Glutamate normalization with ECT treatment response in major depression.
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ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC3896297 | biostudies-literature | 2013 Mar
REPOSITORIES: biostudies-literature
Publications
Glutamate normalization with ECT treatment response in major depression.
Zhang J J Narr K L KL Woods R P RP Phillips O R OR Alger J R JR Espinoza R T RT
Molecular psychiatry 20120508 3
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Project description:Background:Electroconvulsive therapy (ECT) is arguably the most effective available treatment for severe depression. Recent studies have used MRI data to predict clinical outcome to ECT and other antidepressant therapies. One challenge facing such studies is selecting from among the many available metrics, which characterize complementary and sometimes non-overlapping aspects of brain function and connectomics. Here, we assessed the ability of aggregated, functional MRI metrics of basal brain activity and connectivity to predict antidepressant response to ECT using machine learning. Methods:A radial support vector machine was trained using arterial spin labeling (ASL) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) metrics from n?=?46 (26 female, mean age 42) depressed patients prior to ECT (majority right-unilateral stimulation). Image preprocessing was applied using standard procedures, and metrics included cerebral blood flow in ASL, and regional homogeneity, fractional amplitude of low-frequency modulations, and graph theory metrics (strength, local efficiency, and clustering) in BOLD data. A 5-repeated 5-fold cross-validation procedure with nested feature-selection validated model performance. Linear regressions were applied post hoc to aid interpretation of discriminative features. Results:The range of balanced accuracy in models performing statistically above chance was 58-68%. Here, prediction of non-responders was slightly higher than for responders (maximum performance 74 and 64%, respectively). Several features were consistently selected across cross-validation folds, mostly within frontal and temporal regions. Among these were connectivity strength among: a fronto-parietal network [including left dorsolateral prefrontal cortex (DLPFC)], motor and temporal networks (near ECT electrodes), and/or subgenual anterior cingulate cortex (sgACC). Conclusion:Our data indicate that pattern classification of multimodal fMRI metrics can successfully predict ECT outcome, particularly for individuals who will not respond to treatment. Notably, connectivity with networks highly relevant to ECT and depression were consistently selected as important predictive features. These included the left DLPFC and the sgACC, which are both targets of other neurostimulation therapies for depression, as well as connectivity between motor and right temporal cortices near electrode sites. Future studies that probe additional functional and structural MRI metrics and other patient characteristics may further improve the predictive power of these and similar models.
| S-EPMC5871748 | biostudies-literature
Project description:ObjectiveIncreased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects.MethodsInterleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment "response" was defined as ≥50% decrease in HDRS ratings over 8 weeks of treatment.ResultsAfter controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p<0.001), TNF-α (p<0.001), 8-OHdG (p=0.018), and F2-isoprostanes (p=0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p=0.006), and after eight weeks of treatment (p=0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p=0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p=0.019).ConclusionOur results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.
| S-EPMC5272818 | biostudies-literature
Project description:ObjectiveThe N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically heterogeneous populations.MethodData were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed).ResultsHigher body mass index correlated with greater HDRS improvement at 230 minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37, P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7 (standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized β = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively.ConclusionsDespite its post hoc nature, this study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.
| S-EPMC4310499 | biostudies-literature
Project description:BackgroundOxidative stress and oxidation-induced DNA damage may contribute to the pathophysiology of depression. Two key mediators of base excision repair (BER) in response to oxidative damage of DNA are OGG1 and PARP1. Few studies have examined changes in OGG1 or PARP1 mRNA in patients with depression or following antidepressant treatment. We examined PARP1 and OGG1 mRNA levels in patients with depression at baseline/pre-electroconvulsive therapy (baseline/pre-ECT) vs in healthy controls and in patients following a course of ECT.MethodsPARP1 and OGG1 were examined in whole blood samples from medicated patients with depression and controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine associations between PARP1 and OGG1 and mood (Hamilton Depression Rating Scale 24-item version) scores as well as with vitamin B3, SIRT1, PGC1α, and tumor necrosis factor alpha levels, as previously reported on in this cohort.ResultsPARP1 levels were reduced in samples from patients with depression vs controls (P = .03), though no difference was noted in OGG1. ECT had no effect on PARP1 or OGG1. Higher baseline PARP1 weakly correlated with greater mood improvement post ECT (P = .008). Moreover, PARP1 positively correlated with SIRT1 at baseline and post ECT, and positive correlations were noted between change in PARP1 and change in OGG1 with change in tumor necrosis factor alpha post ECT.ConclusionsTo our knowledge, this is the first study to examine the effect of ECT on BER enzymes. A better understanding of BER enzymes and DNA repair in depression could unearth new mechanisms relevant to the pathophysiology of this condition and novel antidepressant treatments.
