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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

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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).

Project description:Accumulating evidence suggests that neuroinflammation is involved in bipolar disorder (BD) pathogenesis. The tumor necrosis factor-alpha (TNF-?) antagonist infliximab was recently reported to improve depressive symptoms in a subpopulation of individuals with BD and history of childhood maltreatment. To explore the mechanistic mediators of infliximab's effects, we investigated its engagement with biomarkers of cellular response to inflammation derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We hypothesized that infliximab, compared to placebo, would decrease TNF-? receptors (TNFRs) and nuclear factor-kappa B (NF-?B) pathway signaling biomarkers, and that history of childhood abuse would moderate infliximab's effects. We immunocaptured NEVs from plasma samples collected at baseline and at weeks 2, 6, and 12 (endpoint) from 55 participants of this clinical trial and measured NEV biomarkers using immunoassays. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging at baseline and endpoint. Childhood physical abuse moderated treatment by time interactions for TNFR1 (?2 = 9.275, p = 0.026), NF-?B (?2 = 13.825, p = 0.003), and inhibitor of NF-?B (I?B?)? (?2 = 7.990, p = 0.046), indicating that higher levels of physical abuse were associated with larger biomarker decreases over time. Moreover, the antidepressant response to infliximab was moderated by TNFR1 (?2 = 7.997, p = 0.046). In infliximab-treated participants, reductions in TNFR1 levels were associated with improvement of depressive symptoms, an effect not detected in the placebo group. Conversely, reductions in TNFR1 levels were associated with increased global cortical thickness in infliximab- (r = -0.581, p = 0.029), but not placebo-treated, patients (r = 0.196, p = 0.501). In conclusion, we report that NEVs revealed that infliximab engaged the TNFR/NF-?B neuro-inflammatory pathway in individuals with BD, in a childhood trauma-dependent manner, which was associated with clinical response and brain structural changes.

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

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