ArticleLiterature Review

Relationship of neurotransmitters to the symptoms of major depressive disorder

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Abstract

A relationship appears to exist between the 3 main monoamine neurotransmitters in the brain (i.e., dopamine, norepinephrine, and serotonin) and specific symptoms of major depressive disorder. Specific symptoms are associated with the increase or decrease of specific neurotransmitters, which suggests that specific symptoms of depression could be assigned to specific neurochemical mechanisms, and subsequently specific antidepressant drugs could target symptom-specific neurotransmitters. Research on electroconvulsive therapy has supported a correlation between neurotransmitters and depression symptoms. A 2-dimensional model of neurotransmitter functions is discussed that describes depression as a mixture of 2 separate components--negative affect and the loss of positive affect--that can be considered in relation to the 3 amine neurotransmitters. Owing to the different methods of action of available antidepressant agents and the depression symptoms thought to be associated with dopamine, serotonin, and norepinephrine, current treatments can be targeted toward patients' specific symptoms.

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... According to different monoamines hypothesis of depression, deficiencies or imbalance of monoamine neurotransmitters, i.e., serotonin, dopamine, nor-epinephrine induces the development of depressive-like symptoms [148][149][150]. The causal link between neurotransmitter and depression is the disturbances of monoamine metabolism and their receptor abnormalities. ...
... These neurotransmitters are prone to metabolism by different enzymes at each step from synthesis to binding with respective receptors. The degrading enzymes such as monoamine oxidase does metabolism of neurotransmitter after their release from vesicles [149][150][151]. It has been reported that many flavonoids possess anti-inflammatory, antidepressant and antioxidant activities in animal studies via balancing the neurotransmitters level in brain by acting at transcription factors, enzymes and kinases ( Figure 47) [145][146][147][148][149][150][151][152]. ...
... The degrading enzymes such as monoamine oxidase does metabolism of neurotransmitter after their release from vesicles [149][150][151]. It has been reported that many flavonoids possess anti-inflammatory, antidepressant and antioxidant activities in animal studies via balancing the neurotransmitters level in brain by acting at transcription factors, enzymes and kinases ( Figure 47) [145][146][147][148][149][150][151][152]. Flavonoids such as rutin, amentoflavone, luteolin, nobiletin, vitexin, fisetin, kaempferitrin, quercetin, hesperidin and naringenin were found to possess anti-depressant action via modification of neurotransmitters or via acting on their pre-or post-receptors [8,45,64,66,77,83,98,101,117,120]. ...
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Depression is one of the most frequently observed psychological disorders, affecting thoughts, feelings, behavior and a sense of well-being in person. As per the WHO, it is projected to be the primitive cause of various other diseases by 2030. Clinically, depression is treated by various types of synthetic medicines that have several limitations such as side-effects, slow-onset action, poor remission and response rates due to complicated pathophysiology involved with depression. Further, clinically, patients cannot be given the treatment unless it affects adversely the job or family. In addition, synthetic drugs are usually single targeted drugs. Unlike synthetic medicaments, there are many plants that have flavonoids and producing action on multiple molecular targets and exhibit anti-depressant action by affecting multiple neuronal transmissions or pathways such as noradrenergic, serotonergic, GABAnergic and dopaminergic; inhibition of monoamine oxidase and tropomyosin receptor kinase B; simultaneous increase in nerve growth and brain-derived neurotrophic factors. Such herbal drugs with flavonoids are likely to be useful in patients with subclinical depression. This review is an attempt to analyze pre-clinical studies, structural activity relationship and characteristics of reported isolated flavonoids, which may be considered for clinical trials for the development of therapeutically useful antidepressant.
... One promising model for affective disorders, anxiety and attention deficit and hyperactivity disorder (ADHD) might be iPSCs-derived monoaminergic neurons when considering symptoms like sadness, loss of pleasure, increased anxiety, and attention as neurotransmitter-specific (Nutt 2008) and the mechanism of action of most current antidepressants, anxiety and ADHD medication. Using iPSCs generated from fibroblasts (as well as human embryonic stem cells), Lu et al. were among the first to generate central serotonin neurons that express key serotonin markers and that respond to the selective serotonin reuptake inhibitor (SSRI) escitalopram, with a dose-dependent increase of serotonin concentration, implicating their technique as a potential serotonergic drug screening assay (Lu et al., 2016). ...
... Midbrain dopaminergic neurons generated from iPSCs by Kriks et al. were shown to be engraftable in a model of Parkinson's disease (Kriks et al., 2011). Regarding psychiatric disorders iPSC-derived dopaminergic neurons have so far been predominantly used in psychiatric research for the study of schizophrenia and bipolar disorders (Sauerzopf et al., 2017) but, through the link of the dopaminergic system to reward, pleasure and motivation (Nutt, 2008), these neuronal subtypes could also be applied as models for MDD and ADHD. Regarding hippocampal neurons, Yu et al. were 9 able to model hippocampal neurogenesis using iPSC-derived cells (Yu et al., 2014) and to show the formation of a functional neuronal network when culturing the cells on hippocampal astrocytes. ...
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The improvement of experimental models for disorders requires a constant approximation towards the dysregulated tissue. In psychiatry, where an impairment of neuronal structure and function is assumed to play a major role in disease mechanisms and symptom development, this approximation is an ongoing process implicating various fields. These include genetic, animal, and post-mortem studies. To test hypotheses generated through these studies in vitro models using non-neuronal cells such as fibroblasts and lymphocytes have been developed. For brain network disorders, cells with neuronal signatures would, however, represent a more adequate tissue. Considering the limited accessibility of brain tissue, research has thus turned towards neurons generated from induced pluripotent stem cells, as well as directly induced neurons, cerebral organoids, and olfactory neuroepithelium. Regarding the increasing importance and amount of research using these neuronal cells, this review aims to provide an overview of all these models, to make sense of the current literature. The development of each model system and its use as models for the various psychiatric disorder categories will be laid out. Also, advantages and limitations of each model will be discussed including a reflection on implications and future perspectives.
... Neurotrophic factors and their corresponding receptors, as well as the abundance of neurotransmitter-related enzymes, play an important role in supporting the maintenance of neuronal functions and which are downregulated in the brain under depression [19,20]. e depression-related proteins were determined in the brains of herbal-treated rats by RT-PCR with specific primers (Table S1). ...
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Medicinal food homology is referring to a group of food itself being considered as herbal medicine without a boundary of usage. Under the guidance of this food/medicine principle, the current study aims to develop anti-depressant from this food/medicine catalog. The herbal mixture of Sesami Semen Nigrum and Longan Arillus was evaluated in cultured PC12 rat pheochromocytoma cells, rat primary cortical neurons, and in chronic mild stress (CMS)-induced depressive rat model. The combination of two ethanolic extracts of Sesami Semen Nigrum and Longan Arillus in 1 : 1 ratio mimicked the function of nerve growth factor (NGF) and synergistically induced neurite outgrowth of PC12 cells. Besides, the expression and phosphorylation of tropomyosin receptor kinase A (TrkA) of the cultured cells were also elevated. This neurotrophic activity of herbal mixture was further supported by the increased expressions of biomarkers for neurogenesis and synaptogenesis in cortical neurons. Moreover, the depressed rats were soothed by the intake of herbal mixture, showing improved performance in behavior tests, as well as reversed levels of neurotransmitters and neurotrophic factors. Our results provide a new way to make full use of the current food/medicine resources, as to accelerate the development of therapeutics for depression.