| S-EPMC9926051 | biostudies-literature
Project description:The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study revealed poorer antidepressant treatment response among black compared with white participants. This racial disparity persisted even after socioeconomic and baseline clinical factors were taken into account. Some studies have suggested genetic contributions to this disparity, but none have attempted to disentangle race and genetic ancestry. Here we used genome-wide single-nucleotide polymorphism (SNP) data to examine independent contributions of race and genetic ancestry to citalopram response. Secondary data analyses included 1877 STAR*D participants who completed an average of 10 weeks of citalopram treatment and provided DNA samples. Participants reported their race as White (n=1464), black (n=299) or other/mixed (n=114). Genetic ancestry was estimated by multidimensional scaling (MDS) analyses of about 500 000 SNPs. Ancestry proportions were estimated by STRUCTURE. Structural equation modeling was used to examine the direct and indirect effects of observed and latent predictors of response, defined as change in the Quick Inventory of Depressive Symptomatology (QIDS) score from baseline to exit. Socioeconomic and baseline clinical factors, race, and anxiety significantly predicted response, as previously reported. However, direct effects of race disappeared in all models that included genetic ancestry. Genetic African ancestry predicted lower treatment response in all models. Although socioeconomic and baseline clinical factors drive racial differences in antidepressant response, genetic ancestry, rather than self-reported race, explains a significant fraction of the residual differences. Larger samples would be needed to identify the specific genetic mechanisms that may be involved, but these findings underscore the importance of including more African-American patients in drug trials.
| S-EPMC3828530 | biostudies-literature
Project description:BackgroundWe investigated the efficacy of electroconvulsive therapy in patients with major depressive disorder and concomitant anxiety symptoms and explored the relationships between depression symptoms and anxiety symptoms during acute electroconvulsive therapy.MethodsMajor depressive disorder inpatients (N = 130) requiring electroconvulsive therapy were recruited for a maximum of 12 treatments each. Depression symptoms, using the core factor subscale derived from the 17-item Hamilton Depression Rating Scale, and anxiety symptoms, using the anxiety/somatization subscale from the Hamilton Depression Rating Scale-17, were assessed before electroconvulsive therapy, after every 3 electroconvulsive therapy treatments, and after the final electroconvulsive therapy. Both core factor subscale and anxiety/somatization subscale scores were converted to T-score units to compare the degrees of changes between depression symptoms and anxiety symptoms after electroconvulsive therapy. The relationships between core factor subscale and anxiety/somatization subscale were analyzed using the cross-lagged longitudinal model during acute electroconvulsive therapy.ResultsA total 116 patients who completed at least the first 3 electroconvulsive therapy treatments were included in the analysis. Reduction of core factor scale T-scores was significantly greater than that of anxiety/somatization subscale T-scores. The model satisfied all indices of goodness-of-fit (chi-square = 30.204, df = 24, P = 0.178, Tucker-Lewis Index = 0.976, Comparative Fit Index = 0.989, Root Mean Square Error of Approximation = 0.047). Core factor subscale changes did not definitely predict subsequent anxiety/somatization subscale changes.ConclusionsElectroconvulsive therapy is effective in the acute treatment of major depressive disorder patients associated with anxiety symptoms. Anxiety symptoms improved less than depression symptoms during acute electroconvulsive therapy. However, earlier reduction in depression symptoms does not definitely drive subsequent relief in anxiety symptoms.
| S-EPMC6822139 | biostudies-literature
Project description:The search for a biological marker predicting the future failure or success of electroconvulsive therapy (ECT) remains highly challenging for patients with treatment-resistant depression. Evidence suggests that Brain-Derived Neurotrophic Factor (BDNF), a protein known to be involved in brain plasticity mechanisms, can play a key role in both the clinical efficacy of ECT and the pathophysiology of depressive disorders. We hypothesized that mature BDNF (mBDNF), an isoform of BDNF involved in the neural plasticity and survival of neural networks, might be a good candidate for predicting the efficacy of ECT. Total BDNF (tBDNF) and mBDNF levels were measured in 23 patients with severe treatment-resistant depression before (baseline) they received a course of ECT. More precisely, tBDNF and mBDNF measured before ECT were compared between patients who achieved the criteria of remission after the ECT course (remitters, n = 7) and those who did not (non-remitters, n = 16). We found that at baseline, future remitters displayed significantly higher mBDNF levels than future non-remitters (p = 0.04). No differences were observed regarding tBDNF levels at baseline. The multiple logistic regression model controlled for age and sex revealed that having a higher baseline mBDNF level was significantly associated with future remission after ECT sessions (odd ratio = 1.38; 95% confidence interval = 1.07-2.02, p = 0.04). Despite the limitations of the study, current findings provide additional elements regarding the major role of BDNF and especially the mBDNF isoform in the clinical response to ECT in major depression.
