Major Depressive Disorder

R.H. Belmaker, M.D., and Galila Agam, Ph.D.

抑郁症是关于正常忧愁和哀伤的情感，即使这些情感消散，外部原因驱除，它也并不缓和。经典的严重抑郁状态经常没有直接原因。无论如何，清晰地画出抑郁伴有与没有那些心理社会直接事件之间的区别是困难的。严重抑郁症的诊断要求分离出情绪的变化，具有忧愁和易怒的特征，至少伴有几个身心改变，诸如睡眠、食欲或性欲被干扰；工作中或与朋友相处体验快乐的能力丧失；叫喊哭闹；自杀念头；说话和行动变慢。这些改变应该持续最少的 2 周，对工作和家庭关系带来相当的干扰。这是基于宽广的定义，在美国一生中的发生率男性超过 12% 女性 20% 。有些人主张更为精确的严重抑郁的定义，他们叫 melancholia 或 vital depression 。 3

Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3

有严重抑郁症的病人的百分比较小，有或将有躁狂性发作，包括活动过度，和寻求快乐增加。尽管在这些案例中与严重抑郁障碍案例一些病理性机制重叠，躁狂症病史定义一种不同的疾病称双极紊乱。

A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4

抑郁症是一种异形紊乱，有高度可变的过程，对治疗反应不一致，没有确定的机制。这里复习大多数当前的处理，来理解严重抑郁症的生物学机制。

Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

Genetics 遗传学

在单合子卵双生和双卵双生之间的严重抑郁的研究比较一致率，提示大约有 37% 的遗传可能性，明显低于双阳性精神障碍或精神分裂症的遗传率。一些正常人格方面，诸如回避伤害、神志不定和悲观，部分也是可遗传的。肯德勒等显示抑郁部分由于可遗传的抑郁 - 倾向于人性品质，但也是可遗传因素的结果，其不依赖于人性品质。早期 - 发作，严重和再发的抑郁症比其他形式的抑郁症有较高的遗传可能性。从严重抑郁症的家族研究清楚表明，任何单基因不引起抑郁症，但是一个有复杂遗传特点的疾病。有严重抑郁症多种案情的谱系研究已确认有与疾病链合染色体区域，超过一个研究发现，这些位置被复制，尽管没有单个染色体区在基因连锁的每一个家族研究中被复制。郝尔曼斯等发现再发连锁证据，早期 - 发作性抑郁症染色体 15q25-q26 ，但人群归因危险度是小的。

Studies comparing concordance rates for major depression between monozygotic and dizygotic twins suggest a heritability of about 37%, 5 which is much lower than the heritability of bipolar disorder or schizophrenia. Some aspects of the normal personality, such as avoidance of harm, anxiousness, and pessimism, are also partly heritable. 6 Kendler et al. 7 showed that although depression is due in part to heritable depression-prone personality traits, it is also the result of heritable factors that are independent of personality. Early-onset, severe, and recurrent depression may have a higher heritability than other forms of depression. 8 It is clear from studies of families that major depression is not caused by any single gene but is a disease with complex genetic features. Studies of pedigrees with multiple cases of major depression have identified chromosomal regions with linkage to the disorder, and some of these loci have been replicated in more than one study, although no single chromosomal region has been replicated in every family study of genetic linkage in depression. Holmans et al. 9 found evidence of linkage of recurrent, early-onset depression to chromosome 15q25-q26, but the population attributable risk was small.

非特异性分子风险因子已被可靠确认。 5 羟色胺运载体链锁多形区（ 5-HTTLPR ）的共同多态变形体，影响 5 羟色胺运载体基因启动子，在脑内引起 5 羟色胺神经递质进入突触前细胞的摄取减少。一些研究已表明这个多态现象赠予抑郁的易感性，但它也给予焦虑和悲观主义品格的易感性。

No specific molecular risk factor has been reliably identified. One common polymorphic variant of the serotonin-transporter–linked polymorphic region ( 5-HTTLPR ), which affects the promoter of the serotonin-transporter gene, causes reduced uptake of the neurotransmitter serotonin into the presynaptic cells in the brain. 10 Some studies have shown that this polymorphism confers a predisposition to depression, 11 but it also confers a predisposition to an anxious and pessimistic personality. 10

脑影像提示脑的情绪相关区域的功能差别，在 5-HTTLPR 的共同多态现象的不同携带者中，尽管与抑郁症的直接关系尚不清楚。在一个大的未来流行病学研究中，卡斯皮等发现 5-HTTLPR 仅在合并有确定的生活紧张时预测抑郁症。一些环境因子可能赠予抑郁易感性，累及后生染色体 — 例如，在啮齿动物的糖皮质激素受体基因启动子区增加母体的忧虑可引起后生变化。

Brain imaging reveals functional differences in emotion-related areas of the brain among carriers of the different common polymorphisms of 5-HTTLPR, 12 although a direct relation to depression is unclear. In a large, prospective epidemiologic study, Caspi et al. 13 found that 5-HTTLPR predicted depression only in association with defined life stresses. Some environmental factors could confer a predisposition to depression by affecting the genome epigenetically — for example, increased maternal care in rodents causes an epigenetic change in the promoter region of the glucocorticoid-receptor gene. 14

The Monoamine-Deficiency Hypothesis 单胺不足假说

去甲肾上腺素能和 5- 羟色胺能系统起自大脑深部，散开几乎遍布全脑，提示系统有能力调节情感、思维和行为的许多区域。早期抗抑郁药阻滞突触前神经元对去甲肾上腺素和 5- 羟色胺的再摄取。药理学活性的瞬即效应是为了提高突触对去甲肾上腺素和 5- 羟色胺的利用率，也为了增值突触后神经元的兴奋。单胺氧化酶的抑制因素有看抑郁的性质也被发现。此酶分解代谢去甲肾上腺素和 5- 羟色胺在他们各自的突触前神经元。这样的抑制作用可能预期增加神经递质的利用率。

The noradrenergic and serotonergic systems originate deep in the brain and fan out over almost the entire brain, suggesting a system capable of modulating many areas of feeling, thinking, and behaving. The early antidepressants blocked the reuptake of norepinephrine and serotonin by the presynaptic neuron. The immediate effects of this pharmacologic action are to increase the availability of norepinephrine and serotonin in the synapse and to increase stimulation of the postsynaptic neuron. Inhibitors of the enzyme monoamine oxidase were also discovered to have antidepressant properties. This enzyme catabolizes norepinephrine and serotonin in their respective presynaptic neurons, and such inhibition could be expected to increase the availability of neurotransmitters.

这些发现导致叫做抑郁症单胺不足假说的主要理论。去甲肾上腺素和 5- 羟色胺在血浆、尿和脑脊液内代谢产物的大多数研究，和抑郁症病人的尸体解剖研究一样，仍为了辨别单胺不足可靠性的传说。无论如何，色氨酸羟化酶形成的新近发现，定为 TPH-2 ，脑内特异，可以解释为什么早先的尸体解剖研究，色氨酸羟化酶的总体活性，在抑郁症病人和对照组之间，没有显示差异。最近用脑单胺氧化酶的一个配基的 PET 研究，显示抑郁症病人亚组的酶有 30% 的上升。一个研究测量了颈内静脉和肱动脉之间单胺代谢产物的差别，显示了抑郁症病人比对照组脑去甲肾上腺素代谢产物要低。单胺不足假说继续鼓舞研究，每逢颅脑一个新的技术窗的开启。

These discoveries led to a major theory of depression known as the monoamine-deficiency hypothesis. Numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal fluid, as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably. However, a newly discovered form of the enzyme tryptophan hydroxylase, designated TPH-2, is specific to the brain 15 and could explain why previous postmortem studies of total enzyme activity did not show differences in tryptophan hydroxylase activity between patients with depression and controls. 16 A recent positron-emission tomographic study using a ligand for brain monoamine oxidase showed a 30% increase of the enzyme in a subgroup of patients with depression. 17 A study measuring differences in monoamine metabolites between the internal jugular vein and the brachial artery showed lower production by the brain of norepinephrine metabolites in patients with depression than in controls. 18 The monoamine-deficiency hypothesis continues to stimulate research whenever a new technical window into the brain is opened.

人类口服治疗实验， 5- 羟色胺和去甲肾上腺素可能被排出。饮用含有除了色氨酸以外的所有氨基酸，刺激肝脏合成蛋白，色氨酸迅速排出血浆（和所以脑）。在脑中色氨酸限制 5- 羟色胺合成的速率。健康受试者这样口服色氨酸排除不诱导抑郁症，但会引起住院病人抑郁症的复发，这些病人用 5- 羟色胺再摄取抑制剂已成功治疗。相似地， α- 甲基异酪氨酸抑制酪氨酸羟化酶，限速儿茶酚胺合成的步骤。用 α- 甲基异酪氨酸治疗不诱导正常受试者的抑郁症。但会诱导住院病人的复发，这些病人已被成功治疗，用去甲肾上腺素再摄取抑制剂。这些发现提示这些抑郁症的治疗机制上具有关键的作用，但另外的神经化学因子在引起抑郁症上是必要的。

Serotonin and norepinephrine can be depleted experimentally in humans by oral treatments. 19 A drink containing all amino acids except tryptophan stimulates the liver to synthesize proteins and rapidly depletes the plasma (and therefore the brain) of tryptophan. Tryptophan is rate-limiting for serotonin synthesis in the brain. Such oral tryptophan depletion does not induce depression in healthy subjects but will cause a relapse of depression in patients who have been successfully treated with a serotonin-reuptake inhibitor. 19 Similarly, -methyl paratyrosine inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. Treatment with -methyl paratyrosine does not induce depression in normal subjects but will induce a relapse in patients who have been treated successfully with a norepinephrine-reuptake inhibitor. 19 These findings suggest that norepinephrine and serotonin have critical roles in the mechanisms of these treatments of depression but that additional neurochemical factors are necessary to cause depression.

