うつ病
うつ病（うつびょう、鬱病、欝病、: clinical depression）または大うつ病性障害（だいうつびょうせいしょうがい、: major depressive disorder）とは、一般的な精神障害であり、より厳密には精神障害内の気分障害内の一つ。
主な症状として、少なくとも2週間にわたり抑うつ気分（悲しみ・苛立ち・虚しい感覚）や、喜びの喪失〔アンヘドニア〕や活動的興味の喪失が続く。他にあり得る症状としては集中力低下、過剰な罪悪感、自尊心の低下、将来への絶望、死や自殺についての考え、不安定な睡眠、食欲や体重の変化、疲労感、エネルギー低下感など。WHOの推計では、全世界の成人の5%が罹患している。
2000～2010年代以降の神経精神医学では、ヒトヘルペスウイルス6が脳神経細胞を部分的に死滅させることでうつ病が発症するという仕組みが解析されつつある
PMID: 35821494/DOI: 10.1002/jmv.27995
Infections can lead to the onset of mood disorders in adults, partly through inflammatory mechanisms. However pediatric data are lacking. The aim of this study is to evaluate the relationship between depressive disorder and seropositivity of herpes virus infections in children. The sample group consisted of patients diagnosed with depressive disorder according to DSM-5 diagnostic criteria and healthy volunteers, being between 11 and 18 years with clinically normal mental capacity. All children completed DSM-5-Level-2 Depression Scale, DSM-5-Level-2 Irritability Scale, DSM-5-Level-2 Sleep Scale, DSM-5-Level-2 Somatic Symptoms Scale. The levels of anti-HSV1-IgG, anti-CMV-IgG, anti-EBNA, and anti-HHV6-IgG were examined in all participants. Patients with an antibody value above the cut-off values specified in the test kits were evaluated as seropositive. The mean age was 15.54 ± 1.57 years in the depression group (DG), 14.87 ± 1.76 years in the healthy control group (CG). There were 4 boys (11.2%), 32 girls (88.8%) in the DG, 9 boys (21.9%) and 32 girls (78.04%) in the CG. There was no statistically significant difference between the groups in terms of the presence of seropositivity of HSV1, CMV, EBV, and HHV6. HHV6 antibody levels were significantly higher in the DG (p = 0.000). A significant positive correlation was found between HHV6 antibodies and DSM-5 level-2 somatic symptoms scale score. HHV6 antibody levels were found to be significantly higher in patients with existing suicidal ideation in the DG (n = 13) compared to those without existing suicidal ideation in the DG (p = 0.043). HHV6 persistent infections may be responsible for somatic symptoms and etiology of suicidal ideation in childhood depressive disorder.
日本のうつ病の診療ガイドラインは、うつ病と、DSM-IVの大うつ病性障害、また単極型（短極性）うつ病はほぼ同じ意味であるとしている[15]。第5版のDSM-5の邦訳書では、うつ病の用語は、大うつ病性障害の診断名と、うつ病エピソード（定義されたうつ状態、後述）とを指すために用いることが記されている[2]。以上の範囲を本記事のおもな対象とする。なお訳語では、major depressive disorderの major が日本語で大と訳されているが、本来これは「主要な」あるいは「中心的な」という意味で用いられているものであり、誤訳であるとする意見もある[16]。
うつ病という用語は、狭い意味ではDSM-IVにおける大うつ病性障害に相当するものを指しているが、広い意味でのうつ病は、一般的には抑うつ症状が前景にたっている精神医学的障害を含める。そのなかには気分変調性障害をはじめとするさまざまなカテゴリーが含まれている[17]。
操作的診断基準による「大うつ病性障害」などの概念と、従来の分類による「内因性うつ病」（後述）などは同じ「うつ病」であっても異なる概念であるが、このことが専門家の間でさえもあまり意識されずに使用されている場合があり、時にはそれを混交して使用しているものも多い。そのため一般社会でも、精神医学会においても、うつ病に対する大きな混乱が生まれている[18]。つまり、うつ病という言葉の意味が異なっている場合がある。
The Role of Neurons and Glial Cells in Depression
3.1. The Association between Neuronal Cells and Depression
Neurons, or neuronal cells, are the most basic structural and functional units of the nervous system and are divided into two parts: the cell body and the protrusion. In recent years, the mechanisms by which neurons regulate relevant physiological functions and thus produce depression have been elucidated.
Extensive studies have shown that inflammation negatively affects mitochondrial health, leading to excitotoxicity; oxidative stress; energy deficiency; and, ultimately, neuronal death. In addition, damaged mitochondria can release multiple molecular patterns associated with damage, which can lead to a cycle including oxidative stress, mitochondrial damage, etc. This vicious cycle can be involved in regulating the mechanisms of inflammation-related depression, indicating that inflammation-induced neuronal death may be an important factor in the pathogenesis of depression [17]. Related studies suggested that although impaired dopaminergic neurotransmission is not considered a core neurochemical alteration in depression [18,19], there is now significant evidence that inflammation preferentially affects midbrain dopaminergic neurons such as by reducing dopamine synthesis and release and increasing dopamine reuptake [20]. Related studies have found that the antidepressant effects of amantadine may be due to an increase in extracellular DA concentration in the striatum and/or the indirect neuroprotective effect on dopaminergic neurons in the substantia nigra. Another possible cause of depression is a decrease in the reuptake and release of dopaminergic neurons [21]. Moreover, it was experimentally demonstrated that glutamate and hippocampal neuronal apoptosis are, respectively, key signals for and direct contributors to diabetes-associated depression. A previous study further suggested that in diabetes-related depression, the abnormal Glu–GluR2–Parkin pathway leads to the mitochondrial autophagy-mediated apoptosis of hippocampal neurons, showing that depression is also inextricably linked to hippocampal neurons [22]. Based on the above studies, the connection between neurons and depression is mediated mainly through inflammation and associated with apoptosis. Thus, the various responses mediated by neurons may be key to explaining the pathogenesis of depression in the future.
3.2. The Association between Glial Cells and Depression
Related studies have found that some triggers of depression are associated with glial cells [23]. This association is believed to be closely related to many nervous system diseases [24]. Taking astrocytes, oligodendrocytes, and microglia as examples, we analyze the association between these three types of glial cells and depression.
3.2.1. Astrocytes and Depression
Astrocytes are a highly heternogeneous populatio of nerve cells responsible for central nervous system homeostasis, contributing to central nervous system homeostasis and providing defense against a variety of harmful effects. For example, astrocytes have the potential to promote or prevent inflammation and neurodegeneration by responding to signals in the microenvironment [25]. Chronic low-grade inflammation may lead to changes in brain structure and synaptic plasticity, leading to neurodegeneration, coupled with decreased neuroprotection and neuronal repairs due to increased glucocorticoid levels. These symptoms may be the initial pathological markers of depression and a prelude to dementia. Therefore, maintaining the normal physiological state of astrocytes is of great significance for the prevention and treatment of depression [26,27]. The dysfunction of the purinergic system in astrocytes is a typical example of this phenomenon. ATP released from astrocytes can regulate depression-like behavior in animal models and may also regulate clinical depression in patients. Astrocytes have purinergic receptors, such as adenosine A2A receptors and P2 × 7 and P2Y11 receptors. These receptors further regulate depression mechanisms by mediating neuroinflammation, neuroglial transmission, and synaptic plasticity in depression-related regions (e.g., the medial prefrontal cortex, hippocampus, and amygdala) [28]. This mechanism further shows that the relationship between depression and astrocytes is inseparable and that astrocyte damage can lead depressed patients into a vicious cycle of increased symptoms and astrocyte damage.
Astrocytes express a variety of neurotransmitter receptors, including the serotonin 5-HT2B receptor, and interact with neurons in the synapses. In major depression, the number, morphology, and functions of astrocytes deteriorate, which can lead to neurotransmitter imbalance and abnormal synaptic connections, exacerbating depression [28]. In addition, studies have found that a positive astrocyte glial fibrillary acidic protein immune response is associated with suicide in depression and speculated that the density of astrocyte IR–vimentin and GFAP–IR astrocytes in brain tissue will change when depression occurs, decreasing the number of astrocyte primary processes. The above factor further indicates that depression is closely related to astrocytes. Damage to the astrocytes will cause depression patients to fall into a vicious cycle of worsening symptoms and astrocyte damage [29]. In addition, relevant studies have shown that the KIR6.1-K-ATP channel (Kir6.1/K-ATP), as a metabolic stress receptor, is significantly expressed in astrocytes. Kir6.1 interacts with NLRP3 to prevent the assembly and activation of the NLRP3 inflammasome, thus inhibiting the programmed death of astrocytes. This activity may provide an important direction for the treatment of depression by regulating astrocytes [30]. Thus, astrocytes may be involved in the production of depression through a variety of mechanisms, including mediating neuroinflammation and metabolic dysfunction and leading to potassium-channel-driven neuronal explosion [31]. The involvement of astrocytes in the pathogenesis of depression is currently understood primarily in neuroinflammatory and metabolic responses and could be elucidated, in the future, at other mediating levels.
