New hypothesis and treatment targets of depression: an integrated view of key findings.
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ABSTRACT:
SUBMITTER: Cai S
PROVIDER: S-EPMC5562637 | biostudies-other | 2015 Feb
REPOSITORIES: biostudies-other
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Project description:BackgroundWe aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma.MethodsForty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS).ResultsMedian age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively).ConclusionOur results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.
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Project description:Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, Wnt/?-catenin and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.
| S-EPMC6315088 | biostudies-other
Project description:Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine's pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine's efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness.
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Project description:BackgroundPrimary Care-Mental Health Integration (PC-MHI) may improve mental health services access and continuity of care.ObjectiveTo assess whether receipt of integrated PC-MHI services on the date of an initial positive depression screen influences receipt of depression treatment among primary care (PC) patients in the Veterans Health Administration.DesignRetrospective cohort study.SubjectsThirty-six thousand, two hundred and sixty-three PC patients with positive depression screens between October 1, 2009 and September 30, 2010.Main measuresSubjects were assessed for depression diagnosis and initiation of antidepressants or psychotherapy on the screening day, within 12 weeks, and within 6 months. Among individuals with PC encounters on the screening day, setting of services received that day was categorized as PC only, PC-MHI, or Specialty Mental Health (SMH). Using multivariable generalized estimating equations (GEE) logistic regression, we assessed likelihood of treatment initiation, adjusting for demographic and clinical measures, including depression screening score.Key resultsPatients who received same-day PC-MHI services were more likely to initiate psychotherapy (OR: 8.16; 95 % CI: 6.54-10.17) and antidepressant medications (OR: 2.33, 95 % CI: 2.10-2.58) within 12 weeks than were those who received only PC services on the screening day.ConclusionsReceipt of same-day PC-MHI may facilitate timely receipt of depression treatment.
| S-EPMC3579958 | biostudies-literature
Project description:Studies have identified longitudinally that there exists an association between depression, cerebral blood flow (CBF), and white matter hyperintensities that are thought to be due to vascular pathologies in the brain. However, the changes in CBF, a measure that reflects cerebrovascular integrity, following pharmacotherapy are not well understood. In this study, we investigated the dynamic CBF changes over the course of antidepressant treatment and the association of these changes with depressive symptoms. We used pseudocontinuous arterial spin labeling to investigate CBF changes in a sample of older patients (≥ 50 years of age; N = 46; 29 female) with a DSM-IV diagnosis of major depressive disorder. Participants had 5 magnetic resonance imaging scans (at baseline, the day after receiving a placebo, the day after receiving a first dose of venlafaxine, a week after starting venlafaxine treatment, and at the end of trial [12 weeks]). Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate depression severity and treatment outcome. We investigated the association between changes in depression severity with changes in voxel-wise CBF while adjusting for potential confounding factors. Increased CBF in the middle and posterior cingulate between baseline and end of treatment was significantly associated with percent decrease in MADRS score, independent of sex and Mini-Mental State Examination score (5,000 permutations, cluster forming threshold P < .005, family-wise error P < .05). No significant effects were detected between baseline and other scans (ie, placebo, acute [single dose], or subacute [after a week]). Regional CBF increases were associated with decreases in depressive symptoms. This observation is consistent with the vascular depression hypothesis in late-life depression. ClinicalTrials.gov identifiers: NCT00892047 and NCT01124188.
| S-EPMC6419103 | biostudies-literature
Project description:Clinical depression is a serious mental disorder characterized by low mood, anhedonia, loss of interest in daily activities, and other symptoms, and is associated with severe consequences including suicide and increased risk of cardiovascular events. Depression affects nearly 15% of the population. The standard of care for the last 50 years has focused on monoamine neurotransmitters, including such treatments as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, these treatments have significant limitations: they can take weeks before showing mood-altering effects, and only one to two out of ten patients shows clinical effects beyond those associated with placebo. A major paradigm shift in research into the treatment of depression is underway, based on promising results with the glutamatergic NMDA receptor antagonist ketamine. Further research has demonstrated the significance of glutamatergic pathways in depression and the association of this system with the stress pathway and magnesium homeostasis. Treatment with NMDA receptor antagonists and magnesium have shown the ability to sprout new synaptic connections and reverse stress-induced neural changes, opening up promising new territory for the development of drugs to meet the unmet need in patients with clinical depression.
| S-EPMC3936783 | biostudies-literature
Project description:Schizophrenia is a highly heritable disorder, but the identification of specific genes has proven to be a difficult endeavor. Genes involved in the dopaminergic system are considered to be major candidates since the "dopamine hypothesis" of impairment in dopaminergic neurotransmission is one of the most widely accepted hypotheses of the etiology of schizophrenia. The overall findings from candidate studies do provide some support for the "dopamine hypothesis." However, results from the first systematic genome-wide association (GWA) studies have implicated variants within ZNF804A, NRGN, TCF4, and variants in the MHC region on chromosome 6p22.1. Although these genes may not immediately impact on dopaminergic neurotransmission, it remains possible that downstream impairments in dopaminergic function are caused. Furthermore, only a very small fraction of all truly associated genetic variants have been detected and many more associated variants will be identified in the future by GWA studies and alternative approaches. The results of these studies may allow a more comprehensive re-evaluation of the dopamine hypothesis.
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Project description:ContextResearch on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity.ObjectiveTo evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression.DesignTwo-site, prospective, nonrandomized controlled trial.SettingOutpatient clinics at Washington University and Duke University.ParticipantsA total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time.ResultsBaseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores.ConclusionsComprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity.Trial registrationclinicaltrials.gov Identifier: NCT00045773.
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Project description:BackgroundVogt-Koyanagi-Harada (VKH) disease is a complex disease associated with multiple molecular immunological mechanisms. As the underlying mechanism for VKH disease is unclear, we hope to utilize an integrated analysis of key pathways and drug targets to develop novel therapeutic strategies.MethodsCandidate genes and proteins involved in VKH disease were identified through text-mining in the PubMed database. The GO and KEGG pathway analyses were used to examine the biological functions of the involved pathways associated with this disease. Molecule-related drugs were predicted through Drug-Gene Interaction Database (DGIdb) analysis.ResultsA total of 48 genes and 54 proteins were associated with VKH disease. Forty-two significantly altered pathways were identified through pathway analysis and were mainly related to immune and inflammatory responses. The top five of significantly altered pathways were termed as "inflammatory bowel disease," "cytokine-cytokine receptor interaction," "allograft rejection," "antigen processing," and "presentation and Herpes simplex infection" in the KEGG database. IFN-? and IL-6 were identified as the key genes through network analysis. The DGIdb analysis predicted 48 medicines as possible drugs for VKH disease, among which Interferon Alfa-2B was co-associated both with IFN-? and IL-6.ConclusionsIn this study, systematic analyses were utilized to detect key pathways and drug targets in VKH disease via bioinformatics analysis. IFN-? and IL-6 were identified as the key mediators and possible drug targets in VKH disease. Interferon Alfa-2B was predicted to be a potentially effective drug for VKH disease treatment by targeting IFN-? and IL-6, which warrants further experimental and clinical investigations.
| S-EPMC7769821 | biostudies-literature
Project description:Introduction: Treatment-resistant depression (TRD) is a complex, multifactorial, and biologically heterogeneous disorder with debilitating outcomes. Understanding individual reasons why patients do not respond to treatment is necessary for improving clinical recommendations regarding medication regimens, augmentation strategies, and alternative treatments.Areas covered: This manuscript reviews evidence-based treatment strategies for the clinical management of TRD. Current developments in the field and potential future recommendations for personalized treatment of TRD are also discussed.Expert opinion: Treatment guidelines for TRD are limited by the heterogeneous nature of the disorder. Furthermore, current strategies reflect this heterogeneity by emphasizing disease characteristics as well as drug trial response or failure. Developing robust biomarkers that could one day be integrated into clinical practice has the potential to advance specific treatment targets and ultimately improve treatment and remission outcomes.
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