Author | Penny Pang
Editor | Valuri Yang
Abstract
"Black bile" - this is associated with the ancient Greek theory of the four humors. Ancient Greek medical pioneers, including Hippocrates, believed that depression was caused with an excess of "black bile" in the body. However, with the continuous development of human cognition, biologists have given a preliminary explanation for the etiology of depression: under the adverse intervention of social environment, interpersonal relationships and other factors; the body's hormone levels, neurotransmitter levels, intracellular signaling and other activities are affected, or even over-regulated, thus triggering a series of clinical manifestations of depression. In the biological field, scientists are continuing to conduct research on the molecular mechanisms of depression, drug therapy, diversity, gender differences, and other directions.
Mechanisms
Regarding the causative mechanisms of depression, abnormal regulation of excitatory synapses has received much attention in recent years. Let's start with the stress response. Stress responses are activities that release hormones and other cellular mediators. These mediators promote organismal adaptation when the response is turned on and off appropriately, but they can also lead to systemic damage when the response is over-regulated or disordered. Over-activation of the hypothalamic-pituitary-adrenal axis (HPA axis), caused by prolonged exposure to a constant state of high stress, is a key mechanism of depression[1]. Stress is perceived by the brain cortex, and transmitted to the hypothalamus leading to HPA activation. HPA activity is regulated by adrenocorticotropic hormone-releasing factor (corticotropin-releasing factor, CRF) secreted from the hypothalamus and vasopressin (AVP) released from the posterior pituitary gland. This in turn stimulates the pituitary to secret the adrenocorticotropic hormone (ACTH) that finally activates the secretion of glucocorticoids (cortisol in humans, which regulates activities such as neuronal survival, neurogenesis, and emotional appraisal of events, and is a key link between stress and brain functioning) from the adrenal cortex. Glucocorticoids then bind to their receptors localized within the HPA axis as well, where they exert feedback control on CRF, AVP, and ACTH secretion.
As a result, the HPA axis in depressed patients is "overloaded" due to constant activation, with elevated levels of salivary, plasma, and urinary cortisol.
Fig. 1: Mechanism of action of HPA in response to pressure stimuli. Figure from https://zhuanlan.zhihu.com/p/36886303
The pathogenic mechanisms of depression also involve a variety of neurotransmitter and metabolic systems. From the perspective of neurotransmitter theory, it is the monoamines that have the most significant impact on depression, which primarily include norepinephrine (NE) and 5-hydroxytryptophan (5-HT), as well as dopamine, which has a relatively small impact [3]. It has been found that these neurotransmitters are heavily concentrated in the limbic system associated with sleep regulation, appetite, and emotional processing. As shown in Figure 2, 5-HT and NE are synthesized in presynaptic neuron cells, respectively, and their concentration is regulated by monoamine oxidase (MAO), and then released into the synaptic gap where they bind to a family of receptors on the postsynaptic neuron, which in turn mediate neural signaling. Neurotransmitter recycling receptors are present on presynaptic neuron cells, which results in lower concentrations of neurotransmitters in the process of neurotransmission. In depressed patients, 5-HT levels are reduced by "overloading" of the HPA axis and high cortisol concentrations, ultimately leading to depression.
Fig. 2: Mechanisms of 5-HT and norepinephrine neurotransmission and sites of pharmacotherapeutic action. Figure fromhttps://www.nejs.app/2014/10/blog-post_55.html
Nowadays, the most mainstream mechanism of depression is the HPA axis-5-HT hypothesis, and the rest of the hypotheses are related to inflammatory response, immune response, mitochondrial function, etc. The various hypotheses complement each other and explain the complex mechanism of depression together.
Fig. 3: Interaction between hypotheses on the pathophysiology of depression [2]
Widely used antidepressants are mainly based on the inhibition of reuptake processes, such as 5-hydroxytryptamine reuptake inhibitors (selective serotonin reuptake inhibitors,
SSRIs) norepinephrine reuptake inhibitors (SNRIs), and heterocyclic antidepressants (TCAs), or based on inhibition of hormone oxidation processes, such as monoamine oxidase inhibitors (MAOIs). However, all of these drugs are associated with extreme side effects and there is an urgent need to develop highly effective psychotropic drugs with low side effects.
Gender difference
Even though the causative mechanisms of depression are broadly the same, there are gender differences in the regulation of some important hormones. For example, in the presence of CRF overproduction, male LC neurons decrease their response to CRF, thereby preventing high levels of hyperarousal (disruptive feeling of being on edge). Female LC neurons are more sensitive to acute doses of CRF, and the tonic firing rate of their LC neurons is three times higher than that of males under the same conditions, so women are more likely to exhibit differences in stress responses compared to men, potentially leading to variations in symptomatology. The circuits and mechanisms responsible for these differences have not been adequately investigated because clinical studies in the past used male rodents as subjects and loosely assumed that females should show the same findings too. Today, this neglect of gender differences is beginning to be addressed. Gender differences underlie the characterization of a wide range of psychiatric disorders, and these findings allow us to conceptualize various types of gender differences in the brain, which in turn has broader implications for considering gender as a biological variable. Importantly, comparisons between genders can help to develop new treatments [4].
Conclution
Nowadays, it is generally accepted that the pathogenesis of depression is related to the regulatory mechanisms of HPA and the adaptive mechanisms of the neurotransmitter system, and hypotheses about these mechanisms are constantly being demonstrated through experiments. At the present stage, drugs for depression have extreme side effects and limited application. To develop more effective antidepressant drugs, future research should take side effects into consideration and be based on respect for gender differences, experimental validation should be carried out on both genders of subjects separately.
When external stimuli come, the HPA does not stop releasing cortisol even if it takes a huge risk of overloading, it does not know how serious the consequences will be, so depression is just a case of the body "doing something bad with good intentions". So, when feeling depressed and isolated, think about the fact that our body is always trying to protect us, do something that can make us happy, or get treatment and tell our body and ourselves: Don't worry, everything will be fine!
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