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.

Keywords: D-Cycloserine; MRS—1H nuclear magnetic resonance spectra; N-methyl-D-aspartate; biomarker; bipolar depression; glutamate; lurasidone.

Conflict of interest statement

JK reports having received consulting payments within the last 24 months from Alphasights, Charles River Associates, Medscape, Putnam, techspert.io, Third Bridge, MEDACorp, Parexel, GroupH, Simon Kucher, ECRI Institute, ExpertConnect, Parexel, Schlesinger Group, CelloHealth, Acsel Health, Strafluence, Guidepoint, L.E.K. and System Analytic. He serves on the MedinCell Psychiatry and Karuna Mechanism of Action (MOA) Advisory Boards. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Alkermes, Cerevance, Corcept, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX and Teva within the last 24 months. JK was a co-investigator on a study that receives lumeteperone and reimbursement for safety testing for an investigator-initiated research from Intra-Cellular Therapies Inc. He owns a small number of shares of common stock from GSK. JM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Dong, Grunebaum, Lan, Wagner, Choo, Milak, Sobeih, Mann and Kantrowitz.

Figures

Figure 1

CONSORT chart.

Figure 2

Examples of voxel placement (red outline) on the axial and sagittal localizer images showing the size and location in the medial ventral prefrontal cortex (Left) and the original, estimated, and their difference spectra from the voxel (Right).

Figure 3

A scatter plot of mean change in Glu vs. improvement from baseline MADRS (rs = −0.83, p = 0.04) on the DCS/Lurasidone days (Left). Spaghetti plot of MADRS over time by subject (Right).