3.2.2. Oligodendrocytes and Depression
Oligodendrocytes are myelin cells of the central nervous system that are differentiated from oligodendrocyte precursor cells (OPCs) under the regulation of various factors and can generate an insulating myelin sheath to promote the rapid conduction of axon action potential. OPCs can express a variety of neurotransmitter receptors and ion channels to maintain cell ion and water homeostasis and metabolism. In this way, the integrity of neurons and axons can be maintained, whereas the destruction of the integrity of neurons and axons can accelerate the progression of depression [32,33]. Studies have shown that oligodendrocyte lineage cells, including mature oligodendrocyte (OLs) and oligodendrocyte progenitor cells, have many important CNS-related functions, such as forming myelin sheaths that wrap axons of the central nervous system, mediating some forms of neuroplasticity, expressing neurotransmitter receptors, and enabling communication with neighboring neurons and axons. Such cells also provide nutritional and metabolic support for axons. Consequently, OLs in patients with depression will continue to change, further demonstrating the close relationship between oligodendrocytes and depression [34]. In addition, studies have shown that oligodendrocytes can be directly coupled to astrocytes in the neocortex [35] and that the metabolism of astrocytes, neurons, and oligodendrocytes will interact with each other. Therefore, we speculate that astrocytes and oligodendrocytes will affect each other’s metabolism through mutual influence and further regulate the onset and aggravation of depression [36]. Based on the above studies, astrocytes and oligodendrocytes can influence together through a synergistic relationship in the pathogenesis of depression, providing new ideas for the interpretation of this pathogenesis in the future.
3.2.3. Microglia and Depression
Microglial cells are tissue-specific macrophages in the central nervous system that play an important role in neuroinflammation. During the generation of neuroinflammation, some microglial cells are activated and transformed into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. Increasingly more studies have found that an increase in the microglia fine M1 type can promote the onset of depression. This phenomenon is also consistent with the condition that depression develops through an inflammatory pathway. In the central nervous system, neurons regulate microglial cells according to their own state and subsequently regulate the activity of neurons, which is reflected in the observation that some soluble factors are mainly expressed in neurons, and their receptors are mainly expressed in microglia. For example, CX3CL1 is highly expressed in neurons. Its receptor CXCR1 is highly expressed in the microglia. Soluble factors released by the microglia can also affect neuronal activity and the transport of neurotransmitter receptors. For example, TNF-α released by activated microglia can regulate synaptic plasticity through the release of glutamic acid. In addition, the activation of PI3K/Akt, ERK1/2, and mitogen-activated protein kinase (MAPK) is associated with neuroinflammation and the activation of M1 microglia. Notably, the activation of the PI3K/Akt pathway is critical for neurite repair and anti-apoptosis in central nervous system injury. These mechanisms all confirm that microglia influence the course of depression by regulating inflammation and neuronal activity. Moreover, the activation of adenosine 5’-monophosphate-activated protein kinase (AMPK) is also related to the activation of microglial cells, which can induce antidepressant effects by enhancing hippocampal neurogenesis and PKC-signaling pathways in neurons [37]. In addition, as a very important resident immune cell in the brain, microglial cells have an immune function in the brain and can further affect depression by regulating inflammation, synaptic plasticity, and the formation of neural networks. MDD is a mental disease that affects different cell dysfunctions in the brain and is associated with inflammation. Therefore, patients with depression will fall into a vicious cycle where pathological changes in microglial cells and the aggravation of MDD promote each other [38].