... First, LDAEP may reflect other symptoms affected by the serotonin system, such as decreased attention and impulsiveness, in addition to depression [80]. Second, major depression may be due to complex actions of neurotransmitter systems such as norepinephrine, as well as to other pre-and post-synaptic receptors and gene regulation [81,82]. ...
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Objective: The loudness dependence of the auditory evoked potential (LDAEP) is a reliable indicator that is inversely related to central serotonergic activity, and recent studies have suggested an association between LDAEP and suicidal ideation. This study investigated differences in LDAEP between patients with major depressive disorder and high suicidality and those with major depressive disorder and low suicidality compared to healthy controls. Methods: This study included 67 participants: 23 patients with major depressive disorder with high suicidality (9 males, mean age 29.3 ± 15.7 years, total score of SSI-BECK ≥ 15), 22 patients with major depressive disorder with low suicidality (9 males, mean age 42.2 ± 14.4 years, total score of SSI-BECK ≤ 14), and 22 healthy controls (11 males, mean age 31.6 ± 8.7 years). Participants completed the following assessments: Patient Health Questionnaire-9, Beck Depression Inventory-II, Beck Scale for Suicidal ideation, State Anxiety Scale of the State-Trait Anxiety Inventory, Beck Anxiety Inventory, and LDAEP (measured at electrode Cz). Results: There were no sex-related differences among groups (p = 0.821). The high-suicidality group exhibited significantly higher LDAEP compared to the low-suicidality group (0.82 ± 0.79 vs. 0.26 ± 0.36, p = 0.014). No significant differences were found between the control and high-suicidality (p = 0.281) or the control and low-suicidality groups (p = 0.236). Conclusion: LDAEP was applied to demonstrate the association between serotonergic activity and suicidal ideation and suicide risk in major depression and may be a candidate of biological marker for preventing suicide in this study.
... Since monoaminergic neurotransmitters (Norepinephrine, dopamine, and serotonin) in the central nervous system are key transmitters involved in the regulation of various essential brain functions, such as arousal and mood (Nutt, 2008), we mainly analyzed the chemo-connectome of the central monoaminergic system through combined ISH data with the connection data (Figures 5A,B). As shown in Figure 5B, three monoaminergic nuclei localized in the hindbrain (locus ceruleus, LC; Barrington's nucleus, B; nucleus raphe pallidus, RPa) not only connected with each other but also displayed extensive interconnections with other monoaminergic nuclei. ...
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The various brain functions rely on the intricate connection networks and certain molecular characteristics of neurons in the brain. However, the databases for the mouse brain connectome and chemo-connectome are still inadequate, hindering the brain circuital and functional analysis. Here, we created mice brain connectome and chemo-connectome databases based on mouse brain projection data of 295 non-overlapping brain areas and in situ hybridization (ISH) data of 50 representative neurotransmission-related genes from the Allen Brain Institute. Based on this connectome and chemo-connectome databases, functional connection patterns and detailed chemo-connectome for monoaminergic nuclei were analyzed and visualized. These databases will aid in the comprehensive research of the mouse connectome and chemo-connectome in the whole brain and serve as a convenient resource for systematic analysis of the brain connection and function.
... As such, they are very important for normal brain function [1]. Their dysfunction causes several mental disorders, such as neurodegeneration, depression, schizophrenia, stress, and addiction [2,3]. Analysis of these neurotransmitters helps an entire analytical methodology, from sample collection to final determination, so as to provide specific information related to the greenness of each analytical method. ...
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The assessment of greenness of analytical protocols is of great importance now to preserve the environment. Some studies have analyzed either only the neurotransmitters, dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA), together or with other neurotransmitters and biomarkers. However, these methods have not been investigated for their greenness and were not compared with each other to find the optimum one. Therefore, this study aims to compare seven published chromatographic methods that analyzed the four neurotransmitters and their mixtures using the National Environmental Method Index, Analytical Eco-Scale Assessment (ESA), and Green Analytical Procedure Index (GAPI). As these methods cover both qualitative and quantitative aspects, they offer better transparency. Overall, GAPI showed maximum greenness throughout the analysis. Method 6 was proven to be the method of choice for analyzing the mixture, owing to its greenness, according to NEMI, ESA, and GAPI. Additionally, method 6 has a wide scope of application (13 components can be analyzed), high sensitivity (low LOQ values), and fast analysis (low retention times, especially for glutamate and GABA).
... In addition to the described mechanisms mentioned above (BDNF release), there are several other important mechanisms worth mentioning that can influence depression and depressive symptoms (See Cooney et al., 2014 for a meta-analysis). There is a large body of literature that suggests a primary mechanism in depression is the deficit/dysfunction of neurotransmittersspecifically norepinephrine, dopamine, and serotonin (Nutt, 2008). These three neurotransmitters work in harmony to improve mood and mental health: Norepinephrine, the alertness chemical which wakes up the brain, is associated with self-esteem; Dopamine, the motivation and attention chemical, is associated with the feeling of contentment; and serotonin, the happiness chemical, counteracts cortisol (the stress hormone), and helps to control impulses (Ratey, 2008). ...
Article
Physical activity can have a profound impact on the cognitive, emotional, and social aspects of our clients’ lives, and can even boost and sustain therapy outcomes. And yet, family therapists may not be trained or educated in the importance of physical activity nor how to assess, educate, and collaborate with health professionals to incorporate physical activity in treatment. As the evidence grows on the connection between physical activity and biopsychosocial functioning and more family therapists enter medical and healthcare settings, a framework for physical activity competencies is needed. As such, the purpose of this conceptual and empirical review paper is to (a) review the important brain‐boosting benefits of physical activity for mental, cognitive, and social health, (b) provide a framework for the domains for family therapists for incorporating exercise in assessment and treatment, and finally, (c) outline recommendations for practice, education and supervision, and research for family therapists.
... Studies have shown that bacteria inhabiting our gut have the ability to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA) (91)(92)(93)(94)(95)232). Since it is well-known that disturbance of these neurotransmitters is linked to a variety of mental disorders including depression (233)(234)(235)(236)(237), a target of many antidepressant pharmacological treatments, a possible approach to rebalance these neurotransmitters, although not completely discovered, is by modulating the abundance of these bacteria. However, some gut-derived neuro transmitters function differently from brain-derived neurotransmitters (238). ...
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The significant stressors brought about and exacerbated by COVID-19 are associated with startling surges in mental health illnesses, specifically those related to depressive disorders. Given the huge impact of depression on society, and an incomplete understanding of impactful therapeutics, we have examined the current literature surrounding the microbiome and gut-brain axis to advance a potential complementary approach to address depression and depressive disorders that have increased during the COVID-19 pandemic. While we understand that the impact of the human gut microbiome on emotional health is a newly emerging field and more research needs to be conducted, the current evidence is extremely promising and suggests at least part of the answer to understanding depression in more depth may lie within the microbiome. As a result of these findings, we propose that a microbiome-based holistic approach, which involves carefully annotating the microbiome and potential modification through diet, probiotics, and lifestyle changes, may address depression. This paper's primary purpose is to shed light on the link between the gut microbiome and depression, including the gut-brain axis and propose a holistic approach to microbiome modification, with the ultimate goal of assisting individuals to manage their battle with depression through diet, probiotics, and lifestyle changes, in addition to offering a semblance of hope during these challenging times.
... Thus, a decrease in noradrenaline may be associated with loss of alertness, attention, energy, and interest in life. A reduction in serotonin induces anxiety, obsessions, and compulsions; contrarily, a decrease in dopamine from the prefrontal cortex to loss of motivation and pleasure [82]. Indeed, increased dopamine transporter levels and decreased dopamine levels were observed in patients with the major depressive disorder [83,84]. ...