因为单胺神经传递的直接测量不得出与抑郁症有关的决定性的发现，单胺神经传递下游区效应被探究（图 1 ）。 5- 羟色胺 -1B 受体位于突触前，由反馈抑制调节 5- 羟色胺的释放。尸体解剖研究显示 p11 的水平，一种增强 5- 羟色胺 -1B 受体发信号效率的蛋白，抑郁症病人的脑内是减少的。 5- 羟色胺 -1A 受体突触前和突触后都有，调节 5- 羟色胺功能（图 1 ）。抑郁症病人的受体可被检查，注射特异性显效药，测量特异性神经内分泌反应，诸如提高泌乳素的水平，结果提示抑郁症病人的这个受体的敏感性降低。 2 - 去甲肾上腺素受体，通常位于突触前，由反馈抑制调节去甲肾上腺素的释放（图 1 ）。抑郁症病人提高受体的敏感性已被描述，其与降低去甲肾上腺素释放相符合。

Because direct measurements of monoamine neurotransmission did not yield definitive findings in relation to depression, the downstream effects of monoamine neurotransmission were explored ( Figure 1 ). The serotonin-1B receptor is located presynaptically and regulates the release of serotonin by feedback inhibition. Postmortem studies show that the levels of p11, a protein that enhances the efficiency of serotonin-1B receptor signaling, are decreased in the brains of patients with depression. 20 The serotonin -1A receptor is located both presynaptically and postsynaptically to regulate serotonin function ( Figure 1 ). The receptor can be evaluated in patients with depression by injecting specific agonists and measuring specific neuroendocrine responses, such as elevation of the prolactin level. 21 Results suggest that the sensitivity of this receptor is reduced in patients with depression. 21 The 2 -noradrenergic receptor, which is usually presynaptic, modulates norepinephrine release by feedback inhibition ( Figure 1 ). Heightened receptor sensitivity has been described in patients with depression, 22 which is consistent with reduced norepinephrine release.

Figure 1. The Monoamine-Deficiency Hypothesis Extended.

抑郁症单胺假说假定脑内 5- 羟色胺和去甲肾上腺素不足。单胺能神经递质由 5- 羟色胺（ 5- 羟色胺 1A [5-HT 1A ] 和 5- 羟色胺 1B[5-HT1B] 或去甲肾上腺素 (noradrenaline) 从突触前神经元释放（ 5- 羟色胺能神经元，显示在左侧，和去甲肾上腺素能神经元，显示在右侧 [ 事实上浓缩 ] ）介导。 5- 羟色胺由色氨酸合成，在合成路径的起步阶段由色氨酸羟化酶催化；去甲肾上腺素从酪氨酸合成，起步阶段由酪氨酸羟化酶催化。单胺递质存储于突触前神经元的小囊泡内，释放进入突触间隙，从而影响突触前和突触后神经元。通过特异 5- 羟色胺和去甲肾上腺素运载体的再摄取和通过突触前 5-HT 1A 和 5-HT1B 调控自身受体释放的反馈控制 5- 羟色胺，α 2- 去甲肾上腺素自身受体释放的反馈控制去甲肾上腺素，籍此发生神经递质突触活动的停止。单胺氧化酶 A(MAO-A) 分解代谢突触前单胺，借此简介调节囊泡内容物。蛋白 p11 ，与 5-HT1B 受体相互作用，提高它们的功能。

The monoamine hypothesis of depression postulates a deficiency in serotonin or norepinephrine neurotransmission in the brain. Monoaminergic neurotransmission is mediated by serotonin (5-hydroxytryptamine 1A [5-HT 1A ] and 5-hydroxytryptamine 1B [5-HT1B]) or norepinephrine (noradrenaline) released from presynaptic neurons (serotonergic neuron, shown on the left side, and noradrenergic neuron, shown on the right side [condensed virtually]). Serotonin is synthesized from tryptophan, with the first step in the synthetic pathway catalyzed by tryptophan hydroxylase; norepinephrine is synthesized from tyrosine, with the first step catalyzed by tyrosine hydroxylase. Both monoamine transmitters are stored in vesicles in the presynaptic neuron and released into the synaptic cleft, thereby affecting both presynaptic and postsynaptic neurons. Cessation of the synaptic action of the neurotransmitters occurs by means of both reuptake through the specific serotonin and norepinephrine transporters and feedback control of release through the presynaptic 5-HT 1A and 5-HT1B regulatory autoreceptors for serotonin and the 2-noradrenergic autoreceptors for norepinephrine. Monoamine oxidase A (MAO-A) catabolizes monoamines presynaptically and thereby indirectly regulates vesicular content. The protein p11, which interacts with 5-HT1B receptors, increases their function.

Postsynaptically, both serotonin and norepinephrine bind two kinds of guanine nucleotide triphosphate – binding protein (G protein) – coupled receptors: cyclic AMP (cAMP) – coupled receptors, which activate adenylate cyclase (AC) to generate cAMP, and phosphatidylinositol (PI) – coupled receptors, which activate phospholipase C (PLC). PLC generates inositol triphosphate (IP 3 ) and diacylglycerol (DAG); cAMP activates protein kinase A (PKA), and IP 3 and DAG activate protein kinase C (PKC). The two protein kinases affect the cAMP response element – binding protein (CREB). Findings in patients with depression that support the monoamine-deficiency hypothesis include a relapse of depression with inhibition of tyrosine hydroxylase or depletion of dietary tryptophan, an increased frequency of a mutation affecting the brain-specific form of tryptophan hydroxylase (TPH-2), increased specific ligand binding to MAO-A, subsensitive 5-HT 1A receptors, malfunctioning 5-HT1B receptors, decreased levels of p11, polymorphisms of the serotonin-reuptake transporter associated with depression, an inadequate response of G proteins to neurotransmitter signals, and reduced levels of cAMP, inositol, and CREB in postmortem brains.

抑郁症 5- 羟色胺能和去甲肾上腺素能第二信使系统失灵是可能，因此原因，磷脂酰肌醇和环磷酰苷已被广泛的评估。肌醇水平的降低已被发现，在死于自杀的人脑尸体解剖以及抑郁症病人额皮质磁共振波谱的研究中。抑郁症病人脑尸体解剖研究中环磷腺苷对刺激钝圆反应被发现。第二信使功能降低可能损害神经递质功能，甚至单胺水平和受体数量没有改变的情况下。这些数据间接支持起初抑郁症单胺不足假说的确立（图 1 ）。

It is conceivable that the second-messenger systems for serotonergic and noradrenergic neurotransmission malfunction in depression, and for this reason the phosphatidylinositol and cyclic AMP second-messenger systems have been extensively evaluated. Reduced inositol levels have been found in postmortem studies of the brains of persons who have died by suicide 23 and in magnetic resonance spectroscopic studies of the frontal cortex in patients with depression. 24 A blunted cyclic AMP response to stimulation was found in postmortem studies of the brains of patients with depression. 25 These reductions in second-messenger function may impair neurotransmitter function even without changes in monoamine levels or receptor numbers. These data indirectly support elaborations of the original monoamine-deficiency hypothesis of depression ( Figure 1 ).

在抑郁症病人中，在受体和第二信使系统之间间接发信号的 G 蛋白也已被调查，在脑的尸体解剖研究和外周血细胞的研究中都有进行。尽管这些系统清楚受累，但没有一致的图片出现，因为 G 蛋白形式多样，随脑中不同区域而改变。环磷腺苷反应单元 - 粘蛋白（ CREB ）是一种转录蛋白，受细胞内环磷腺苷牵制。在抑郁症动物模型中，老鼠齿状回有 CREB 的过表达行为，相似于老鼠用抗抑郁症治疗，但当 CREB 在伏核内是过表达的，可发现相反的效应。因此，抑郁症内 CREB 的角色对脑局部是特异的。大多数但不是所有的研究显示长期用抗抑郁治疗刺激 CREB 功能，可能依赖于药物和剂量类型。 CREB 和磷酸 -CREB 水平在严重抑郁性障碍病人而且不服抗抑郁药的皮质的尸体解剖研究中是降低的，当与对照组比较。在抑郁症第二信使系统和转录蛋白的许多研究是鼓舞人心的，相信抗抑郁药治疗，化几周时间就会有效；因而，研究设计检查时间依赖的细胞内生物化学变化。新的大样本分析提示抗抑郁药效果开始迅速，不管如何，从此支持单胺不足假说。

G proteins that mediate signaling between receptors and second-messenger systems have also been investigated in patients with depression, both in postmortem studies of the brain 26 and in studies of peripheral-blood cells. 27 Although these systems are clearly affected, no consistent picture has emerged because there are numerous forms of G proteins that vary in different areas of the brain. The cyclic AMP response element–binding protein (CREB) is a transcription factor affected by cyclic AMP in the cell. In an animal model of depression, rats with overexpression of CREB in the dentate gyrus behaved similarly to rats treated with antidepressants, but the opposite effect was found when CREB was overexpressed in the nucleus accumbens. 26 , 28 Thus, the role of CREB in depression is specific to the region of the brain. Most but not all studies show that long-term treatment with antidepressants stimulates CREB function, possibly depending on the type of drug and the dosage. 28 Levels of CREB and phospho-CREB were reduced in postmortem studies of the cortexes of patients who had a major depressive disorder and had not taken antidepressants, as compared with controls. 26 , 28 Many studies of second-messenger systems and transcription factors in depression were inspired by the belief that it takes several weeks before antidepressant treatment has an effect; consequently, the studies were designed to detect time-dependent biochemical changes in the cell. New meta-analyses suggest that antidepressant effects begin rapidly, however, 29 thereby supporting the classic monoamine-deficiency hypothesis.