In addition, microglia can usually solve emerging immune and psychological problems by regulating the activity between the nerves and the immune system. For example, microglia can respond to neuroinflammation caused by stress and regulate neurons and astrocytes by releasing pro-inflammatory cytokines and their metabolites, thus regulating depression. This phenomenon is related to the expression degrees of cytokines and a variety of external environmental conditions. Therefore, microglia in patients with depression are generally abnormal, which deregulates the depressive mood of patients and aggravates their condition [16]. All the abovementioned microglial cells can form central nervous system inflammation via phagocytosis, clearing apoptotic cells, releasing inflammatory cytokines, etc., so their dysfunction is associated with a variety of neurological diseases, including depression. These diseases are also called “microglia disease” [39].
Currently, studies suggest that all molecular pathways leading to MDD may be linked to neuroinflammation and hippocampal degeneration through microglia-related neuroinflammation. Microglia can destroy neuroplasticity, affect neuroprotection, and overexpress cellular inflammatory factors, leading to the deterioration of neuroinflammation and depression. This result also suggests that microglia can have neuroprotective and neurotoxic effects that depend on factors such as the expression of cytokines and aging, the presence of pathogens and stress proteins, and external environmental conditions [16].
To summarize, astrocytes, oligodendrocytes, and microglia all play a defensive role in the occurrence of depression under normal physiological conditions. When these components experience pathological changes, they promote neuroinflammation by releasing inflammatory factors or induce depression by disrupting immune responses, the synaptic transmission of neurons, or neuronal integrity and other mechanisms. This outcome suggests that these three types of glial cells are closely related to depression [40].
Neurons and glial cells, as important components of the CNS, were shown to play an important regulatory role in the development of depression. For the regulation of neurons and depression, most current studies focus on dopamine neurons and hippocampal neurons [21,22]. Glial cells also have an irreplaceable role in the development of depression due to their different physiological functions. A clear analysis of the mechanism of CNS and depression would help summarize the mechanisms underlying the viral production of depression. Moreover, according to the above analysis, we learned that glial cells could affect depression by regulating various avenues of interaction, such as hormone release and metabolism, and by regulating neurons [29,37]. Therefore, we chose glial cells as the research object to explore part of the mechanism through which a virus can affect depression.
Table 1 was developed based on the discovery that glial cells have the potential to play a role in the regulatory processes associated with depression. We hope that this table will make it easier to understand the role that the various mechanisms play in this process.
Table 1
Mechanisms by glial cells affect depression.
| Cell Type | Mechanism | Impact | |
|---|---|---|---|
| Astrocytes | Release of ATP | Mediates neuroinflammation, neural (glial) transmission, and synaptic plasticity to further regulate depression mechanisms | |
| Deregulation-regulated purinergic signaling | Develops and aggravates depression | ||
| Quantity reduction and degradation | Neurotransmission imbalance and abnormal synaptic connections | ||
| Express multiple neurotransmitter receptors and interact with neurons at the synapses | Imbalanced neurotransmission and abnormal synaptic connections, aggravating depression | ||
| The density of IR–vimentin and GFAP–IR astrocytes in brain tissue is altered | Falling into a vicious cycle of increased disease and astrocyte damage | ||
| Regulation of Kir6.1-K-ATP channels | Falling into a vicious cycle of increased disease and astrocyte damage. Contribute to depression | ||
| Mediate neuroinflammation and metabolic dysfunction | Contribute to depression | ||
| Oligodendrocytes | Form a myelin sheath that encapsulates the CNS axons | Contribute to depression | |
| Mediate some forms of neuroplasticity and provide nutritional and metabolic support to the axons | Contribute to depression | ||
| Interact with astrocytes and neurons | Contribute to depression | ||
| Microglia | Some microglia will activate to become pro-inflammatory (M1) phenotypes | Reduce neuroinflammation and promote the progression of depression | |
| Microglia activate to release soluble factors | Affect neuronal activity and trafficking of neurotransmitter receptors, regulating depression | ||
| Regulation of inflammation and synaptic and neural plasticity | Impact the course of depression |
4.5. Human Herpes Virus 6
4.5.1. Overview of Human Herpes Virus 6
Based on its molecular signature, HHV-6 was found in 1986 to be the oldest human herpes virus [120]. HHV-6 is the causative agent of one of the most common childhood diseases, rosacea, and adult latent infection rates exceed 90% [121]. HHV-6 is a neuroaffinity virus, and some research suggests a link to Alzheimer’s disease [122]. HHVs are neurotropic viruses that induce severe chronic neurological diseases, including PNS and CNS. HHV-6 reactivation is associated with many systemic clinical manifestations, including lung, kidney, heart, brain, and gastrointestinal tract disorders. HHV-6 can infect a variety of central nervous system cells in vitro and is associated with several neurological diseases, including encephalitis, seizures, chronic fatigue syndrome, medial temporal lobe epilepsy, Alzheimer’s disease, and multiple sclerosis [123].