| S-EPMC8870188 | biostudies-literature
Project description:More than one-third of depressive patients do not achieve remission after the first antidepressant treatment. The "watch and wait" approach used to find the most effective antidepressant leads to an increased personal, social, and economic burden in society. In order to overcome this challenge, there has been a focus on studying neural biomarkers associated with antidepressant response. Diffusion tensor imaging measures have shown a promising role as predictors of antidepressant response by pointing to pretreatment differences in the white matter microstructural integrity between future responders and non-responders to different pharmacotherapies. Therefore, the aim of the present study was to explore whether response to paroxetine treatment was associated with differences in the white matter microstructure at baseline. Twenty drug-naive patients diagnosed with major depressive disorder followed a 6- to 12-week treatment with paroxetine. All patients completed magnetic resonance brain imaging and a clinical assessment at baseline and 6-12 weeks after treatment. Whole-brain tract-based spatial statistics was used to explore differences in white matter microstructural properties estimated from diffusion magnetic resonance imaging. Voxel-wise statistical analysis revealed a significant increase in fractional anisotropy and a decrease in radial diffusivity in forceps minor and superior longitudinal fasciculus in responders compared to non-responders. Thus, alterations in white matter integrity, specifically in forceps minor and the superior longitudinal fasciculus, are associated with paroxetine treatment response. These findings pave the way for personalized treatment strategies in major depression.
| S-EPMC8341904 | biostudies-literature
Project description:Deficits in the executive control of attention greatly impact the quality of life of patients diagnosed with major depressive disorder (MDD). However, attentional deficits are often underemphasized in clinical contexts compared with mood-based symptoms, and a comprehensive approach for specifically evaluating and treating them has yet to be developed. The present study evaluates the efficacy of bifrontal electroconvulsive therapy (ECT) combined with drug therapy (DT) in alleviating mood-related symptomatology and executive control deficits in drug-refractory MDD patients and compares these effects with those observed in MDD patients undergoing DT only. The Hamilton Rating Scale for Depression and the Lateralized Attentional Network Test-Revised were administered across two test sessions to assess treatment-related changes in mood-based symptoms and conflict processing, respectively, in patients undergoing ECT + DT (n = 23), patients undergoing DT (n = 33), and healthy controls (n = 40). Although both groups showed an improvement in mood-based symptoms following treatment and a deficit in conflict processing estimated on error rate, a post-treatment reduction of an executive control deficit estimated on RT was solely observed in the ECT + DT patient group. Furthermore, Bayesian correlational analyses confirmed the dissociation of mood-related symptoms and of executive control measures, supporting existing literature proposing that attentional deficits and mood symptoms are independent aspects of MDD. The cognitive profile of MDD includes executive control deficits, and while both treatments improved mood-based symptoms, only ECT + DT exerted an effect on both measures of the executive control deficit. Our findings highlight the importance of considering the improvement in both mood and cognitive deficits when determining the efficacy of therapeutic approaches for MDD.
| S-EPMC8946784 | biostudies-literature
Project description:The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain.Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocognitive effects of ketamine in depressed patients. Therefore, the aims of the current study were to characterize the relationship between baseline neurocognition and antidepressant response to ketamine, measure the acute impact of ketamine on neurocognition, and investigate the relationship between acute neurocognitive effects of ketamine and antidepressant response.Neurocognitive functioning was assessed in 25 patients with TRD using a comprehensive battery: estimated premorbid intelligence quotient (IQ), current IQ, and tests from the MATRICS Consensus Cognitive Battery (MCCB). A subset of the MCCB was repeated immediately following a 40-min intravenous infusion of ketamine (0.5 mg/kg).Patients who responded to ketamine 24 h following treatment had poorer baseline neurocognitive performance relative to nonresponders and, in particular, slower processing speed (F?=?8.42; df?=?23; p?=?0.008). Ketamine was associated with selective impairments in memory recall, and the degree of cognitive change carried negative prognostic significance (e.g., negative cognitive effects immediately after ketamine predicted lower response rate at 24 h; Fisher's exact test two-sided p?=?0.027).Taken together, our findings suggest a potential baseline neurocognitive predictor of ketamine response and an inverse relationship between the cognitive effects of ketamine and antidepressant efficacy.
| S-EPMC3952038 | biostudies-literature