Article
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Depressive-like behavior is a highly prevalent worldwide neuropsychiatric disorder that owns a complex pathophysiologic mechanism. The available pharmacotherapy is ineffective for most patients and shown several adverse effects. Therefore, it is important to find efficacy and safe antidepressive compounds. Some phytochemicals compounds regulate the same genes and pathways targeted by drugs; therefore, diets rich in fruits and vegetables could be considered novel treatment approaches. Currently, the functional properties of quercetin acquired great interest, due to its beneficial effects on health. Quercetin is a flavonoid ubiquitously present in vegetables and fruits, interestingly for its strong antioxidant properties. The purpose of this review is to summarize the preclinical studies present in the literature, in the last ten years, aimed at illustrating the effects of quercetin pre-treatment in depressive-like behaviors. Quercetin resulted in antidepressant-like actions due to its antioxidant, anti-inflammatory, and neuroprotective effects. This pointed out the usefulness of this flavonoid as a nutraceutical compound against the development of psychological stress-induced behavioral perturbation. Therefore, quercetin or a diet containing it may become a prospective supplementation or an efficient adjuvant therapy for preventing stress-mediated depressive-like behavior.
... The aetiology of depression is unclear, but the mechanisms of action of antidepressants currently used in therapy are strongly related to the monoaminergic theory. The deficiency of certain monoaminergic neurotransmitters (serotonin, noradrenaline and dopamine) could be responsible for depressive features [56], and the effectiveness of antidepressants is based on increased neurotransmitter levels. Furthermore, it has been evidenced that major depression is accompanied by an activation of the inflammatory response [57]. ...
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Nowadays, gluten and FODMAP food components (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) are increasingly studied due to their possible relation with extraintestinal-associated conditions. In recent years, gluten-free diets (GFD) and low-FODMAP diets (LFD) are becoming more popular not only in order to avoid the food components that cause intolerances or allergies in some people, but also due to the direct influence of marketing movements or diet trends on feeding habits. Likewise, neurological and psychiatric diseases are currently of increasing importance in developed countries. For this reason, a bibliographic systematic review has been carried out to analyse whether there is a pathophysiological relationship between the dietary intake of gluten or FODMAPs with mental disorders. This review collects 13 clinical and randomized controlled trials, based on the PRISMA statement, which have been published in the last ten years. Based on these results, limiting or ruling out gluten or FODMAPs in the diet might be beneficial for symptoms such as depression, anxiety (7 out of 7 articles found any positive effect), or cognition deficiency (improvements in several cognition test measurements in one trial), and to a lesser extent for schizophrenia and the autism spectrum. Nevertheless, further studies are needed to obtain completely reliable conclusions.
... 18 No treatment has been efficient in treating anhedonia; in this regard SSRIs have been shown to be ineffective for positive affect deficits. 19 In this mini-review, therefore, we focus on dysregulation of brain DA systems in the pathophysiology of MDD and propose new cellular targets for potential medication development focused on DA-modulated micro-circuits and novel cellular targets. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through DAergic substrates in the developing brain. ...
Article
High-risk human papillomaviruses (HPV) cause 5% of all human cancers and are primary etiologic agents of cervical, anal, and oropharyngeal cancer. HPV infection is necessary, but not sufficient per se to produce cancer: additional changes must occur that transform HPV-infected cells to malignancy. The HPV oncoproteins E6 and E7 immortalize human keratinocytes, cervical cells, and fibroblasts in culture. Each oncoprotein interacts with a variety of cellular binding partners; most important for transformation are E6 and E7’s interactions with p53 and RB (respectively) which lead to degradation of p53 and RB through the ubiquitin pathway. Inactivation of p53 and RB leads to inactivation of pivotal cell cycle checkpoints, thereby stimulating cell proliferation and allowing cell division to occur independently of the presence of DNA damage, replicative stress, and other such insults, leading to genome instability. Continuous expression of E6/E7 drives the proliferation and progression of most HPV-mediated cancers of the cervix and a substantial fraction of those of the oropharynx. However, at both cancer sites, “HPV-inactive” tumors that contain HPV DNA, but do not express E6/E7 arise. We propose that these HPV-inactive cancers begin as HPV-driven lesions, but lose E6/E7 expression at some point during progression. We have recently shown that p53 deletion in HPV-immortalized, premalignant cells allows for the emergence of cell populations that no longer express E6/E7. These findings corroborate the notion of a pivotal role of p53 in the context of HPV-mediated transformation, both at the initiation and progression stages of cancer development.
... Correspondingly, several lines of evidence point to hypodopaminergic states in MDD. Blunted mesolimbic dopamine signaling has been more directly implicated in anhedonia, a cardinal symptom of MDD that is ineffectively treated by SSRIs [114]. Animal models of depression that reliably induce anhedonia are associated with mesolimbic dopamine abnormalities [115]. ...
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The incidence of depression and anxiety is amplified by obesity. Mounting evidence reveals that the psychiatric consequences of obesity stem from poor diet, inactivity, and visceral adipose accumulation. Resulting metabolic and vascular dysfunction, including inflammation, insulin and leptin resistance, and hypertension, have emerged as key risks to depression and anxiety development. Recent research advancements are exposing the important contribution of these different corollaries of obesity and their impact on neuroimmune status and the neural circuits controlling mood and emotional states. Along these lines, this review connects the clinical manifestations of depression and anxiety in obesity to our current understanding of the origins and biology of immunometabolic threats to central nervous system function and behavior.
... Thus, the thresholds for neuronal activation in different brain areas should be studied further. (2) There is evidence that activation of the VTA can inhibit sustained nociceptive transmission by a mechanism related to VTA projections to GABAergic nerve fibers in the PAG region [40,41]. Experiments have shown that there is a cardiovascular inhibitory pathway from the VTA to the PAG area [42]. ...
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Evidence in animals suggests that deep brain stimulation or optogenetics can be used for recovery from disorders of consciousness (DOC). However, these treatments require invasive procedures. This report presents a noninvasive strategy to stimulate central nervous system neurons selectively for recovery from DOC in mice. Through the delivery of ultrasound energy to the ventral tegmental area, mice were aroused from an unconscious, anaesthetized state in this study, and this process was controlled by adjusting the ultrasound parameters. The mice in the sham group under isoflurane-induced, continuous, steady-state general anaesthesia did not regain their righting reflex. On insonation, the emergence time from inhaled isoflurane anaesthesia decreased (sham: 13.63 ± 0.53 min , ultrasound: 1.5 ± 0.19 min , p < 0.001 ). Further, the induction time (sham: 12.0 ± 0.6 min , ultrasound: 17.88 ± 0.64 min , p < 0.001 ) and the concentration for 50% of the maximal effect (EC50) of isoflurane (sham: 0.6%, ultrasound: 0.7%) increased. In addition, ultrasound stimulation reduced the recovery time in mice with traumatic brain injury (sham: 30.38 ± 1.9 min , ultrasound: 7.38 ± 1.02 min , p < 0.01 ). This noninvasive strategy could be used on demand to promote emergence from DOC and may be a potential treatment for such disorders.
... Depression is related to the change in neurotransmitters [28]. DA is a catecholamine neurotransmitter and plays a key role in cognitive function [29]. ...
