Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial

Abstract

Background: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization.

Methods: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores.

Results: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4.

Conclusion: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Trial registration: ClinicalTrials.gov NCT03166501.

Keywords: EEG/evoked potentials; PTSD/posttraumatic stress disorder; clinical trails; pharmacotherapy; startle.

Figure 1:

Study Schematic

Figure 2:

A) APS T-score at Infusion #3 as a function of condition controlling for baseline (Infusion #1). Red indicates Lanicemine group and Blue indicates Placebo group. B) Bayesian results for APS T-score at Infusion #3 (Lanicemine vs Placebo), including the median and Credible Interval (Crl) of the posterior distribution as well as the posterior probability that an effect of treatment exists. C) APS T score as a function of Time and Group. D) Bayesian results for APS T-score (Lanicemine vs Placebo) at Infusion #1.

Figure 3:

A) resting-gamma at Infusion #1 at 0.5- and 1.5-hour measurements. Bar plots are relative to pre-infusion (before infusion #1 values using subtraction). Red indicates Lanicemine group and Blue indicates Placebo group. B) resting-gamma at Infusion #3. Bar plots are relative to pre-infusion values (before Infusion #1 using subtraction). C) Bayesian results for resting-gamma at Infusion #1 (Lanicemine vs Placebo) at 0.5- and 1.5-hour measurements, including the median and Credible Interval (Crl) of the posterior distribution as well as the posterior probability that an effect of treatment exists. Analysis controlled for pre-infusion values before infusion #1. D) Bayesian results for resting-gamma at Infusion #3 at 0.5- and 1.5-hour measurements. Analysis controlled for pre-infusion values before infusion #1.

Figure 4:

A) ASSR Time Frequency plots at Infusion #1 at 0.5- and 1.5-hour measurements. Red indicates Lanicemine group and Blue indicates Placebo group. B) ASSR Time Frequency plots at Infusion #3 at 0.5- and 1.5-hour measurements. C) Bayesian results for ASSR at Infusion #1 (Lanicemine vs Placebo), including the median and Credible Interval (Crl) of the posterior distribution as well as the posterior probability that an effect of treatment exists. Analysis controlled for pre-infusion values before 1st infusion. D) Bayesian results for ASSR at Infusion #3. Analysis controlled for pre-infusion values before infusion #1.