“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.
“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.
The study wasin JAMA Psychiatry.
Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.
“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”
One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.
“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.
The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.
However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.
To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.
Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).
Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.
Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).
“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.