单胺理论的有力要点是它的预测力。已合成抑制去甲肾上腺素或 5- 羟色胺再摄取目的的几乎每一种混合物，已证明临床抗抑郁有效。抑郁的行为模型已被发展，啮鼠动物被放置在玻璃圆筒内，倒满水，透明逼没有提供逃脱机会。动物挣扎一会儿，而后顺从地漂浮（强迫游泳实验）。一种抗抑郁药预先注射增加挣扎时间；这个模型的结果有优秀的先兆可靠性，作为抗抑郁新药。别的动物模型已被发展，由选择性饲养抑郁样行为的老鼠，这些遗传上可疑的啮齿类对抗抑郁药也有反应。仍然可能被生物化学研究另外的模型诱导抑郁症，长期使用轻压力或获得性无能。无论怎样，没有抑郁症动物模型抓取抑郁行为周期性的改变，而这在抑郁症病人中随处可见。

A strong point of the monoamine theory has been its predictive power. Almost every compound that has been synthesized for the purpose of inhibiting norepinephrine or serotonin reuptake has been proved to be a clinically effective antidepressant. A behavioral model of depression has been developed in which a rodent is placed in a glass cylinder filled with water, the sheer wall offering no chance of escape. The animal struggles for a while and then floats passively (the forced swim test). A single prior injection of antidepressant increases the struggling time; results in this model have excellent predictive validity for new antidepressants. Other animal models have been developed by selective breeding of rats for depression-like behavior, and these genetically susceptible rodents also have a response to antidepressants. 30 Still other models that can be studied biochemically induce depression with the use of long-term mild stress or learned helplessness. However, no animal model of depression captures the periodic change of behavior into and out of depression that is seen in patients with depression.

诸如基因部分敲除的分子技术支持抑郁症的单胺理论。 5- 羟色胺再摄取运载体敲除小鼠非常焦虑，而且在强制游泳实验中具有增加不动性的特征。这些影响与那些 5- 羟色胺受体低活力多态异形体相似，在人类个性上，但与 5- 羟色胺再摄取抑制剂抗抑郁药期望效应的相对。然而，这个矛盾可能被解释，在脑发育期间慢性单胺异常和假设抑郁症成人的急性单胺消耗之间的差异。表 1 显示老鼠敲除与单胺神经递质有关的基因的效应。

Molecular techniques such as gene knockout partially support the monoamine theory of depression. The serotonin-reuptake–transporter knockout mouse is excessively anxious and characterized by increased immobility in the forced swim test. 31 This effect is similar to that of the low-activity polymorphic variant of the serotonin receptor on human personality 10 but is the opposite of the expected effects of serotonin-reuptake–inhibitor antidepressants. However, this inconsistency could be explained by the difference between a chronic monoamine abnormality during brain development 31 and the hypothesized acute monoamine depletion in an adult with depression. Table 1 shows the effects in mice of knocking out genes related to monoamine neurotransmitters.

Table 1. Monoamine-Related Gene Knockouts That Affect Depression-Related Behavior in Mice.

表 1. 单胺有关基因敲除。影响老鼠抑郁有关的行为。

情绪刺激效应间接支持抑郁症单胺不足假说，显示情绪能被迅速改变。可卡因和苯乙丙胺强烈释放单胺进入突触同时抑制再摄取。他们的情绪提高反应是立即的，但严重抑郁病人，常被报道引起激动而不是缓解抑郁。这一发现反应了这些消耗突触前单胺的能力，如此引起 “ 坠落 ” 进入抑郁。最近研究支持对单剂量苯乙丙胺急性反应的理论，其在预测病人对单胺再摄取抑制剂较长期反应上。

The effects of stimulants on mood indirectly support the monoamine-deficiency hypothesis of depression and show that mood can be altered rapidly. Cocaine and amphetamines are powerful releasers of monoamines into the synapse as well as inhibitors of reuptake. Their mood-elevating effects are immediate, but in patients with severe depression they have often been reported to cause agitation rather than relief of depression. This finding could reflect the ability of these stimulants to deplete the presynapse of monoamines and thus cause a "crash" into depression. Recent studies support the theory that an acute response to a single dose of amphetamine predicts a patient's longer-term response to monoamine-reuptake inhibitors. 46

抑郁症多巴胺不足的角色，从帕金森病人抑郁频繁中得到提示，利血平有效，帕金森病消耗了 5- 羟色胺，去甲肾上腺素和多巴胺，动物引起活动减退的情状。抗抑郁药 buproprin 抑制多巴胺再摄取。一些多巴胺受体激动剂，诸如普拉克索，被报道在治疗抑郁症上灵敏的，尽管它们是为帕金森病开发的。

The role of dopamine deficiency in depression is suggested by the frequency of depression in patients with Parkinson's disease and the effect of reserpine, which depletes serotonin, norepinephrine, and dopamine, causing a hypoactive state in animals. The antidepressant agent buproprion inhibits the reuptake of dopamine. Some direct dopamine-receptor agonists, such as pramipexole, have been reported to be efficacious in the treatment of depression, even though they were developed for Parkinson's disease. 47

单胺不足假说的主要易感性是由当前可得抗抑郁药机制的诱导而来。将近 2/3 的病人对这些药有临床反应，而 1/3 病人对安慰剂有反应。或许抑郁的机制在这些案例里一半是与单胺不相关的。

A major liability of the monoamine-deficiency hypothesis is its derivation from the mechanism of currently available antidepressants. Approximately two thirds of patients have a clinical response to these agents, whereas one third have a response to placebo. 48 Perhaps the mechanism of depression is not related to monoamines in two of three cases.