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This study aimed to investigate the therapeutic effects of candesartan combined with music therapy on diabetic retinopathy with depression and to assess the molecular mechanisms. Associated animal model of diabetes mellitus and depression was established in rats. Pathological changes in the hippocampus were detected by haematoxylin eosin (H&E) staining. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was used to detect retinal cell apoptosis. Angiotensin II (Ang II) in peripheral blood and neurotransmitters, including serotonin (5-HT), dopamine (DA), and norepinephrine (NE) in the hippocampus, was measured by enzyme linked immunosorbent assay (ELISA). Fluorescence quantitative PCR and western blotting were used to detect the expression of brain-derived neurotrophic factor (BDNF) and c-fos in the hippocampus. Our data showed that chromatin aggregation and cytoplasmic vacuolation were observable in the hippocampal cells of the rats in the model group, while candesartan and music therapy could reduce morphological changes in the hippocampus of diabetic rats with depression. Compared with the control group, the apoptosis of retinal cells was significantly higher, the contents of 5-HT, DA, and NE in the hippocampus were significantly lower, Ang II level in peripheral blood was significantly higher, and the expression of BDNF and c-fos in the hippocampus decreased significantly in the model group. By contrast, candesartan or candesartan + music therapy ameliorated the changes in retina cell apoptosis, reduction of neurotransmitters, increase in AII, and the expression of c-fos and BDNF. Especially, music therapy further improved the effects of candesartan on retina cell apoptosis and neurotransmitter release in diabetic retinopathy rats with depression. In conclusion, candesartan and music therapy have an additive effect in DM with both visual impairment and depression, which might serve a potential alternative treatment for this complex disease.
... Thus, on a neurochemical level, BED may be related to the dysfunction of the serotonergic, dopaminergic, noradrenergic, and glutamatergic pathways (67). This tri-monoaminergic neurotransmitter system, with the recent focusing on glutamate, is the pathophysiology basis of depression as well, and still leads existing treatment options (68,69). Therefore, a medication to target binge eating, as well as BED in comorbidity with depression, needs to be multi-modal in terms of its pharmacology, and VTX pharmacological profile theoretically addresses all these needs (70). ...
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Background: Binge eating disorder (BED) is clinically relevant by virtue of the global impairment, poor quality of life, and increased overall medical morbidity. The high comorbidity with psychiatric disorders, particularly depression, has received attention as a possible mediator of the poor outcome. Further, BED and depression share cognitive dysfunctions. This naturalistic and uncontrolled pilot study aimed at evaluating the efficacy of vortioxetine (VTX) on depressive symptoms in patients with BED, secondly the efficacy in improving a broad array of executive functions, and third to explore the effect on eating behavior and body weight. Methods: This pilot study involved 30 patients with BED and comorbid MDD, treated with VTX for 24 weeks. Assessments were run at baseline ( t 0 ), 4 ( t 1 ), 8 ( t 2 ), 12 ( t 3 ), and 24 ( t 4 ) weeks. Changes in depressive symptoms (HDRS and BDI), executive functions, eating behaviors (binge frequency and severity, night eating, food addiction), and body weight were estimated after treatment with VTX through GLM. Results: Significant improvements emerged after treatment with VTX in: depression (HDRS p < 0.001; BDI p = 0.002) regardless the dose of VTX and first diagnosis (BED/MDD), working memory (RAVLT acquisition p = 0.01, delay recall p < 0.001, RCFT percentage of recall p = 0.01, and Attentional Matrices p = 0.05), binge days frequency ( p < 0.001), binge eating severity (BES p < 0.001), night eating ( p = 0.001), food addiction (YFAS 2.0 p = 0.039), and body weight ( p = 0.039). The improvement in depressive symptoms was associated with the concurrent improvement in night eating as assessed by the I-NEQ. Conclusions: VTX can be a valid therapeutic choice for patients with BED with comorbid depression in controlling the depressive symptoms, working memory, and eating behavior. Indeed, by acting on affective symptoms, neurocognitive functioning, and eating behaviors, it confirms the results already obtained with VTX in other disorders, expanding them to BED.
... It has been proposed that modulating brain monoaminergic neurotransmitter systems is a realistic solution to the treatment of depression (Delgado & Moreno, 1999;Nutt, 2007). While some selective antidepressants (such as fluoxetine and reboxetine) are still widely used in clinical treatment and experimental assessment, similar to other multifactorial disorders, 'multi-target' drugs may be best suited to better treat depressive conditions (Millan, 2006;Stahl, 2013). ...
Article
Depression is a state of low mood that can seriously affect the quality of life of society. Therefore, finding new antidepressant agents with high efficacy is needed. Dextromethorphan (DXM) is an antitussive drug that has a potential effect on treating mood disorders, especially depression. However, because of limited data that relies on a few experimental animal studies mechanisms of action are yet not clear. The present study investigated the DXM effect in the forced swimming (FST) and tail suspension (TST) tests in mice and also the potential influence of the noradrenergic system in this effect. DXM (30 mg/kg, intraperitoneal (i.p.)) significantly decreased the immobility times in FST (P < 0.001) and TST (P < 0.01) comparable with positive controls, imipramine (IMI) 10 mg/kg and fluoxetine (20 mg/kg). Nevertheless, the number of crossings in the open-field test was not affected. The pretreatment with prazosin (1 mg/kg, i.p.; α1-adrenoceptor antagonist) or yohimbine (1 mg/kg, i.p.; α2-adrenoceptor antagonist) prevented the antidepressant effect of DXM (30 mg/kg, i.p). Moreover, the administration of a sub-effective dose of phenylephrine (5 mg/kg, i.p.; α1-adrenoceptor agonist) or clonidine (0.06 mg/kg, i.p.; α2-adrenoceptor agonist) potentiated the sub-effective dose of DXM (3 mg/kg, i.p.) in the FST and TST. The pretreatment with propranolol (5 mg/kg, i.p.; β-adrenoceptor antagonist) did not reverse the antidepressant-like effect of DXM. Thus, the present study suggests that the antidepressant-like effect of DXM may be partially related to α1/α2 adrenoceptors.
... One of the most common hypotheses, the neurotransmitter hypothesis, suggests that low levels of brain neurotransmitters, including serotonin, norepinephrine, and dopamine, can cause depression. [3][4][5][6] Accordingly, several drugs have been developed to modulate the levels of these neurotransmitters. [6][7][8] However, one in three patients with depression do not respond to conventional treatments. ...
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Purpose: Depression is one of the most common psychological disorders. The nutritional etiology of the depression proposes that vitamin D may play a significant role in the pathogenesis of depression. Further, vitamin D deficiency has been found to aggravate depression in animals. Therefore, vitamin D treatment might be a potential therapeutic aid in depression management. This study aimed to explore the antidepressant effects of vitamin D in a Bacillus Calmette-Guerin (BCG)-induced depression model. Methods: Thirty-six mice were randomly assigned to short-term and long-term experimental groups. In each group, mice were randomly subcategorized into three subgroups: 1. control (received vehicle), 2. BCG (received BCG [107 CFU/mouse]), and 3. BCG + vitamin D (received vitamin D [60.000 IU/kg] before BCG [107 CFU/mouse] inoculation). After completion of the two experimental periods (3 days for the short-term group and 2 weeks for the long-term group), the mice underwent three behavioral tests: locomotor activity, the forced swimming test (FST), and the tail suspension test (TST). Results: Locomotor activity did not significantly differ among the subgroups in either the long-term or short-term groups. In the short-term group, the total immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. However, in the TST, no significant difference was found between the vitamin D-treated group and the BCG group. In the long-term group, the immobility time on the FST was decreased in the vitamin D-treated group compared to the BCG group. Similarly, the total immobility time on the TST was also significantly lower in the vitamin D-treated mice than in the BCG-treated mice. Conclusion: Vitamin D is useful in the management of depressive behavior. The potential role of vitamin D in the etiology of depression should be investigated in future work.
