Adjunctive D-cycloserine to intermittent theta-burst transcranial magnetic stimulation in fibromyalgia: a randomized placebo-controlled trial

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iTBS to left DLPFC yielded a large FIQR improvement (Cohen's d = 1.41) with no significant difference between adjunctive D-Cycloserine and placebo.
Trial was terminated for futility after a planned interim analysis at n = 47 participants.
Adjunctive D-Cycloserine produced greater reduction in depressive symptoms compared with placebo, despite no additional benefit for overall fibromyalgia severity.

Neuropsychopharmacology. 2026 May 20. doi: 10.1038/s41386-026-02441-y. Online ahead of print.

ABSTRACT

Fibromyalgia is a chronic condition with a substantial unmet treatment need. Repetitive Transcranial Magnetic Stimulation (rTMS) has shown promise in decreasing fibromyalgia symptom severity. Emerging data suggest that adjunctive administration of the N-methyl-D-aspartate receptor partial agonist, D-Cycloserine, with rTMS can significantly improve clinical outcomes for other rTMS indications. Accordingly, this trial investigated adjunctive D-Cycloserine to intermittent Theta-Burst Stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) in adults with fibromyalgia. All participants received 20 daily (Monday-Friday) active iTBS treatments (600 pulses per session) delivered to the left DLPFC at 80% resting motor threshold, with double-blind, random assignment to adjunctive D-Cycloserine (100 mg) or placebo, taken prior to each iTBS session. The primary outcome was change on the Fibromyalgia Impact Questionnaire – Revised (FIQR) from baseline to treatment end. Secondary outcomes included self-report and clinician-rated measures of fibromyalgia-associated symptoms and quantitative sensory testing. Following a planned interim analysis, the trial was terminated for futility at n = 47 participants. There was a very large overall treatment effect on the FIQR (Cohen’s d = 1.41, 95% CI: 0.82-2.00) with no significant between-group difference. There was, however, a greater decrease in depressive symptoms in the iTBS+D-Cycloserine group compared to the iTBS+Placebo group. In conclusion, iTBS+/-D-Cycloserine was associated with a large improvement in fibromyalgia symptom severity, while iTBS+D-Cycloserine was superior to iTBS+Placebo only for improvements in depressive symptoms. The large effect of iTBS on fibromyalgia symptoms may have masked specific effects of adjunctive D-Cycloserine. Trial Registration: NCT05395494.

PMID:42162266 | DOI:10.1038/s41386-026-02441-y

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