Stress, the Hypothalamic–Pituitary–Adrenal Axis, and Growth Factors 应激，下丘脑 - 垂体 - 肾上腺轴，和生长因子

应激被大脑皮层感知，传到下丘脑，在那儿促肾上腺皮质素释放激素（ CRH ）释放到垂体受体。这一刺激导致促肾上腺皮质激素分泌进入血浆，肾上腺皮质内促肾上腺皮质激素受体兴奋，释放皮质醇入血。下丘脑皮质醇受体反应，由 CRH 产物降低来维持调节体内平衡作用（图 2 ）。

Stress 49 is perceived by the cortex of the brain and transmitted to the hypothalamus, where corticotropin-releasing hormone (CRH) is released onto pituitary receptors. This stimulus results in the secretion of corticotropin into plasma, stimulation of corticotropin receptors in the adrenal cortex, and release of cortisol into the blood. Hypothalamic cortisol receptors respond by decreasing CRH production to maintain homeostasis ( Figure 2 ).

Figure 2. The Hypothalamic – Pituitary – Cortisol System in Depression.

图 2. 抑郁症下丘脑 - 垂体 - 皮质醇系统

抑郁症下丘脑 - 垂体 - 皮质醇假说假定皮质醇对应激反应异常可能是抑郁症的基础。黑箭头显示对应激的反应，脑皮质和杏仁核获取感知后，传到下丘脑，促肾上腺皮质素释放激素（ CRH ）被释放，诱导垂体前叶腺分泌促肾上腺皮质激素进入血流。促肾上腺皮质激素兴奋肾上腺皮质分泌糖皮质激素考的松。红线显示考的松反过来诱导反馈抑制下丘脑和垂体，压制 CGH 产物和促肾上腺皮质激素，各自地。

The hypothalamic – pituitary – cortisol hypothesis of depression postulates that abnormalities in the cortisol response to stress may underlie depression. The black arrows show that in response to stress, which is perceived by the brain cortex and the amygdala and transmitted to the hypothalamus, corticotropin-releasing hormone (CRH) is released, inducing the anterior pituitary gland to secrete corticotropin into the bloodstream. Corticotropin stimulates the adrenal cortexes to secrete the glucocorticoid hormone cortisol. The red lines show that cortisol, in turn, induces feedback inhibition in the hypothalamus and the pituitary, suppressing the production of CRH and corticotropin, respectively.

在抑郁症病人内的发现支持下丘脑 - 垂体和皮质醇假说包括以下：严重抑郁症皮质醇水平有时升高，垂体前叶腺和肾上腺皮质增大，脑脊液 CRH 水平和缘脑区域 CRH 表达升高。海马大小和神经元数目和神经胶质减少（小），可能反应了神经发生减少，由于皮质醇水平提高或由于脑源性神经营养因子的减少。

Findings in patients with depression that support the hypothalamic – pituitary – cortisol hypothesis include the following: cortisol levels are sometimes increased in severe depression, the size of the anterior pituitary and adrenal cortex is increased, and CRH levels in the cerebrospinal fluid and CRH expression in the limbic brain regions are increased. Hippocampal size and the numbers of neurons and glia are decreased, possibly reflecting reduced neurogenesis due to elevated cortisol levels or due to reduced brain-derived neurotrophic factor.

抑郁症累及皮质醇和它的中心释放因子， CRH ，有相当的证据。抑郁症病人可能有血浆考的松水平升高，脑脊液内 CRH 水平升高，缘脑区域 CRH 信使 RAN 和蛋白升高。在利用地塞米松评价下丘脑反馈信号敏感性研究中，抑制 CRH 释放，大约一半最严重的抑郁病人中正常考的松抑制反应是缺乏的。抗抑郁药 - 诱导临床减轻有些伴有逆转，在这些异常病人中。

There is considerable evidence that cortisol and its central releasing factor, CRH, are involved in depression. 50 , 51 Patients with depression may have elevated cortisol levels in plasma, 38 elevated CRH levels in cerebrospinal fluid, 50 and increased levels of CRH messenger RNA and protein in limbic brain regions. 50 In studies using dexamethasone to evaluate the sensitivity of the hypothalamus to feedback signals for the shutdown of CRH release, the normal cortisol-suppression response is absent in about half of the most severely depressed patients. 52 Antidepressant-induced clinical remission is accompanied by reversal of some of these abnormalities. 52