... Neurotransmitters play a major role in the etiology of depression, ranging from affecting neurogenesis levels (Apple et al., 2017) to changes in mood (Jenkins et al., 2016). Serotonin, dopamine, and norepinephrine are implicated neurotransmitters in depression (Nutt, 2008). Any disturbance to optimal brain insulin signaling may parallel hampered neurotransmitter function. ...
Article
Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic-pituitary-adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin, and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut-brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin-sensitizing agents can help to manage the distressing condition. The possibility of Glucagon-like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.
... Neurotransmitters play a major role in the etiology of depression, ranging from affecting neurogenesis levels (Apple et al., 2017) to changes in mood (Jenkins et al., 2016). Serotonin, dopamine, and norepinephrine are implicated neurotransmitters in depression (Nutt, 2008). Any disturbance to optimal brain insulin signaling may parallel hampered neurotransmitter function. ...
Article
Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic-pituitary-adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin, and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut-brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin-sensitizing agents can help to manage the distressing condition. The possibility of Glucagon-like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.
... 18 No treatment has been efficient in treating anhedonia; in this regard SSRIs have been shown to be ineffective for positive affect deficits. 19 In this mini-review, therefore, we focus on dysregulation of brain DA systems in the pathophysiology of MDD and propose new cellular targets for potential medication development focused on DA-modulated micro-circuits and novel cellular targets. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through DAergic substrates in the developing brain. ...
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Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression-no established mechanism can explain all aspects of the disease. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. This mini-review focuses on dysregulation of brain dopamine (DA) systems in the pathophysiology of MDD and describing new cellular targets for potential medication development focused on DA-modulated micro-circuits. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through dopaminergic substrates in the brain.
... Therefore, detection of early markers that can predict the treatment outcome is important for the improvement of the treatment. In the past decades, great efforts have been made to find the potential early biomarkers, including neurotropic factors, neurotransmitters, cytokines, as well as other molecules in the blood (Nutt, 2008;Dowlati et al., 2010;Tavakolizadeh et al., 2018;Xu et al., 2019). However, up to date, none of the individual predictors is robust enough to guide first-line treatment options (Kessler, 2018). ...
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Background: Current mainstream treatment of major depressive disorder (MDD) has a disadvantage in delayed onset of efficacy, making detection of early signatures predicative of the long-term treatment efficacy urgent. Methods: MDD patients were scored with HAMD-24 and serum brain-derived neurotrophic factor (BDNF) levels were measured at different times in two independent trials: a single-arm observation of Yueju pill, a clinically approved traditional multiherbal medicine, and a two-arm random placebo-controlled trial for Yueju vs escitalopram. The ratio of the BDNF level to HAMD-24 score, or neuroplasticity index (NI), and its derived parameters were used for correlation analysis and receiver operating characteristic (ROC) analysis. Results: On both the early (4th) and final (28th) days, Yueju and escitalopram significantly reduced HAMD-24 scores, compared to baselines, but only Yueju increased BDNF at both times. For either Yueju or escitalopram treatment, NI, but not BDNF, at baseline was correlated to NIs at the early or final treatment day. NI at early time was significantly correlated to early NI enhancement from the baseline for both Yueju and escitalopram, and to final NI enhancement from the baseline for Yueju in both trials. ROC analysis supported the predictability of Yueju’s final treatment efficacy from early NI enhancement. Limitations: The small sample size and 28 days of treatment time may lead to the impossibility of ROC analysis of escitalopram. Conclusion: Early NI enhancement is useful for prediction of long-term efficacy of Yueju and presumably some other antidepressants. Clinical Trial Registration: [ www.ClinicalTrials.gov ], identifier [ChiCTR1900021114].
... Many patients with MDD only partially respond to and some have no clinically meaningful response to these antidepressants. In addition, potent 5-HT reuptake inhibition often leads to hypodopaminergic adverse effects such as decreased sexual function, weight gain and emotion blunt (Nutt, 2008). Mesolimbic dopaminergic system is crucially involved in cognition, motivation and reward-related behaviors (Nestler and Carlezon, 2006). ...
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Toludesvenlafaxine hydrochloride dihydrate is a novel chemical entity and a potential triple monoamine reuptake inhibitor. This study characterized the in vitro triple reuptake inhibition activity, antidepressant-like activity in animals, and pharmacokinetic profiles in rats of toludesvenlafaxine. Binding affinity was determined using human serotonin transporter (SERT) protein, norepinephrine transporter (NET) protein and dopamine transporter (DAT) protein, and the reuptake inhibition was determined using Chinese hamster ovary cells expressing human SERT, NET and DAT. The antidepressant-like activity was examined in rat chronic unpredictable mild stress model and olfactory bulbectomized model. In rats, the tissue distribution and pharmacokinetic parameters were determined. Toludesvenlafaxine had high binding affinity on SERT, NET and DAT, and significantly inhibited the reuptake of serotonin (IC 50 = 31.4 ± 0.4 nM), norepinephrine (IC 50 = 586.7 ± 83.6 nM) and dopamine (IC 50 = 733.2 ± 10.3 nM) in vitro . Toludesvenlafaxine demonstrated significant antidepressant-like effects in rat models at 8–16 mg/kg. In addition, toludesvenlafaxine significantly reduced serum corticosterone and significantly increased testosterone levels in rats. Toludesvenlafaxine was quickly absorbed and converted to O -desvenlafaxine (ODV) after oral administration, both of which were selectively distributed into the hypothalamus with high concentration. Plasma ODV exposure was proportionally related to the doses after oral dosing. These results suggest that toludesvenlafaxine is a triple reuptake inhibitor with relatively fast-acting antidepressant-like activity and good therapeutic profile including improvement of anhedonia and sexual function.
... Lastly, there is recognition that the unknown mechanism of action of current lithiumbased therapies for neurological disorders [158][159][160][161] may involve i-motif regulation as lithium cations were shown to destabilize the i-motif of telomeric C-rich oligomers [162]. Given that i-motif folding and unfolding is a relatively long process, in order to obtain robust folding kinetics by adequately capturing multiple transition states, Kim et al. developed a modified single-molecule FRET technique with extended fluorescent reads. ...
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Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA.
... Depression is one of the most common psychiatric diseases with a prevalence of 15-25% and can cause a significant decline in patient performance in all occupational areas and social and family relationships [1]. Decreased function of neurotransmitters such as serotonin (5-HT), norepinephrine or noradrenaline (NA), and dopamine (DA) are some of the causes of depression [2]. ...
