Adjunctive Memantine for the Treatment of Borderline Personality Disorder: A 12-Week, Double-Blind, Randomised, Placebo-Controlled Trial

Background: Borderline Personality Disorder (BPD) is a highly prevalent, severe mental illness with no substantially efficacious pharmacological treatments. The aetiology of BPD is poorly understood with adverse early life experiences and subsequent chronic stress hypothesised to play a key role via excessive glutamatergic signalling. This study aimed to determine the clinical efficacy of adjunctive memantine, an N-methyl-D-aspartate receptor antagonist, in the treatment of BPD. Methods: This was a 12-week, double-blind, randomised, placebo-controlled trial evaluating the effectiveness of memantine (20 mg/day) in adults with BPD in addition to their usual care therapy. Participants were aged 16-65 years, with a current diagnosis or symptoms of BPD, stabilised on medications and psychotherapy. The primary outcome was the change from baseline to week 12 on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD). All analyses were modified intention-to-treat; a linear mixed effects model was used to investigate the treatment effects. The trial was registered with ClinicalTrials.gov (NCT02097706). Findings: 234 participants were screened (July 7, 2017, to April 29, 2025), of whom 186 were randomly allocated, and 155 completed baseline, 112 completed to week 12. Initial sample size calculation was 62 for each group. Participants had a median age of 36 years (IQR 16 years) and 77% were female. Considering all post-baseline time points, there was a significant effect in testing differential changes in ZAN-BPD score between memantine and placebo groups (X2(6) = 14.84, p = 0.02). Cohen’s D effect sizes for the between-group differential change ranged 0.38 – 0.56, showing relatively large effects at follow-up measurement. The most common adverse events reported across all participants included tiredness, dizziness and headaches. Interpretation: Memantine was associated with a clinically significant improvement in BPD symptoms. Memantine, via restoration of glutamatergic homeostasis, may be a clinically useful option for treatment of BPD.FundingAustralian National Health and Medical Research Council (Grant 1129815) and the Wolinski Foundation.