Adjunctive D-Cycloserine in Fibromyalgia iTBS Trial

Key Takeaways

• Adjunctive D-cycloserine was not associated with better FIQR change than placebo at treatment end, and enrollment stopped for futility.
• Both groups showed marked overall FIQR improvement, while depressive symptoms and clinician-rated CGI-I ratings for depressive improvement favored D-cycloserine.
• No serious adverse events were reported, and all participants received active iTBS without a sham comparator.

A randomized double-blind placebo-controlled fibromyalgia trial stopped at 47 participants after a planned futility analysis found no significant between-group difference on the prespecified FIQR endpoint. Depressive symptoms favored adjunctive D-cycloserine, while fibromyalgia symptom severity improved substantially in both groups. No serious adverse events were reported.

The single-site study used a 4-week randomized, double-blind, placebo-controlled design in adults aged 18-65 years who met 2016 American College of Rheumatology fibromyalgia criteria. Eligibility also required FIQR scores greater than 41. Randomization assigned 24 participants to placebo and 23 to D-cycloserine. All participants received 20 weekday sessions of active iTBS to the left dorsolateral prefrontal cortex at 80% resting motor threshold, with 600 pulses per session. They took D-cycloserine 100 mg or placebo 90 minutes before each session, and the prespecified primary endpoint was change in FIQR from baseline to treatment end.

In the prespecified analysis, the group effect on FIQR change was not significant, with ANCOVA F(1,41)=1.63, p=0.21. Across both groups, FIQR scores improved markedly by treatment end, with Cohen's d=1.41 (95% CI 0.82-2.00), and that improvement remained evident at 8 weeks, with Cohen's d=1.11 (95% CI 0.60-1.62). The fibromyalgia symptom signal reflected broad improvement across both randomized groups rather than separation between groups.

Clinician-rated depressive symptoms favored D-cycloserine at treatment end, with MADRS F(1,41)=8.78, p=0.0051, and again 4 weeks after completion, with F(1,41)=8.49, p=0.0057. The depressive symptom effect sizes were Cohen's d=0.52 (95% CI -0.22 to 1.26) at treatment end and Cohen's d=0.80 (95% CI -0.0099 to 1.59) at follow-up. CGI-I ratings for depressive improvement also favored D-cycloserine, with a group coefficient of -1.40 (95% CI -2.55 to -0.25, p=0.02). Investigators found no evidence for group-by-time interactions in pain, sleep, fatigue, quality of life, cognitive function, or anxiety symptoms. Depressive symptoms were the main secondary domain that differed between groups.

No serious adverse events were reported, and fatigue was the most common event, affecting 19 participants in each group, including 82.6% of the D-cycloserine group and 79.2% of placebo. Serum D-cycloserine levels were measured after the first dose, and blinding was preserved because participant, operator, and rater guesses were not above chance. The authors noted early stopping for futility, a modest sample, no sham control, and exclusions involving benzodiazepines, cyclopyrrolones, pregabalin, and anticonvulsants as limits on generalizability. Overall, active iTBS was paired with robust symptom improvement, but adjunctive D-cycloserine did not change the prespecified fibromyalgia outcome.