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Background Depression is one of the most common mental illnesses worldwide. Nitric oxide (NO) is involved in the pathophysiology of depression. Auraptene (a coumarin derivative) has been shown to possess pharmacological effects on neurological diseases. Purpose The present study aimed to investigate the possible role of the NO pathway in Auraptene antidepressant effects in male mice. Methods Behavioral tests were used to assess depression-like behaviors. The mice received Auraptene at 10, 30, and 100 mg/kg, the combination of the sub-effective (ineffective) dose of Auraptene (10 mg/kg) and L-NAME, and the combination of the effective dose of Auraptene (30 mg/kg) and L-arginine. Finally, OFT, TST, FST, brain, serum MDA level, antioxidant capacity, hippocampus, and serum NO level were measured. Results The data analysis showed that Auraptene (30 mg/kg) improved depression-like behaviors. Auraptene (30 mg/kg) also significantly reduced serum NO levels (P < 0.05) and significantly increased serum MDA (10 mg/kg, P < 0.05). Auraptene at 30 mg/kg also increased serum antioxidant capacity (P < 0.01). Co-administration of L-NAME and the sub-effective dose of Auraptene enhanced the effects of Auraptene. However, co-administration of the effective dose of Auraptene and L-arginine reduced the impacts of Auraptene. Conclusions The results showed that Auraptene causes antidepressant effects in a dose-dependent manner and acts as a prooxidant at 100 mg/kg, and exacerbates oxidative stress. The antidepressant effects of this active molecule are exerted by reducing the NO level in the hippocampus and serum, increasing the antioxidant capacity, and reducing the MDA level in the serum.
... It has been hypothesized that the imbalance in monoamine neurotransmitter levels (i.e., serotonin and norepinephrine) is a key factor in the pathophysiology of depressive symptoms and anxiety disorders 29 . Thus, high comorbidity between IBS and emotional distress, including anxiety and depressive symptoms, may be a consequence of an alteration in serotonin and norepinephrine 30,31 . Both the CNS and the enteric nervous system have the capability to produce neurotransmitters 28 . ...
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Evidence highlights the comorbidity between emotional distress and irritable bowel syndrome (IBS) through the gut-brain axis. However, the underlying mechanism is largely unknown. Thus, the present study aimed to evaluate the associations among neurotransmitter levels and the gut microbiome profiles in persons with IBS and emotional distress. In this nested case-controlled study, emotional symptoms, including anxiety and depressive symptoms, were evaluated in 40 persons with IBS and 20 healthy controls (HC). Plasma neurotransmitters levels (serotonin and norepinephrine) and the gut microbiome profile of the collected fecal samples were examined. Emotional distress and microbiome profile were significantly different between IBS and HC groups. Lower but not significant neurotransmitters’ levels (serotonin and norepinephrine) were observed in the IBS group compared to the HC. A negative correlation was found between norepinephrine levels and alpha diversity (Shannon and Simpson indices) in the IBS group. Moreover, serotonin levels were positively associated with the abundance of Proteobacteria , and norepinephrine were positively correlated with Bacteroidetes , but negatively associated with Firmicutes phylum. The present study demonstrated alteration in the gut microbiome between persons with IBS and emotional distress compared to HC. The correlations between plasma neurotransmitters and the gut microbiome suggest that the gut microbiome may impact the regulation of neurotransmitters.
... The reduction of L-phenylalanine levels in female students with ScD may be due to decreased phenylalanine hydroxylase enzyme activity [6]. The catecholamine neurotransmitters such as 5-hydroxytryptamine (5-TH), dopamine, adrenaline, and norepinephrine are synthesized from phenylalanine and tyrosine through hydroxylation and decarboxylation reactions [38]. Numerous studies have found that the concentration of monoamines (such as 5-TH, norepinephrine and dopamine) in the synaptic gap drops in depressive states [39]. ...
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This study aimed to investigate the association between complex brain functional networks and the metabolites in urine in subclinical depression. Electroencephalography (EEG) signals were recorded from 78 female college students, including 40 with subclinical depression (ScD) and 38 healthy controls (HC). The phase delay index was utilized to construct functional connectivity networks and quantify the topological properties of brain networks using graph theory. Meanwhile, the urine of all participants was collected for non-targeted LC-MS metabolic analysis to screen differential metabolites. The global efficiency was significantly increased in the α-2, β-1, and β-2 bands, while the characteristic path length of β-1 and β-2 and the clustering coefficient of β-2 were decreased in the ScD group. The severity of depression was negatively correlated with the level of cortisone (p = 0.016, r = −0.40). The metabolic pathways, including phenylalanine metabolism, phenylalanine tyrosine tryptophan biosynthesis, and nitrogen metabolism, were disturbed in the ScD group. The three metabolic pathways were negatively correlated (p = 0.014, r = −0.493) with the global efficiency of the brain network of the β-2 band, whereas they were positively correlated (p = 0.014, r = 0.493) with the characteristic path length of the β-2 band. They were mainly associated with low levels of L-phenylalanine, and the highest correlation sparsity was 0.11. The disturbance of phenylalanine metabolism and the phenylalanine, tryptophan, tyrosine biosynthesis pathways cause depressive symptoms and changes in functional brain networks. The decrease in the L-phenylalanine level may be related to the randomization trend of the β-1 frequency brain functional network.
... Several bacterial strains can independently synthesize (or modulate the synthesis of) a number of neurotransmitters, including γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT, serotonin), dopamine, and noradrenaline (Khan et al., 2015;Fung et al., 2017;Calvani et al., 2018;Sherwin et al., 2018;Strandwitz, 2018). Alteration in the levels of neurotransmitters are observed in various neurological disorders, including Parkinson's disease and AD (Francis, 2005;Nutt, 2008;Barone, 2010;Brisch et al., 2014). While these changes likely reflect neuronal loss, it is possible that peripheral production of neurotransmitters by bacteria could contribute. ...
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Alzheimer’s disease (AD) is a neurodegenerative disease that impacts 45 million people worldwide and is ranked as the 6th top cause of death among all adults by the Centers for Disease Control and Prevention. While genetics is an important risk factor for the development of AD, environment and lifestyle are also contributing risk factors. One such environmental factor is diet, which has emerged as a key influencer of AD development/progression as well as cognition. Diets containing large quantities of saturated/trans-fats, refined carbohydrates, limited intake of fiber, and alcohol are associated with cognitive dysfunction while conversely diets low in saturated/trans-fats (i.e., bad fats), high mono/polyunsaturated fats (i.e., good fats), high in fiber and polyphenols are associated with better cognitive function and memory in both humans and animal models. Mechanistically, this could be the direct consequence of dietary components (lipids, vitamins, polyphenols) on the brain, but other mechanisms are also likely to be important. Diet is considered to be the single greatest factor influencing the intestinal microbiome. Diet robustly influences the types and function of micro-organisms (called microbiota) that reside in the gastrointestinal tract. Availability of different types of nutrients (from the diet) will favor or disfavor the abundance and function of certain groups of microbiota. Microbiota are highly metabolically active and produce many metabolites and other factors that can affect the brain including cognition and the development and clinical progression of AD. This review summarizes data to support a model in which microbiota metabolites influence brain function and AD.
... Over the past 60 years, pharmacological treatment for depression has focused on drugs targeting monoamine neurotransmitters, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) 5 . These treatments, however, can take up to six weeks to have an effect. ...
Article
Background : Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods : The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results : In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions : This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration : ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.
... body. Abnormalities in the release and regulation of neurotransmitters are also related to a series of pathological processes, such as depression and bipolar disorder 43 . There are hundreds of neurotransmitters in the human brain, including both excitatory neurotransmitters and inhibitory neurotransmitters. ...
