Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be ...the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium's specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3β, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Stress-induced changes in the immune system, which lead to neuroinflammation and consequent brain alterations, have been suggested as possible neurobiological substrates of anxiety disorders, with ...previous literature predominantly focusing on panic disorder, agoraphobia, and generalized anxiety disorder, among the anxiety disorders. Anxiety disorders have frequently been associated with chronic stress, with chronically stressful situations being reported to precipitate the onset of anxiety disorders. Also, chronic stress has been reported to lead to hypothalamic-pituitary-adrenal axis and autonomic nervous system disruption, which may in turn induce systemic proinflammatory conditions. Preliminary evidence suggests anxiety disorders are also associated with increased inflammation. Systemic inflammation can access the brain, and enhance pro-inflammatory cytokine levels that have been shown to precipitate direct and indirect neurotoxic effects. Prefrontal and limbic structures are widely reported to be influenced by neuroinflammatory conditions. In concordance with these findings, various imaging studies on panic disorder, agoraphobia, and generalized anxiety disorder have reported alterations in structure, function, and connectivity of prefrontal and limbic structures. Further research is needed on the use of inflammatory markers and brain imaging in the early diagnosis of anxiety disorders, along with the possible efficacy of anti-inflammatory interventions on the prevention and treatment of anxiety disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Chronic stress can lead to increases in pro-inflammatory cytokine levels.•Inflammation leads to alterations in the ratio of kynurenine pathway metabolites.•Pro-inflammatory cytokines and kynurenine ...pathway metabolites can be neurotoxic.•Neurotoxicity causes changes in the hippocampus, amygdala, and cingulate cortex.•Alterations in brain regions are associated with the pathophysiology of depression.
Major depressive disorder (MDD) is a condition which has often been associated with chronic stress. The sympathetic nervous system is continuously activated without the normal counteraction of the parasympathetic nervous system under the influence of chronic stress. As a result, epinephrine and norepinephrine levels are increased, and acetylcholine levels are decreased, which in turn can increase the levels of pro-inflammatory cytokines. Peripheral inflammatory responses can access the brain, with neuroinflammation contributing to the increase in neurotoxic kynurenine pathway metabolites such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid, and decrease in neuroprotective metabolites such as kynurenic acid. Pro-inflammatory cytokines can also exert direct neurotoxic effects on specific brain regions. Previous imaging studies have reported associations between pro-inflammatory states and alterations in brain regions involved in emotional regulation, including the hippocampus, amygdala and anterior cingulate cortex. Alterations in structure and function of such brain areas due to the neurotoxic effects of increased inflammation may be associated with the pathophysiology of depression. This review focuses the influence of stress on neuroinflammation which may cause alterations in brain structure and function in MDD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pro-inflammatory systemic conditions that can cause neuroinflammation and subsequent alterations in brain regions involved in emotional regulation have been suggested as an underlying mechanism for ...the pathophysiology of major depressive disorder (MDD). A prominent feature of MDD is disruption of circadian rhythms, of which melatonin is considered a key moderator, and alterations in the melatonin system have been implicated in MDD. Melatonin is involved in immune system regulation and has been shown to possess anti-inflammatory properties in inflammatory conditions, through both immunological and non-immunological actions. Melatonin has been suggested as a highly cytoprotective and neuroprotective substance and shown to stimulate all stages of neuroplasticity in animal models. The ability of melatonin to suppress inflammatory responses through immunological and non-immunological actions, thus influencing neuroinflammation and neurotoxicity, along with subsequent alterations in brain regions that are implicated in depression, can be demonstrated by the antidepressant-like effects of melatonin. Further studies that investigate the associations between melatonin, immune markers, and alterations in the brain structure and function in patients with depression could identify potential MDD biomarkers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. Although novel antipsychotics have been developed, the negative and cognitive ...symptoms of schizophrenia are still unresponsive to pharmacotherapy. The high level of social impairment and a chronic deteriorating course suggest that schizophrenia likely has neurodegenerative characteristics.
Inflammatory markers such as pro-inflammatory cytokines are well-known etiological factors for psychiatric disorders, including schizophrenia. Inflammation in the central nervous system is closely related to neurodegeneration. In addition to pro-inflammatory cytokines, microglia also play an important role in the inflammatory process in the CNS. Uncontrolled activity of pro-inflammatory cytokines and microglia can induce schizophrenia in tandem with genetic vulnerability and glutamatergic neurotransmitters. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, anti-inflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Further studies should consider the confounding effects of systemic factors such as metabolic syndrome and smoking. In addition, the unique mechanisms by which pro-inflammatory cytokines are involved in the etiopathology of schizophrenia should be investigated. In this article, we aimed to review (1) major findings regarding neuroinflammation and pro-inflammatory cytokine alterations in schizophrenia, (2) interactions between neuroinflammation and neurogenesis as possible neural substrates for schizophrenia, and (3) novel pharmacological approaches.