4.5.2. Analysis of the Mechanism of Human Herpes Virus 6 Affecting Depression
It was proposed that infection with the human herpes virus 6 may be associated with the development of depression [124]. According to the findings of one study, the human herpes virus 6 (HHV-6) may be responsible for depression because it damages astrocytes [125]. Data from a clinical study indicate the more frequent detection of HHV-6A late protein in the cerebellum of patients with MDD. At the same time, HHV-6A and HHV-6B DNA and protein contents were found to be higher in MDD patients than in the controls. These results indicate that HHV-6A and HHV-6B are more common in major depression [126]. HHV-6 can lie dormant in the central nervous system and other tissues. When this virus is activated, it can cause cognitive and behavioral impairments. In addition, a study based on the results of a comprehensive analysis of HHV-6A-infected HA1800 cells identified several genes that are associated with neurological disorders. In particular, seven genes associated with CNS disorders, CTSS, PTX3, CHI3L1, Mx1, CXCL16, BIRC3, and BST2, were found to be altered, which led to the development of related neurological disorders [125]. Relevant studies have shown that PTX3 could be detected 3.5 times more strongly in patients with depression compared to the rates of those in the control group, indicating that PTX3 is positively correlated with the onset of depression and can be used as a marker of depression [127]. Human herpesvirus infection affects the brain and interferes with the function of microglia, causing chronic viral infection with mild neuritis. The long-term persistence of HHV may help maintain the corresponding immune response and cause persistent chronic low-grade neuroinflammation, thereby inducing and accelerating the brain aging process [128]. Clinical data indicated that the degree of brain aging was more pronounced in patients with depression than in the controls. This phenomenon could be observed from the onset of the disease (<3/6 months) throughout the first 2 years of the disease. There was little difference in the degree of brain aging after 2 years [129]. These results suggest that brain aging may be an indicator of the development of depression. In addition, both HHV and novel coronaviruses are associated with antibodies against myelin oligodendrocyte glycoproteins. These phenomena suggest that human herpesviruses have factors in common with other viruses in the sense that both may contribute to depression by affecting astrocytes, oligodendrocytes, and microglia [130].
Relevant studies indicated that the expression levels of Varicella–Zoster virus responder cell frequency (VZV–RCF) in patients with depression were lower than those in the control group and were negatively correlated with the severity of depressive symptoms. The VZV–RCF levels in patients with depression who received antidepressant treatment were higher than those in patients with depression who did not receive treatment, indicating that the VZV–RCF levels in HHV patients can be used as a relevant indicator for the detection of depression [131]. Recent studies have used SITH-1 as a specific protein marker for HHV-6 infection. The experimental results indicate that the expression of SITH-1 increased in HHV-6-infected animal models. At the same time, part of the HPA axis was enhanced, and the experimental animals developed depression-related symptoms [132]. Based on this study, it can be assumed that the cause of depression caused by HHV-6 is regulated through HPA. Studies have shown that ATP binds to the membrane purinergic P2 receptor (P2R) of neurons and astrocytes, leading to an increase in intracellular Ca2+ to activate the concentration of GSK-3β, which can effectively promote HSV-1 replication [133]. At the same time, relevant clinical studies have shown that repeated infection with HSV-1 can greatly increase the probability of depression [134]. This result indicates that HSV-1 can promote the onset of depression.
In summary, HHV-6 can affect the secretion of a variety of cytokines by affecting glial cells and leading to the expression of related genes. This virus can affect the normal physiological functions of the central nervous system through neuroinflammation, resulting in the pathogenesis of depression.
