Adding Antibiotic to Brain Stim Bolstered Effects in Major Depression

Adding D-cycloserine to the mix may enhance the benefits of intermittent theta-burst stimulation (iTBS) for those with major depressive disorder, a randomized trial showed.

Among 50 patients, those who took the antibiotic during the first 2 weeks of a 4-week course of iTBS had greater improvements in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) compared with those receiving iTBS plus placebo (mean difference -6.15, 95% CI -2.43 to -9.88), reported Alexander McGirr, MD, PhD, of the University of Calgary in Canada, and colleagues.

Patients in the D-cycloserine group also saw a higher clinical response rate at 4 weeks than the iTBS group (73.9% vs 29.3%; OR 6.88, 95% CI 1.91-24.77, P=0.003), as well as a higher clinical remission rate (39.1% vs 4.2%; OR 14.78, 95% CI 1.68-129.52, P=0.01), the group wrote in JAMA Psychiatry.

Furthermore, those receiving the antibiotic had lower Clinical Global Impression (CGI)-severity scores and higher CGI-improvement scores, as well as improved self-reported anxiety symptoms.

“One notable feature of the course of improvement is a larger treatment effect after 4 weeks than after 2 weeks of treatment, despite the adjuvant being present for the first 2 weeks,” McGirr and team wrote. “We speculate that despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score compared with 9 of 25 participants (36%) in the iTBS plus DCS [D-cycloserine] group.”

The authors noted that D-cycloserine, an NMDA-receptor partial-agonist often used to treat urinary tract infections, has previously been studied for other psychiatric conditions like anxiety, obsessive-compulsive disorder, and trauma. “Despite inconsistent results across studies, DCS is associated with a small but statistically significant efficacy signal in meta-analyses for these conditions,” they wrote, pointing out that a weak dose might have been to blame for previous null results.

Another recent randomized trial looking at the same course of iTBS (20 sessions with the same stimulator), but without adjunctive therapy, flopped in a trial of 37 adults with type I or type II bipolar disorder experiencing an acute major depressive episode.

This single-site, double-blind study, conducted from November 2019 through December 2020, randomized 25 participants with major depressive disorder to each group, the majority of whom were women with a mean age of 41. Twenty percent of the placebo group and 32% of the D-cycloserine group had previously attempted suicide.

Inclusion criteria included a major depressive episode with a score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work.

iTBS was delivered via MagVenture’s MagPro X100 stimulator and a COOL-B70 coil. The stimulation was targeted at the left dorsolateral prefrontal cortex with the Beam F3 method, and consisted of 600 pulses per session delivered in 20 trains of triplets at 50 Hz repeated at 5 Hz — 2 seconds on, 8 seconds off — at 80% resting motor threshold. Participants received daily treatments Monday through Friday for a total of 20 sessions over the 4-week trial.

Those in the D-cycloserine group were given 100 mg for the first 2 weeks of iTBS, followed by iTBS alone for weeks 3 and 4.

While there were no serious adverse events reported, more people in the D-cycloserine group experienced headaches during the first 2 weeks (92% vs 76% with placebo). This subsided during the next 2 weeks of the trial for both groups (52.1% vs 57.1%).

McGirr and team noted that their study was small and conducted at a single site, so “replication in a larger multisite study is required, as is additional investigation into intersectional approaches with other dosing regimens and precision medicine targeting approaches.”