有物质和性滥用史的成人，小儿时就有脑脊液内 CRH 水平的升高。成年啮齿类当它幼小的时候与母亲分离或遭虐待，在强迫游泳实验中显示不动性增加，但可以被抗抑郁药物治疗逆转。有敲除糖皮质激素受体特殊区域的成年老鼠，下丘脑 - 垂体 - 肾上腺轴活性增加，在强迫游泳实验中不动心增大，这两种都可被抗抑郁药逆转。

Adults with a history of physical or sexual abuse as children have increased levels of CRH in cerebrospinal fluid. 53 Adult rodents that were separated from their mothers or abused as pups show increased immobility in the forced swim test, which is reversed by antidepressant treatment. 54 Mice with region-specific knockout of the glucocorticoid receptor at an adult age have increased activity of the hypothalamic–pituitary–adrenal axis and increased immobility in the forced swim test, both of which are reversed by antidepressants. 55

在突触内单胺水平上升，影响下丘脑 - 垂体 - 肾上腺轴，逆转一些长期的紧张效应。抗抑郁药环节抑郁是可能的，降低继发紧张，由痛苦的沮丧情绪引起，而不是由直接提高情绪。抗紧张机制能够解释广泛多变精神病情况下抗抑郁药的一般有用性，包括惊恐性障碍，创伤后精神紧张性障碍，易饿感，月经前综合征，强迫观念 - 强迫性精神障碍。在动物模型中， CRH- 受体拮抗剂显示抗抑郁活力，但大的临床试验的结果却是令人失望的。一种糖皮质激素受体混合块被报道对抑郁症有效，但仅限于最严重和精神病类型。

Increased levels of monoamines in the synapse affect the hypothalamic–pituitary–adrenal axis 56 and reverse some of the long-term effects of stress. 56 It is possible that antidepressants relieve depression by reducing the secondary stress caused by a painfully dispirited mood rather than by directly elevating mood. An antistress mechanism could explain the general usefulness of antidepressants for a wide variety of psychiatric conditions, including panic disorder, post-traumatic stress disorder, bulimia, premenstrual syndrome, and obsessive–compulsive disorder. CRH-receptor antagonists show antidepressant activity in animal models, 57 but the results of large clinical trials have been disappointing. A compound that blocks the glucocorticoid receptor has been reported to be efficacious in depression, but only the most severe and psychotic type. 58

血中单一皮质醇实验不促成抑郁症的诊断，皮质醇水平在调节生理节律上有非常明显的作用，因为病人与对照组之间的值有大量重叠。轻微紧张在实验室里可以被诱导，诸如合并有心理算术计算或模拟公众演说的紧张，导致血浆中皮质醇水平改变较大，抑郁症病人与对照组之间的值比大多数已报道的值差别要明显。皮质醇慢性轻微上升是可能的，尤其晚上，正常受试者很低，而抑郁症患者有一个病理性角色。末梢皮质醇升高也是可能的，仅是 CRH 发信号时中枢受干扰的一个反映，是情绪环境紧张的间接效应。抑郁症下丘脑 - 垂体 - 肾上腺轴主要易患性理论定义从紧张到抑郁之间的关联是困难的。有些一生中单一抑郁发作的人，鉴于有复发或甚至有慢性过程的比例。急性紧张的各种类型，早期儿童外伤，或长期心理社会问题，可能累及或可能导致应急系统的不同反应。紧张在一些案例里可能是原因，在别的情况下可能继发抑郁情绪。

A single test for the cortisol level in blood does not contribute to the diagnosis of depression, since levels of cortisol vary markedly in a circadian rhythm 38 and because the overlap between values in patients and those in controls is considerable. Mild stress induced in the laboratory, such as stress associated with mental arithmetic calculations or simulated public speaking, results in greater changes in plasma cortisol levels than most reported differences between the values in patients with depression and those in controls. 38 It is possible that chronic mild elevations of cortisol, especially at night, when cortisol levels in normal subjects are very low, have a pathogenic role in depression. It is also possible that peripheral cortisol elevations are only a reflection of central disturbances in CRH signaling, which mediate the effects of environmental stress on mood. 59 A major liability of the hypothalamic–pituitary–adrenal axis theory of depression is the difficulty of defining the relationship of stress to depression. Some patients have a single lifetime depressive episode, whereas a larger proportion have a recurrent or even chronic course. Various types of acute stress, early childhood trauma, or long-term psychosocial problems may be involved and may lead to different responses of the stress system. Stress may be causative in some cases and secondary to depressed mood in others.