► Cytokines are closely related to inflammation and neurogenesis in the brain. ► Neuroinflammation and neurodegeneration play important roles in the pathogenesis of schizophrenia. ► Adjuvant anti-inflammatory treatment for schizophrenia is under investigation. ► Specific inflammatory biomarkers for schizophrenia need to be identified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Atypical antipsychotics (AAP) are the prevailing form of schizophrenia treatment today due to their low side effects and superior efficacy. Nevertheless, some issues still need to be addressed. ...First, there are still a large number of patients with treatment-resistant schizophrenia (TRS), which has led to a growing trend to resort to AAP polypharmacy with few side effects. Most clinical treatment guidelines recommend clozapine monotherapy in TRS, but around one third of schizophrenic patients fail to respond to clozapine. For these patients, with clozapine-resistant schizophrenia AAP polypharmacy is a common strategy with a continually growing evidence base. Second, AAP generally have great risks for developing metabolic syndrome, such as weight gain, abnormality in glucose, and lipid metabolism. These metabolic side effects have become huge stumbling blocks in today's schizophrenia treatment that aims to improve patients' quality of life as well as symptoms. The exact reasons why this particular syndrome occurs in patients treated with AAP is as yet unclear though factors such as interaction of AAP with neurotransmitter receptors, genetic pholymorphisms, type of AAPs, length of AAP use, and life style of schizophrenic patients that may contribute to its development. The present article aimed to review the evidence underlying these key issues and provide the most reasonable interpretations to expand the overall scope of antipsychotics usage.
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Alzheimer's disease (AD) is the most common form of dementia worldwide. β-amyloid peptide (Aβ) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but ...the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aβ decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aβ toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.
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•BDNF and CREB are key downstream mediators of Aβ toxicity•BDNF level is correlated with cognitive status•Aβ decreases BDNF primarily by reducing phosphorylated CREB protein
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The autonomic nervous system is one of the major neural pathways
activated by stress. In situations that are often associated with chronic stress, such as
major depressive disorder, the sympathetic ...nervous system can be continuously
activated without the normal counteraction of the parasympathetic nervous system.
As a result, the immune system can be activated with increased levels of proinflammatory
cytokines. These inflammatory conditions have been repeatedly
observed in depression. In the search for the mechanism by which the immune
system might contribute to depression, the enhanced activity of indoleamine 2,3-
dioxygenase by pro-inflammatory cytokines has been suggested to play an important
role. Indoleamine 2,3-dioxygenase is the first enzyme in the kynurenine pathway that
converts tryptophan to kynurenine. Elevated activity of this enzyme can cause imbalances in downstream
kynurenine metabolites. This imbalance can induce neurotoxic changes in the brain and create a
vulnerable glial-neuronal network, which may render the brain susceptible to depression. This review
focuses on the interaction between stress, the autonomic nervous system and the immune system which can
cause imbalances in the kynurenine pathway, which may ultimately lead to major depressive disorder.
Background: The human gut microbiome comprise a huge number of microorganisms
with co-evolutionary associations with humans. It has been repeatedly revealed that bidirectional
communication exists ...between the brain and the gut and involves neural, hormonal, and immunological
pathways. Evidences from neuroscience researches over the past few years suggest that
microbiota is essential for the development and maturation of brain systems that are associated to
stress responses.
Method: This review provides that the summarization of the communication among microbiota, gut
and brain and the results of preclinical and clinical studies on gut microbiota used in treatments for
neuropsychiatric disorders.
Result: Recent studies have reported that diverse forms of neuropsychiatric disorders (such as
autism, depression, anxiety, and schizophrenia) are associated with or modulated by variations in
the microbiome, by microbial substrates, and by exogenous prebiotics, antibiotics, and probiotics.
Conclusion: The microbiota–gut–brain axis might provide novel targets for prevention and treatment
of neuropsychiatric disorders. However, further studies are required to substantiate the clinical
use of probiotics, prebiotics and FMT.
Although anxiety and depression have been considered as two distinct entities according to the diagnostic criteria, anxious depression (comorbid anxiety and depression) is relatively a common ...syndrome. According to the DSM-5 criteria, it uses "with anxious distress specifier" to define anxious depression in its MDD section. Anxious depression is known to have different neurobiological profiles compared to non-anxious depression. Several studies have revealed significant differences between anxious depression and non-anxious depression regarding the hypothalamic-pituitary-adrenal (HPA) axis function, structural and functional brain imaging findings, inflammation markers, etc. Patients with anxious depression were significantly more likely to be found in primary care setting and more likely to be associated with female gender, non-single, unemployed, less educated, and more severe depression. Previous reports also showed that patients with anxious depression had more frequent episodes of major depression and a higher risk of suicidal ideation and previous suicide attempts than those with non-anxious depression. Although anxious depression is known to be associated with poor treatment outcomes in several studies, recent researches have sought to find better treatment strategy to improve patients with anxious depression.
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