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Main classes of medications currently used in major depressive disorder (MDD) treatment, with examples of their members and targets of their action. Trazodone, ketamine, and lithium do not belong to any of the listed groups.
Source publication
Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the patho...
Context in source publication
Citations
... The PI3K/Akt/mTOR signaling pathway can be activated by BDNF, which is a ligand for tropomyosin receptor kinase B (TrkB) (Luo et al. 2019). A large number of experiments suggest that factors influencing the BDNF level in the brain also impact GSK-3β activity (Mai et al. 2002;Duda et al. 2020). GSK-3β activity is associated with the regulation of serotonin, and GSK-3β gene variants play a role in the antidepressant response to selective serotonin reuptake inhibitors. ...
Introduction
Chaigui granules are a novel manufactured traditional Chinese antidepressant medicine, which is originated from the ancient classical prescription of Xiaoyaosan. It ameliorated depression-like behavior and concomitant symptoms in animal models. But its antidepressant mechanism is still unclear. Therefore, network pharmacology and molecular biology were used to explore underlying antidepressant mechanism in this study.
Methods
Firstly, network pharmacology was used to screen main active ingredients and potential targets in the treatment of depression with Chaigui granules, and to perform pathway enrichment analysis. Secondly, chronic and unpredictable mild stress-induced depression model rats were used, and behavioral tests were used to evaluate the antidepressant effect of Chaigui granules. Finally, the core targets and key pathways predicted by network pharmacology were validated by qRT-PCR and Western blot to determine the relevant gene and protein expression levels in rat hippocampus.
Results
The results of network pharmacology indicated that the PI3K/Akt signaling pathway may play a key role in antidepressant of Chaigui granules. The results of animal experiments showed that Chaigui granules significantly modulated behavioral indicators. Subsequently, the upregulation of relative mRNA levels of mTOR, Akt and PI3K and downregulation of GSK-3β and FoxO3a were observed in rat hippocampus by molecular biology diagnosis. In addition, the decreased expression of Akt and mTOR in CUMS rats hippocampus was significantly reversed, and the expression levels of GSK-3β and FoxO3a were upregulated.
Conclusions
Based on the results of network pharmacology and animal experiment validation, Chaigui granules may reverse CUMS-induced depression-like behavior in rats through PI3K/Akt/mTOR signaling pathway.
... We avoided this confounding problem by excluding patients with hyperglycemia, thyroid disease or obesity. Second, in most studies patients were not free from other drugs such as benzodiazepines, antidepressants or mood stabilizers, that are known to affect GSK3 expression (Duda et al. 2020). Third, a complete study of both total and phosphorylated GSK3 in both bipolar and unipolar depression is still lacking. ...
Background
The differential diagnosis of patients presenting for the first time with a depressive episode into unipolar disorder versus bipolar disorder is crucial to establish the correct pharmacological therapy (antidepressants vs mood stabilizers), but no biological markers are currently available. Several lines of evidence indicate an involvement of Glycogen Synthase Kinase-3 (GSK3) in the pathophysiology of depression. However, previous reports about GSK3 in peripheral blood were incomplete or inconsistent, so a specific marker is not yet available. The aim was to search for consistent differences in GSK3α and GSK3β or of their phosphorylated forms in samples of peripheral blood from patients with unipolar and bipolar depression.
Methods
Mononucleate peripheral blood cells (PBMCs) of samples from patients presenting with a depressive episode were analyzed with the western blot technique.
Results
The total amount of GSK3β in PBMCs was significantly lower in patients with bipolar disorder than in patients with unipolar depression. The sensitivity based on GSK3β was 85%. GSK3α was not significantly different but allowed a correct detection of 57% of BD patients. The combination in series of GSK3β and GSK3α yields a sensitivity of about 100%, but with 26.7% false negatives.
Conclusions
Our results suggest that PBMC GSK3β could be a candidate biomarker for the differential diagnosis of bipolar disorder versus unipolar depression. This finding may help in implementing the still limited panel of peripheral biomarkers for differential diagnosis between unipolar and bipolar disorder in patients presenting with a depressive episode.
... GSK3β is a serine/threonine protein kinase. Studies have shown that GSK3β is associated with the development of depression [77] and that inhibition of GSK3 activity produces antidepressant effects associated with neurogenesis [78]. The activity of GSK3β is regulated by phosphorylation and dephosphorylation. ...
Depression is the most prevalent mental disorder, affecting more than 300 million adults worldwide each year, which can lead to serious economic and social problems. Antidepressants are usually the first-line treatment for depression, however, traditional antidepressants on the market have the disadvantage of low remission rates and may cause side effects to patients, therefore, the current focus in the field of depression is to develop novel therapeutic agents with high remission rates and few side effects. In this context, the antidepressant effects of natural compounds have received attention. Baicalin (baicalein-7-O-glucuronide) and its aglycone baicalein (5,6,7-trihydroxyflavone) are flavonoid compounds extracted from the root of Scutellaria baicalensis. Although lacking the support of clinical data, they have been shown to have significantly promising antidepressant activity in many preclinical studies through various rodent models of depression. This paper reviews the antidepressant effects of baicalin and baicalein in experimental animal models, with emphasis on summarizing the molecular mechanisms of their antidepressant effects including regulation of the HPA axis, inhibition of inflammation and oxidative stress, reduction of neuronal apoptosis and promotion of neurogenesis, as well as amelioration of mitochondrial dysfunction. Controlled clinical trials should be conducted in the future to examine the effects of baicalin and baicalein on depression in humans.
... Glycogen synthase kinase-3 beta (GSK3β) plays an important role in AD. 21 A great deal of research indicates that GSK3β is related to the hyperphosphorylation of tau, increased production of Aβ, and memory impairment. [22][23][24] Like AD, GSK3β is associated with depression. ...
Introduction
Alzheimer's disease (AD) is the most common form of dementia. Depression is one of the most critical psychiatric complications of AD, and 20%–30% of patients with AD experience symptoms of depression. Phospho‐glycogen synthase kinase‐3 beta (GSK3β) is known to be associated with AD and depression. Furthermore, the role of disheveled (DVL) is known to regulate GSK3β. Moreover, presenilin‐2 (PS2) and DVL have cross‐talk with each other. Also, it is widely hypothesized that stress leads to hypersecretion of cortisol and is thus associated with depression. Dickkopf WNT signaling pathway inhibitor‐1 (DKK‐1) is a crucial factor regulating depression and both amyloid beta (Aβ) and phosphorylation of tau are widely known as a biomarker of AD.
Methods
To investigate the relationship between AD and depression, and possible pathways connecting the two diseases, we examined memory function and depression‐related behavior test results in PS2 knock‐in AD mice (PS2 MT). Next, we confirmed that there are relationships between DVL, depression, and cognitive disease through the comparative toxicogenomics database (https://ctdbase.org) and STRING (https://string‐db.org) database.
Results
PS2 knock‐in mice showed much more severe memory impairment and depression than PS2 wild‐type mice (PS2 WT). In AD‐related behavioral experiments, PS2 MT mice showed more memory dysfunction compared with PS2 WT group mice. Moreover, Aβ and phosphorylation of tau showed higher expression in PS2 MT mice than in PS2 WT mice. Depression‐related behavioral tests showed that PS2 MT mice exhibited more depressive behaviors than PS2 WT mice. Furthermore, both higher cortisol levels and higher expression of DKK‐1 were found in PS2 MT mice relative to PS2 WT mice. The results indicated that there is a relationship between DVL and the release of AD‐related mediators and expression of the depression‐related glucocorticoid receptor and DKK‐1. In the PS2 knock‐in group, DVL was significantly decreased compared with the PS2 WT group.
Conclusion
Depression increases the risk of developing AD and other forms of dementia. Recent evidence indicates that depression symptoms could trigger changes in memory and thinking over time. However, it is recognized that there are no drugs to facilitate a full recovery for both AD and depression. However, our results suggest that AD and depression could be associated, and DVL could be a significant target for the association between AD and depression.
... We avoided this confounding problem by excluding patients with hyperglycemia, thyroid disease or obesity. Second, in most studies patients were not free from other drugs such as benzodiazepines, antidepressants or mood stabilizers, that are known to affect GSK3 expression 27 . Third, a complete study of both total and phosphorylated GSK3 in both bipolar and unipolar depression is still lacking. ...
Background
The differential diagnosis of patients presenting for the first time with a depressive episode into unipolar disorder versus bipolar disorder is crucial to establish the correct pharmacological therapy (antidepressants vs mood stabilizers), but no biological markers are currently available. Several lines of evidence indicate an involvement of Glycogen Synthase Kinase-3 (GSK3) in the pathophysiology of depression. However, previous reports about GSK3 in peripheral blood were incomplete or inconsistent, so a specific marker is not yet available. The aim was to search for consistent differences in GSK3α and GSK3β or of their phosphorylated forms in samples of peripheral blood from patients with unipolar and bipolar depression.