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The aberrant expression or genomic mutations of microRNA are associated with several human diseases. This study analyzes the relationship between genetic variations of miRNA and schizophrenia or bipolar disorder. We performed case-control studies for ten SNPs in a total sample of 1584 subjects. All these ten SNPs were on or near mature microRNAs. We identified the association between bipolar disorder and the T/C polymorphism at rs895819. To illustrate the function of miR-27a, we constructed several miR-27a knockout (KO) cell lines, determined candidates of miR-27a, and then verified NCAM1 as a target gene of miR-27a. Further studies revealed that the T/C polymorphism on miR-27a led to the differential expression of mature and precursor miR-27a without affecting the expression of primary miR-27a. Furthermore, the C mutation on pre-miR-27a suppresses cell migration and dopamine expression levels. Our study highlights the importance of miR-27a and its polymorphism at rs895819 in bipolar disorder. A T/C variant in miR-27a is associated with bipolar disorder, potentially by reducing the ability of this microRNA to target important neurodevelopmental genes like NCAM1.
... Neurotransmitters play a major role in the etiology of depression, ranging from affecting neurogenesis levels (Apple et al., 2017) to changes in mood (Jenkins et al., 2016). Serotonin, dopamine, and norepinephrine are implicated neurotransmitters in depression (Nutt, 2008). Any disturbance to optimal brain insulin signaling may parallel hampered neurotransmitter function. ...
Article
Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.
... In addition, we will explore the modulatory effects of the two treatments on plasma biochemical indexes, which are believed to play an important role in the pathology of depression. [39][40][41][42] ...
Article
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Objectives Major depressive disorder (MDD) is one of the most common mental illnesses. This study aims to investigate the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) compared with the effectiveness of citalopram, a commonly used antidepressant, in patients with depression. Material and Methods A total of 107 male and female patients with MDD (55 in the taVNS group and 52 in the citalopram group) were enrolled in a prospective 12-week, single-blind, comparative effectiveness trial. Participants were recruited from the outpatient departments of three hospitals in China. Participants were randomly assigned to either taVNS treatment (eight weeks, twice per day, with an additional four-week follow-up) or citalopram treatment (12 weeks, 40 mg/d). The primary outcome was the 17-item Hamilton Depression Rating Scale (HAM-D17) measured every two weeks by trained interviewers blinded to the treatment assignment. The secondary end points included the 14-item Hamilton Anxiety Scale and peripheral blood biochemical indexes. Results The HAM-D17 scores were reduced in both treatment groups; however, there was no significant group-by-time interaction (95% CI: −0.07 to 0.15, p = 0.79). Nevertheless, we found that taVNS produced a significantly higher remission rate at week four and week six than citalopram. Both treatments were associated with significant changes in the peripheral blood levels of 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and noradrenaline, but there was no significant difference between the two groups. Conclusion taVNS resulted in symptom improvement similar to that of citalopram; thus, taVNS should be considered as a therapeutic option in the multidisciplinary management of MDD. Nevertheless, owing to the design of this study, it cannot be ruled out that the reduction in depression severity in both treatment groups could be a placebo effect.
... Animal study indicated the inhibitory GABA could be converted to a paradoxical excitatory neurotransmitter, following neuronal damage (Hökfelt et al., 1994;Ben-Ari et al., 2012). These reorganizational processes usually produce profound impacts on the sensory system as well as contributed to the establishment of concomitant symptoms such as anxiety and depression (Nutt, 2008). Thus, restoring the homeostasis of neurotransmitters is key to cure the root causes of chronic pain. ...
Article
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Chronic pain is one of the most prevalent health problems. The establishment of chronic pain is complex. Current medication for chronic pain mainly dependent on anticonvulsants, tricyclic antidepressants and opioidergic drugs. However, they have limited therapeutic efficacy, and some even with severe side effects. We turned our interest into alkaloids separated from traditional Chinese medicine (TCM), that usually act on multiple drug targets. In this article, we introduced the best-studied analgesic alkaloids derived from TCM, including tetrahydropalmatine, aloperine, oxysophocarpine, matrine, sinomenine, ligustrazine, evodiamine, brucine, tetrandrine, Stopholidine, and lappaconitine, focusing on their mechanisms and potential clinical applications. To better describe the mechanism of these alkaloids, we adopted the concept of drug-cloud (dCloud) theory. dCloud illustrated the full therapeutic spectrum of multitarget analgesics with two dimensions, which are “direct efficacy”, including inhibition of ion channels, activating γ-Aminobutyric Acid/opioid receptors, to suppress pain signal directly; and “background efficacy”, including reducing neuronal inflammation/oxidative stress, inhibition of glial cell activation, restoring the balance between excitatory and inhibitory neurotransmission, to cure the root causes of chronic pain. Empirical evidence showed drug combination is beneficial to 30–50% chronic pain patients. To promote the discovery of effective analgesic combinations, we introduced an ancient Chinese therapeutic regimen that combines herbal drugs with “Jun”, “Chen”, “Zuo”, and “Shi” properties. In dCloud, “Jun” drug acts directly on the major symptom of the disease; “Chen” drug generates major background effects; “Zuo” drug has salutary and supportive functions; and “Shi” drug facilitates drug delivery to the targeted tissue. Subsequently, using this concept, we interpreted the therapeutic effect of established analgesic compositions containing TCM derived analgesic alkaloids, which may contribute to the establishment of an alternative drug discovery model.
... In concurrence with dopamine and serotonin, noradrenaline is also an important neuromodulator that affects mental conditions (Ruhé et al., 2007;Nutt, 2008). The locus coeruleus (LC), which is located in the brainstem just under the cerebellum, is a major noradrenergic source in the brain. ...
Article
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The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.
... Vitamin C is also a cofactor of several important hydroxylation reactions in the human body, such as the synthesis of catecholamine [11,12]. The increase or decrease in catecholamine and other substances may be related to depression [13]. Some studies investigated the relationship between vitamin C and depression. ...
Article
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Vitamin C is a water-soluble antioxidant. Reducing the level of oxidative stress can alleviate depression. Therefore, we investigated the correlation between dietary vitamin C intake and the risk of depressive symptoms in the general population. Data from the 2007–2018 National Health and Nutrition Examination Survey were used in our study. The dietary intake of vitamin C was assessed by two 24-hour dietary recalls. Depressive symptoms were assessed with the Patient Health Questionnaire-9. Logistic regression and restricted cubic spline models were applied to assess the relationship between dietary vitamin C intake and the risk of depressive symptoms. The multivariate adjusted odds ratio (95% confidence interval) of depressive symptoms for the highest vs. lowest category of dietary vitamin C intake and vitamin C intake derived from vegetables were 0.73 (0.58–0.91) and 0.73 (0.56–0.95). In subgroup analyses, dietary vitamin C intake was negatively correlated with the risk of depressive symptoms in females 18–39 years old and 40–59 year-old groups. A dose-response analysis showed that there was a nonlinear relationship between dietary vitamin C intake and the risk of depressive symptoms. Dietary vitamin C intake and vitamin C intake derived from vegetables were inversely associated with the risk of depressive symptoms among the general population. We recommend increasing the intake of vegetables in daily diet.
... For the participants with higher level of depressive symptoms, the dysfunction of sleep may result from the imbalance of multiple neurotransmitters [41]. Therefore, nutrition strategies, such as increasing Mg intake, may not be sufficient to reverse the disruptions of the corresponding biological pathways [42]. Additionally, some causes remotely associated with nutritional intake, such as stressful events and genetic vulnerability, could potentially trigger sleep disturbance among depressive participants. ...
