向心脏传递的信息更多，而且迷走神经中的上行纤维比下行纤维数量更多。上述动态是否可能是导致抑郁症和心脏病之间频繁共存（“共病”）和复杂相互作用的一个未被充分认识的因素？

许多被诊断为抑郁症的患者对随后的两种抗抑郁药物没有充分反应（“治疗抵抗”），这并不奇怪。在过去的几十年里，针对抑郁症的药物和心理疗法的临床试验旨在记录任何新的实验性干预措施与已经巩固的干预措施的“等同性”，而这些干预措施的作用概况的“差异”通常不会成为事实。关注的焦点。因此，治疗指南认为抗抑郁药和基于证据的抑郁症心理疗法本质上都是“等效的”。直到最近，使用创新方法对大型试验数据库进行的二次分析才开始再次关注各种抗抑郁药之间以及抗抑郁药与循证心理疗法之间在作用概况方面的“差异”5 ^{， 6} . 另一方面，在普通实践中，被诊断为抑郁症的患者获得超出诊断结果的详细临床特征以指导治疗选择的情况并不常见。因此，可以理解的是，一个人可能会接受两种或两种以上的抗抑郁药物，尽管这些药物对抑郁症有效，但并不是最适合她的具体情况，因此可能无法引起足够的反应。此外，药物不能在真空中发挥作用：各种“非特定”因素（例如治疗关系、家庭动态、社会文化背景）可能会影响本质上有效的干预的结果。“伪耐药”的概念目前没有充分考虑这些因素（更不用说抗抑郁药“充分反应”的定义问题，确定对已使用的抗抑郁药治疗方案的依从性的困难） ，以及当一组目前被视为治疗抑郁症的一线疗法（即心理疗法）尚未尝试过时将病例定义为“难治性”的基本不一致）。

在本期杂志中，两篇论文和一篇论坛分别涉及抑郁症的生活经历⁷及其多种“身体合并症” ⁸，以及（以批判的方式）“难治性抑郁症”及其管理⁹ . 我认为这些贡献应该受到科学界、抑郁症患者及其家人以及广大公众的欢迎。

个体的精神/身体张力、能量、动力和/或对奖赏刺激的反应的“抑郁”可能是重复和不可避免的不良事件的结果，但也可能是昼夜节律紊乱、非精神疾病或精神疾病的结果。使用某些药物。或者，就患者所知，这种情况可能在没有任何此类证据的情况下发生，就像双相情感障碍中经常发生的那样。也许研究应该更积极地关注这些核心现象，以专家的经验报告为基础，探索其生物相关性，而不会对它们本质上是主要或本质上是精神的还是物理的产生任何偏见。

各种抗抑郁药物的作用或许可以超越目前的刻板印象，以同样的角度进行探索（它们是心理物理学的“补品”吗？它们是否具有激励或去抑制特性？它们是否影响奖赏反应？它们是否影响心理/身体疼痛？），通过更深入、更细致地重建患者对这些药物的“反应”体验，并对其生物学相关性进行更有针对性的调查。这同样可能适用于其他干预措施的效果，从体育锻炼和行为激活到神经刺激技术。对抑郁症的神经科学研究可能应该着眼于自主神经系统和中枢神经系统（除了免疫和内分泌系统之外，还应关注它们与心血管和胃肠系统的相互作用）。最后（或首先），也许应该在当前“抑郁症”的概念化和描述中添加一些更多的精神病理学复杂性。