Methods
Mononucleate peripheral blood cells (PBMCs) of samples from patients presenting with a depressive episode were analyzed with the western blot technique.
Results
The total amount of GSK3β in PBMCs was significantly lower in patients with bipolar disorder than in patients with unipolar depression. The sensitivity based on GSK3β was 85%. GSK3α was not significantly different but allowed a correct detection of 57% of BD patients. The combination in series of GSK3β and GSK3α yields a sensitivity of about 100%, but with 26.7% false negatives.
Conclusions
Our results suggest that PBMC GSK3β could be a candidate biomarker for the differential diagnosis of bipolar disorder versus unipolar depression. To our knowledge, this is the first identification of an easily detectable biological marker that enables a differential diagnosis between unipolar and bipolar disorder in patients presenting for with a depressive episode.
... After its synthesis, DA must be internalized into synaptic vesicles by means of the vesicular monoamine transporter 2 (VMAT2) to be released (Meiser et al., 2013). Impairment of the control of these mechanisms may provoke inadequate levels of DA in particular brain areas, which may contribute to behavioral psychiatric pathologies, such as psychosis, addiction (Salamone et al., 2016) or depression (Duda et al., 2020). Moreover, due to the role of DA in the control of coordinated movements, alterations in the dopaminergic system also contribute to diseases causing locomotion impairment (Smith-Dijak et al., 2019). ...
CHIR99021, also known as laduviglusib or CT99021, is a Glycogen-synthase kinase 3 α/β inhibitor, which has been reported as a promising drug for cardiomyocyte regeneration or treatment of sensorial hearing loss, among other pathologies. Since the activation of dopamine (DA) receptors regulate dopamine synthesis itself and use glycogen-synthase kinase 3β (GSK3β) as an element in the β-arrestin pathway, we decided to check the effect of GSK3β inhibitors (CHIR99021, SB216763 and lithium ion) in the control of DA synthesis. Using ex vivo experiments with minces from rat brain striatum, we observed that CHIR99021, but not SB216763 nor lithium, causes a complete abrogation of DA synthesis and accumulation, pointing to off-target effects of CHIR99021. This decrease can be attributed to tyrosine hydroxylase (TH) inhibition since the accumulation of L-DOPA in the presence of a DOPA decarboxylase inhibitor was similarly decreased. On the other hand, CHIR99021 caused an exponential increase in the DOPAC / DA ratio, an indicator of DA metabolization, and decreased the incorporation of extracellular DA into striatum minces. In addition, CHIR99021 or SB216763, but not lithium, decreased TH phosphorylation in Ser19. These results demonstrate that CHIR99021 can lead to TH inactivation and DA decrease in brain striatum, opening the possibility of its use in DA-related disorders, and shows effects to be considered in future clinical trials.
... Similarly, post-mortem studies have reported elevated GSK-3β mRNA levels in the hippocampus of patients with major depression. Treatment with GSK-3β inhibitors reduces the production of QUIN and subsequently alleviates depressive, anxious, and aggressive behaviors in animal models (137). Moreover, Verdonk and colleagues reported that decreases in QUIN after a ketamine infusion strongly predicted improvements in MADRS scores in patients with treatment resistant depression (138). ...
In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1β, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood–brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.
... By antagonizing 5-HT 2C receptors, AGO can also disinhibit release of dopamine and norepinephrine in the prefrontal cortex, thereby contributing to the effects of antidepressants (Millan et al., 2003;Stahl, 2014). In addition, AGO has neuroprotective effects because it has been shown to improve neuronal plasticity in the rat brain (Calabrese et al., 2011;Dagyte et al., 2011), upregulate brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex and hippocampus (Yucel et al., 2016;Lu et al., 2018), and activate the extracellular signal-regulated kinase-protein kinase B-glycogen synthase kinase 3β (ERK-AKT-GSK3β) signaling pathway (Duda et al., 2020), which can help to ameliorate the depressive disorder. ...
Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B (MT1/MT2) and antagonist of 5-hydroxytryptamine 2C receptors. It is used clinically to treat major depressive episodes in adults. The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B, which work simultaneously to counteract depression and anxiety disorder. Moreover, by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors, agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex, increases the activity of dopamine and noradrenaline, and thereby reduces depression and anxiety disorder. The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression, anxiety, and disturbance of the circadian rhythm. Emotion and sleep are closely related to memory and cognitive function. Memory disorder is defined as any forms of memory abnormality, which is typically evident in a broad range of neurodegenerative diseases, including Alzheimer's disease. Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases. Therefore, whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research "hotspot". This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments. Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.
... Glycogen synthase kinase 3β (GSK3β) is a serine/threonine protein kinase and downstream target of Sema3A (Williams et al., 2004) that participates in numerous physiologic processes such as cell cycle regulation and synaptic transmission and plasticity (Duda et al., 2020). GSK3β also plays a role in major depression; it is a target of mood stabilizers and antidepressants (Li and Jope, 2010), and selective GSK3β inhibitors are shown to exert antidepressant action in rodents (Gould et al., 1999;Kaidanovich-Beilin et al., 2004). ...
... Consistent with previous studies, we found that Ser9 phosphorylation of GSK3β was reduced in the hippocampus of PPD mice, suggesting that the increased activity of GSK3β contributed to the anxiety and depression-like behaviors induced by gestational stress. It is suggested that active GSK3β is strongly associated with the downscaling of synapses, declined neuronal excitability and increased inflammatory response (Duda et al., 2020), so we speculate that the increased GSK3β activity may be involved in PPD by affecting neuroplasticity and neuroinflammation. Protein kinase B (AKT)/GSK3β/CRMP2 signaling was shown to be involved in the development of depression induced by stress (Wei et al., 2021). ...
Introduction
Postpartum depression (PPD) is a common neuropsychiatric disorder characterized by depression and comorbid anxiety during the postpartum period. PPD is difficult to treat because of its elusive mechanisms. Epigallocatechin-3-gallate (EGCG), a component of tea polyphenols, is reported to exert neuroprotective effects in emotional disorders by reducing inflammation and apoptosis. However, the effect of EGCG on PPD and the underlying mechanism are unknown.
Methods
We used a mouse model of PPD established by exposing pregnant mice to gestational stress. Open field, forced swimming and tail suspension tests were performed to investigate the anxiety and depression-like behaviors. Immunohistochemical staining was used to measure the c-fos positive cells. The transcriptional levels of hippocampal semaphorin3A(sema3A), (glycogen synthase kinase 3-beta)GSK3β and collapsin response mediator protein 2(CRMP2) were assessed by RT-PCR. Alterations in protein expression of Sema3A, GSK3β, p-GSK3β, CRMP2 and p-CRMP2 were quantified by western blotting. EGCG was administrated to analyze its effect on PPD mice.
Results
Gestational stress induced anxiety and depression-like behaviors during the postpartum period, increasing Sema3A expression while decreasing that of phosphorylated GSK3β as well as c-Fos in the hippocampus. These effects were reversed by systemic administration of EGCG.
Conclusions
Thus, EGCG may alleviate anxiety and depression-like behaviors in mice by downregulating Sema3A and increasing GSK3β phosphorylation in the hippocampus, and has potential application in the treatment of PPD.
... Our observations are in line with published data demonstrating an association between the PAM pathway and psychiatric illness [39]. PAM pathway disruption of protein synthesis and actin dynamics can lead to abnormal neuronal morphology, learning/memory deficits, and psychiatric disease [19,22,[40][41][42][43][44][45]. Proteins implicated in this pathway are downregulated in the dorsolateral prefrontal cortex in schizophrenia [40]. ...
... Proteins implicated in this pathway are downregulated in the dorsolateral prefrontal cortex in schizophrenia [40]. In murine models, decreased AKT activity in the ventral tegmental area was associated with increased susceptibility to depressive behavior [45]; antipsychotic drugs were shown to activate GSK3β-AKT signaling [41][42][43]; and GSK3β inhibitors had anti-depressant effects in animal models [44]. Furthermore, AKT isoform-and gender-specific effects were seen on levels of anxiety, spatial and contextual memory, and fear extinction [46]. ...
Background
Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms.
Methods
(1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors.
Results
(1) Proteins encoded by AKT3 ( AKT3Q60H ) and AKT1 ( AKT1Q61H ) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1 , respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10 –8 ). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible.
Conclusions
Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.
