A Randomized, Double-Blind Controlled Comparison of NRX-101 vs. Placebo for Adults Being Treated With Transcranial Magnetic Stimulation for Treatment Resistant Depression

Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes. DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When the AMPA one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week. This trial will compare response and remission at six weeks following Transcranial Magnetic Stimulation + D-cycloserine vs. TMS+placebo.

Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes. rTMS and TBS are believed to depend on synaptic plasticity in targeted circuits. Yet, there are several lines of evidence to suggest that synaptic plasticity is not intact in MDD, such as impaired learning and memory and lower expression of trophic factors.Using TMS as a tool to probe synaptic plasticity, individuals with MDD have reduced long-term potentiation-like facilitation in the motor cortex and prefrontal cortex. Importantly, this is observed with the intermittent TBS (iTBS) protocol used in MDD treatment. As such, iTBS treatment effects may be constrained by impaired synaptic plasticity in MDD. One potential strategy to improve outcomes is to adjunctively target the N-methyl-D-aspartate (NMDA) receptor during stimulation, an ionotropic glutamate receptor and key regulator of synaptic plasticity.Synaptic plasticity with continuous and intermittent TBS is NMDA-receptor dependent, as antagonists abolish the effects of both protocols.We have shown that targeting the NMDA receptor with low doses of the partial agonist, D-cycloserine (DCS), normalizes long-term motor cortex plasticity in individuals with MDD. Moreover, it results in greater persistence of iTBS-induced changes compared with placebo.However, a demonstration that these physiological effects have an impact on treatment outcomes is needed DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When the AMPA one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week. This trial will compare response and remission at six weeks following Transcranial Magnetic Stimulation + D-cycloserine vs. TMS+placebo.