Dataset Information

Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study.

ABSTRACT: N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (¹H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of D-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score>17, underwent up to three ¹H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = -0.83, p = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.

SUBMITTER: Dong Z

PROVIDER: S-EPMC8208505 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundWe tested the hypothesis that, after initial improvement with intravenous ketamine in patients with bipolar disorder (BD) with severe depression and acute suicidal thinking or behavior, a fixed-dose combination of oral D-cycloserine (DCS) and lurasidone (NRX-101) can maintain improvement more effectively than lurasidone alone.MethodsThis was a multi-center, double-blind, twostage, parallel randomized trial. Adult BD patients with depression and suicidal ideation or behavior were infused with ketamine or saline (Stage 1); those who improved were randomized to a fixed-dose combination of DCS and lurasidone vs. lurasidone alone (Stage 2) to maintain the improvement achieved in Stage 1. Depression was measured by the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thinking and behavior was measured by the Columbia Suicide Severity Rating Scale (C-SSRS); global improvement was measured by the clinical global severity scale (CGI-S).Clinicaltrialsgov NCT02974010; Registered: November 22, 2016.ResultsThirty-seven patients were screened and 22 were enrolled, randomized, and treated. All 22 patients treated in Stage 1 (17 with ketamine and 5 with saline) were enrolled into Stage 2, and 11 completed the study. The fixed-dose combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvement in depression (MADRS LMS Δ-7.7; p = 0.03) and reducing suicidal ideation, as measured by C-SSRS (Δ-1.5; p = 0.02) and by CGI-SS (Δ-2.9; p = 0.03), and with a non-statistically significant decrease in depressive relapse (0% vs. 40%; p = 0.07). This sequential treatment regimen did not cause any significant safety events and demonstrated improvements in patient-reported side effects.ConclusionsSequential treatment of a single infusion of ketamine followed by NRX-101 maintenance is a promising therapeutic approach for reducing depression and suicidal ideation in patients with bipolar depression who require hospitalization due to acute suicidal ideation and behavior. On the basis of these findings, Breakthrough Therapy Designation was awarded, and a Special Protocol Agreement was granted by the FDA for a registrational trial.

Project description:BackgroundThe pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response.MethodsA total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [11C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment.ResultsPretreatment binding potential (BPF) of [11C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [11C]CUMI-101 BPF was higher in bipolar participants compared with healthy volunteers (P = .00275). [11C]CUMI-101 BPF did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses.ConclusionsA disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier NCT02473250.

Project description:Depressive symptoms associated with bipolar disorder negatively impact health-related quality of life (HRQoL). The efficacy of lurasidone in reducing depressive symptoms has been previously demonstrated. The objective of this study was to examine the direct and indirect effect (mediated through improvement in depression symptoms) of lurasidone in improving patient HRQoL.A secondary analysis of data was conducted of two 6-week, double-blind, placebo-controlled trials assessing the effect of lurasidone (lurasidone monotherapy [20-60 mg/day or 80-120 mg/day]; lurasidone adjunctive to lithium or valproate [20-120 mg/day]) in patients with bipolar depression. Patient HRQoL was measured using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q SF). Depression symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of covariance (ANCOVA) was used to estimate the effect of lurasidone on improvement in the Q-LES-Q SF percentage maximum score from baseline to 6 weeks. Path analysis was used to evaluate the total effect (?1), as well as the indirect (?2*?3) and direct (?4) effect of lurasidone on Q-LES-Q SF change through improvements in MADRS.A total of 340 and 485 patients from the monotherapy and adjunctive therapy, respectively, were included in the analysis. At 6-weeks, ANCOVA analyses demonstrated that lurasidone provided significant improvement in adjusted mean Q-LES-Q SF scores in comparison to placebo for monotherapy (22.9 and 22.7 vs. 15.2, both p?<?0.01) and adjunctive therapy (23.1 vs. 17.9, p?=?0.01). Path analyses indicated that lurasidone treatment predicted MADRS improvement (monotherapy: ?2?=?-0.44, p?<?0.001; adjunctive therapy: ?2?=?-0.34, p?=?0.003), which subsequently predicted improvement in Q-LES-Q SF (monotherapy: ?3?=?-0.73, p?<?0.001; adjunctive therapy: ?3?=?-0.75, p?<?0.001); however, the effect of lurasidone on improvement in Q-LES-Q SF was largely mediated by change in MADRS (monotherapy: ?4?=?0.11, p?=?0.13; adjunctive therapy: ?4?=?0.02, p?=?0.77).Lurasidone as a monotherapy and adjunctive to lithium or valproate is an effective treatment for improving HRQoL in patients with bipolar depression. However, improvement in HRQoL was not independent of improvement in depression, indicating that the effect of lurasidone on improving patient HRQoL may act through a reduction in depressive symptoms associated with bipolar disorder.Clinicaltrials.gov identifiers: NCT00868699 and NCT00868452 (both registered March 23, 2009).

Dataset Information

Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets