In conclusion, there have been so many hypothesis to explain the pathogenesis of MDD associating with many booming researches (Fig. 3). However, it is still hard to adopt only one above hypothesis to completely reveal pathophysiology of MDD. The main problem may contribute to the limitations of the theoretical perspective and the limitations of detection methods. In the pathological conditions, conducting research from the perspective of comprehensive collaboration of the whole body and increasing the proportion of new technological applications in research will open up the new paths to reveal the pathogenesis of MDD in the future. Neuroimaging, including magnetic resonance imaging (MRI) and molecular imaging, provides a non-invasive technique for determining the underlying etiology and individualized treatment for depression.

Neurobiological Pathogenesis of Depressive Disorder

The baseline risk of depression in the population is 10 percent; having a first-degree relative (parent or sibling) with depression doubles or triples an individual’s risk, to 20 to 30 percent over the course of a lifetime. The best forms of exercise for people with depression include aerobic, resistance, and mind-body exercise. In October 2021, researchers demonstrated the potential of resetting brain circuits in people with treatment-resistant depression by implanting a neurostimulation device into a person’s brain.

The USA ranks first in the number of depression-related patent applications, followed by China. The largest number of patents related to depression is the development of antidepressants, and drugs for neurodegenerative diseases such as dementia comorbid with depression. The top 10 technological areas of patents related to depression are shown in Fig. 2C, and the trend in these areas have been stable over the past decade (Fig. 2D).

Continuing Education Activity

SSRIs and SNRIs are the first-line treatments for MDD in the clinic; however, a sizable portion of MDD patients do not respond well to the currently available antidepressants. According to research on real-world sequential therapies, even after numerous treatment attempts, almost 30% of MDD patients do not experience remission. This suggests that the existing theories and hypotheses cannot completely explain the pathogenesis of MDD and that more research on the pharmacological mechanisms of currently available antidepressants is still needed. We mainly discussed the potential etiology and pathogenesis of MDD from the perspective of widely accepted theories, including the neurotransmitter and receptor hypothesis, HPA axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis. A more comprehensive understanding of the pathophysiological mechanisms of MDD might significantly improve our capacity to develop preventive and more effective therapeutic methods that can help reduce the burden of and pain caused by major depression. Knowledge of the cellular processes that drive these alterations and the symptoms they cause may offer crucial will provide insight for new treatments.

Cortisol is especially toxic to cells in the brain’s hippocampus, and one consequence of uncontrolled stress is shrinkage of the hippocampus, manifest in the impaired memory and learning that are characteristic of depression. The nerve cell connections between the amygdala and the prefrontal cortex (PFC) are sometimes called the “depression circuit;” depression results when emotion-laden signals from the amygdala overpower the ability of the PFC to regulate the signals. The prolonged or excessive release of stress hormones can lead to a failure of activation of key nodes in neural networks or impair the strength of signals between them, especially when processing emotion-related or reward stimuli.

1. If someone has any severe symptoms, they should seek immediate medical care.
2. Fatalities result from cardiorespiratory arrest or (direct) myocardial depression.
3. The key cellular role of mitochondria comes with interdependency with numerous depression-relevant pathways.

Clinical research progress

The cerebral cortex, hippocampus, hypothalamus, dorsal raphe (DR) nucleus, arcuate central nervous system depression nucleus, and solitary tract nucleus are some regions of the brain that can express leptin receptors. FMRI, including resting-state and task-based fMRI, can divide the brain into self-related regions, such as the anterior cingulate cortex, posterior cingulate cortex, medial prefrontal cortex, precuneus, and dorsomedial thalamus. Many previous studies have shown the disturbance of several brain areas and intrinsic neural networks in patients with depression which could be rescued by antidepressants 113–116.

Given the diversity of findings, epigenetic factors are now being investigated. Recent studies indicated that epigenetic mechanisms may be the potential causes of “loss of heritability” in GWASs of depression. Over the past decade, a promising discovery has been that the effects of genetic information can be directly influenced by environment factors, and several specific genes are activated by environmental aspects. This process is described as interactions between genes and the environment, which is identified by the epigenetic mechanism. Environmental stressors cause alterations in gene expression in the brain, which may cause abnormal neuronal plasticity in areas related to the pathogenesis of the disease. Epigenetic events alter the structure of chromatin, thereby regulating gene expression involved in neuronal plasticity, stress behavior, depressive behavior, and antidepressant responses, including DNA methylation, histone acetylation, and the role of non-coding RNA.

“The current standard of care for the treatment of depression is based on what we call the ‘monoamine deficiency hypothesis,’ essentially presuming that one of three neurotransmitters in the brain is deficient or underactive,” says Rachel Katz, MD, a Yale Assistant Professor of Clinical Psychiatry. What we know right now is that, on a chemical level, depression involves neurotransmitters, which can be thought of as the messengers that carry signals between brain cells, or neurons. When we think about depression, what comes to mind are feelings and emotions – or, for some, the absence of feelings and emotions. In order to really understand depression, however, it’s important to be aware that the condition has physical aspects as well. Most people understand what depression looks like on the outside, in terms of a person’s behavior, but our medical understanding of the actual progression of the disease and its treatments continues to evolve.

Lifestyle medicine is an evolving medical specialty that aims to prevent chronic, noncommunicable diseases through lifestyle interventions. The goal of lifestyle medicine is to prevent the occurrence and recurrence of disease by improving sleep hygiene and diet, increasing physical exercise, avoiding sedentary behavior, increasing social support, and improving mood. In recent years, an increasing number of studies have demonstrated that the occurrence and recurrence of MDD can be prevented by means of lifestyle medicine;280 we summarize these reports in this section. MDD is accompanied by changes in the levels of proinflammatory cytokines and trophic factors, including BDNF, interleukins (IL-1β, IL-6), and tumor necrosis factor alpha (TNF-α). Increasing data suggest that the production of certain cytokines by brain astrocytes plays a significant role in the pathogenesis of MDD.

Through enhancing conductivity along neuronal axons 223, myelin and myelin-producing oligodendrocytes are obvious candidates for mechanisms of brain diseases in general. Several studies found pronounced alterations in myelination and oligodendrocyte lineage cells in depression and animal models thereof 222. Even though not typically conceptualized in pathways, myelin and oligodendrocytes are known to be affected by stress and by several other factors such as neurotransmitters, neurotrophins, cytokines, ROS, epigenetic factors, intestine microbiome, among others 222, 224. Further, oligodendrocytes shape neuronal function in many ways beyond myelination; the importance of oligodendrocytes and myelination in MDD is corroborated by their response to antidepressant treatment 222.

CNS depressants are substances that can slow down your central nervous system. Benzodiazepines like diazepam and clonazepam are used to treat anxiety and panic attacks. Benzodiazepines are not prescribed for long-term use because of their high risk of developing dependence or addiction. If someone has been on medication for a while or misused it, a doctor may look at their medical history and conduct tests to determine whether CNS depression is an accurate diagnosis.