Article
Study Objectives As an antagonist of calcium (Ca), magnesium (Mg) has been implicated in the regulation of sleep. We aimed to examine the longitudinal associations of Mg intake and Ca-to-Mg intake ratio (Ca:Mg) with sleep quality and duration. Methods The study sample consisted of 3,964 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Dietary and supplementary intake of Mg were obtained using the CARDIA Dietary History at baseline (1985–1986), exam years 7 and 20. Self-reported sleep outcomes were measured at years 15 and 20. Sleep quality was rating from 1 (very good) to 5 (very bad). We categorized sleep duration to <7, 7–9, and >9 h. Generalized estimating equation was used to examine the associations of interest as repeated measures at the two time points. Results After adjustment for potential confounders, Mg intake was borderline associated with better sleep quality [highest quartile (Q4) vs. intake quartile (Q1): odds ratio (OR) = 1.23; 95% CI = 0.999, 1.50, ptrend = 0.051]. Participants in Q4 were also less likely to have short sleep (<7 h) compared to those in Q1 (OR = 0.64; 95% CI = 0.51, 0.81, ptrend = 0.012). The observed association with short sleep persisted among participants without depressive disorders (Q4 vs. Q1: OR = 0.64; 95% CI = 0.49, 0.82, ptrend < 0.001), but not among individuals with depressive disorder. Ca:Mg was not associated with either outcomes, regardless of depression status. Conclusions Mg intake was associated with both sleep outcomes in this longitudinal analysis. Randomized controlled trials with objective measures of sleep are warranted to establish the potential causal inference.
... Dopamine has two major pathways involved in the neurobiology of depression: the mesocortical pathway and the nigro-striatal pathway (Moret & Briley, 2011). Alterations in these pathways are correlated with three important clinical symptoms of depression: 1) loss of energy associated with the dopamine action in the striatum; 2) lack of attention and loss of impulse, caused by low levels of dopamine in the prefrontal cortex; and 3) loss of pleasure in normally pleasurable activities, due to an imbalance of the dopaminergic system in the brain reward system, which includes the nucleus accumbens (Stahl, 2003;Nutt et al. 2007;Dunlop & Nemeroff, 2007;Nutt, 2008). ...
Chapter
Due to its widespread expression, acetylcholine has been termed the ‘universal cytotransmitter’. The cholinergic system regulates the synthesis, actions and degradation of acetylcholine. This phylogenetically ancient signaling system is present in vertebrate and invertebrate organisms. In mammals, acetylcholine has generally been regarded as a classical neurotransmitter, despite the fact that it was first identified in the spleen, an immune organ. Acetylcholine regulates numerous immune functions through stimulation of muscarinic and nicotinic acetylcholine receptors. In fact, the presence of cholinergic system components has also been demonstrated in microbes, but their function in these organisms remains largely unexplored. Furthermore, during viral, bacterial, fungal and parasitic infections, the cholinergic system of the host is significantly altered, suggesting that it holds an important role in their pathogenesis. It is therefore essential to better understand cholinergic interactions during infection to develop novel forms of therapy. This chapter attempts to summarize the current literature on the topic.
Article
Background Attention deficits measured using event-related potentials (ERPs) have been frequently reported in several major psychiatric disorders, e.g. mood disorder (MD), psychotic disorder (PD) and substance use disorder (SUD). However, comparisons between these specific categories are lacking. Here we investigated if electrophysiological parameters of basic information processing are associated with the above-mentioned categories of psychiatric disorders, or instead were associated with general psychopathology. Methods 579 subjects with MD, PD or SUD and healthy controls (HC) were included. Participants were tested in a passive auditory and an active visual oddball paradigm to assess mismatch negativity (MMN), P3A and P3B amplitudes. Additionally, we examined associations between these measures and psychoactive medication treatments. Results All patients had significantly lower P3B amplitudes compared to healthy controls, while only SUD patients had lower P3A amplitudes than MD, PD and HC. PD patients also produced significantly less MMN than both MD and SUD patients. Additionally, we found significantly higher P3B amplitude in HC compared to patients without psychopharmacological treatment and patients treated with two or more psychoactive compounds (polypharmacy), but no significant associations with medication on P3A and MMN amplitudes. Conclusions Our results add to the theory that P3B deficits are associated with general psychopathology, whereas P3A and MMN deficits appear to be associated with substance abuse and psychotic disorders respectively.
Article
Patient: The patient was a 69-year-old woman with a chief complaint of masticatory function and esthetic disorder caused by wearing of complete dentures. Dentures meeting her functional and esthetic requirements were constructed and fitted in the patient three times, and the mastication ability and satisfaction of the patient before and after treatment were evaluated by a multi-axis assessment protocol (OHIP-J54, psychological health condition). We report the long-term continuous application of a multi-axis assessment protocol in edentulous prosthetic treatment. Discussion: All assessments showed an improvement tendency by treatment for the chief complaint at the first visit. On the other hand, in the treatment for the chief complaint at the return visit, immediately after the treatment there was no improvement compared to the denture in use, but it was observed to improve with longer period of use. In addition, the psychological health condition tended to return to the worse state at 1 to 2 years after denture insertion compared to the condition at 1 to 3 months after insertion. In the subscale analysis of OHIP-J54, “Psychological discomfort” and “Psychological disability” tended to worsen over time. This was considered to be a main trigger for the remaking of dentures. Conclusion: In cases suspected of having psychological health condition problems, it was shown that continuous evaluation of patient satisfaction, masticatory function, and a multi-axis assessment protocol are important.
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Ketamine has been shown to acutely and rapidly ameliorate depression symptoms and suicidality. Given that women suffer from major depression at twice the rate of men, it is important to understand how ketamine works in the female brain. This review explores three themes. First, it examines our current understanding of the etiology of depression in women. Second, it examines preclinical research on ketamine's antidepressant effects at a neurobiological level as well as how ovarian hormones present a unique challenge in interpreting these findings. Lastly, the neuroinflammatory hypothesis of depression is highlighted to help better understand how ovarian hormones might interact with ketamine in the female brain.
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Severe psychiatric condition, including major unipolar depression (MDD) and post-traumatic stress disorders (PTSD), are characterized by a strong comorbidity with suicide ideations and attempts. Predictors of suicide risk in humans include impulsivity and aggressiveness, which can be reproduced in rodents by aggressive behavior using the resident-intruder test and other behavioral tests that measure the impulsivity, irritability, and hopelessness of rodents. Animal models of behavioral traits of suicide in humans provide means to better understand the neurobiology of suicidal behavior, as well as they help to understand neural mechanisms and circuits underlying suicide. The search for biomarker-tailored therapies against suicide is urgently needed. Neurosteroid biosynthesis modulates emotional state and stress response and evidence shows that its downregulation during pathophysiological conditions underlays rapid changes in mood and may result in affective disorders. Similarly, several lines of preclinical and clinical evidence suggest that these neuromodulators may underlay suicidal risk and thereby may offer valuable biomarkers. Hereinafter, we analyze animal model approaches that reproduce suicidal-like behaviors in rodents and we highlight findings on the role of neurosteroid biosynthesis in suicidal behavior observed in stress-models of PTSD/suicide in humans.
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Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies allowed the formulation of several theories attempting to describe the development of MDD. However, none of these hypotheses are comprehensive because none of them can explain all cases, mechanisms, and symptoms of MDD. Nevertheless, all of these theories share some common pathways, which lead us to believe that these hypotheses depict several pieces of the same big puzzle. Therefore, in this review, we provide a brief description of these theories and their strengths and weaknesses in an attempt to highlight the common mechanisms and relationships of all major theories of depression and combine them together to present the current overall picture. The analysis of all hypotheses suggests that there is interdependence between all the brain structures and various substances involved in the pathogenesis of MDD, which could be not entirely universal, but can affect all of the brain regions, to one degree or another, depending on the triggering factor, which, in turn, could explain the different subtypes of MDD.
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