啮齿类严重紧张不是通常的儿童期紧张状态必然模型。在有精神病理学疾病儿童期合并虐待，包括抑郁，在成人期可能是由于结合家庭暴力犯罪和他们的受害者的常见因素，包括不仅分享基因而且贫穷的环境，营养缺乏，和糟糕的产前保健。抑郁症在没有精神社会风险的人群中不常见。大多数抑郁症病人治疗没有下丘脑 - 垂体 - 肾上腺机能障碍的证据，

Severe stress in rodents does not necessarily model the common stresses of childhood. The association of abuse in childhood with psychopathologic disorders, including depression, in adulthood could be due to common factors linking family perpetrators of abuse and their victims, including not only shared genes but also a shared environment of poverty, poor nutrition, and poor prenatal care. Depression is not uncommon in people with no psychosocial risk factors. Most patients treated for depression have no evidence of hypothalamic–pituitary–adrenal dysfunction, just as most such patients have no direct evidence of brain monoamine deficiency.

The classic teaching is that neurons do not divide in the adult mammalian brain, but studies have shown that neurogenesis occurs in several areas of the brain, especially the hippocampus. Neurogenesis is more prominent in rodents than in primates, 60 and some have questioned whether it occurs in the human cortex. 61 Elevated levels of glucocorticoids can reduce neurogenesis, and this has been suggested as a mechanism for the decreased size of the hippocampus on magnetic resonance images of the brain in many patients with depression. 62 In postmortem studies of patients with depression, cell loss in the subgenual prefrontal cortex, atrophy in the dorsolateral prefrontal cortex and the orbitofrontal cortex, and increased numbers of cells in the hypothalamus and the dorsal raphe nucleus have been reported. 63 These effects resemble the atrophic changes in the brain in patients with Cushing's disease 64 and in rodents treated with glucocorticoids. 65 However, cortisol elevations in depression are much lower than in Cushing's disease.

Restraint in a small container induces stress in rodents, suppressing neurogenesis, and this effect is countered by antidepressant treatment. 66 Antidepressants also enhance neurogenesis in nonhuman primates. 67 Santarelli et al. 68 irradiated the hippocampus in mice and abolished neurogenesis. They found that the radiation also abolished the ability of the animals to respond behaviorally to antidepressant treatment in the forced swim test, but this phenomenon does not occur in every mouse strain studied. 69 Henn and Vollmayr summarized other studies providing evidence that decreased neurogenesis is a result of stress and anxiety but may not be behaviorally relevant. 70 The relevance of animal models of neurogenesis to clinical studies of depression has been questioned by analogy with studies of neuroprotection strategies in stroke, for which numerous findings in animal models have not been replicated in human studies. 71

Brain-derived neurotrophic factor (BDNF), a neurotrophic peptide, is critical for axonal growth, neuronal survival, and synaptic plasticity, 72 and its levels are affected by stress 73 and cortisol. 74 A postmortem study of patients with depression who had committed suicide showed that BDNF was reduced in the hippocampus. 75 Antidepressant drugs and electroconvulsive therapy up-regulate BDNF and other neurotrophic and growth factors 75 , 76 ; a single bilateral infusion of BDNF into the dentate gyrus has antidepressant-like effects. 77 One study showed that the hippocampus was smaller than normal in patients with depression who carried a met166 BDNF allele. 78 In an animal model of depression, epigenetic histone methylation mediated down-regulation of BDNF transcripts and antidepressant treatment reversed this effect. 79 These studies suggest that BDNF is the link among stress, neurogenesis, and hippocampal atrophy in depression. However, a genetic association of the BDNF val166met polymorphism with depression has not been replicated in most studies, 74 and BDNF may be related not only to depression but to multiple psychiatric disorders. 74 BDNF-knockout mice have behaviors unrelated to depression. 45 Reduced BDNF levels in the peripheral blood of patients with depression seem to derive almost entirely from blood platelets, 80 and many artifacts must therefore be considered in interpreting these findings. Inflammation in the brain and some neurotoxins increase brain BDNF levels, suggesting that the actions of BDNF are not uniformly therapeutic. 81 Castrén 82 has proposed that antidepressant treatments may increase synaptic sprouting and allow the brain to use input from the environment more effectively to recover from depression. This hypothesis highlights the role that cognition may play in depression and suggests that biochemical mechanisms may be nonspecific.

Strong epidemiologic data point to an association between major depressive disorder and increased cardiovascular morbidity and mortality. 83 In many patients, cardiovascular disorders precede depression, and in others, depression precedes the cardiovascular disorder. Both n–3 fatty acid deficiency 84 and elevated plasma homocysteine levels 85 have been implicated in cardiovascular disease and in depression. Elevated cortisol levels in depression could increase the risk of coronary artery disease, since cortisol increases visceral fat. 64 , 86 Antidepressant treatment increases the survival rate among patients who become depressed after coronary occlusion. 86 Endothelial-cell signaling plays a crucial role in brain neurogenesis, 87 and these cells secrete BDNF; thus, both depression and cardiovascular disease could be examples of an endothelial disorder. Signs of inflammatory processes have been described in major depression 88 and in cardiovascular disease. Some data suggest that exercise has protective or therapeutic effects in depression. 89 Rodent models support this possibility. 90