CNS Drugs

, Volume 32, Issue 2, pp 179–187 | Cite as

Effect of the Glutamate NMDA Receptor Antagonist Memantine as Adjunctive Treatment in Borderline Personality Disorder: An Exploratory, Randomised, Double-Blind, Placebo-Controlled Trial

  • Jayashri Kulkarni
  • Natalie Thomas
  • Abdul-Rahman Hudaib
  • Emorfia Gavrilidis
  • Jasmin Grigg
  • Raelene Tan
  • Jacinta Cheng
  • Amelia Arnold
  • Caroline Gurvich
Original Research Article



Borderline personality disorder (BPD) is a complex, severe and highly stigmatised psychiatric illness. Several lines of evidence highlight the causal link between chronic stress, glucocorticoid response to stress and glutamatergic overactivity as a key event in the pathophysiology of BPD. Therefore, molecular mechanisms capable of regulating glutamate excitotoxicity represent novel and potentially promising treatment targets. Memantine-HCl is a voltage-dependent N-methyl-d-aspartate (NMDA) receptor ‘channel blocker’ that selectively blocks pathological glutamate overactivity.


The aim of the current study was to determine if memantine can improve BPD symptoms.


An 8-week, double-blind, placebo-controlled trial of adjunctive memantine to treatment as usual was conducted. Treatment as usual comprised antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, noradrenergic and specific serotonin antagonists and serotonin noradrenaline reuptake inhibitors), mood stabilisers and antipsychotics, as well as psychotherapy and other psychosocial interventions. Sixteen participants received oral placebo while 17 participants received daily oral memantine 10 mg for 7 days, with subsequent titration to daily oral memantine 20 mg. Eligibility criteria included men and women aged between 16–65 years, with a diagnosis of BPD according to the Diagnostic Interview for Borderline Patients. Primary outcome measures included the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD), assessed fortnightly. Secondary measures included an adverse effect questionnaire administered fortnightly to assess adverse effects known to be related to memantine use.


According to intention-to-treat, latent growth curve analyses, a significant change in total score of ZAN-BPD symptom severity was observed in the memantine group at 20 mg/daily across time, compared with placebo (p = 0.02). No adverse effects were significantly more frequent among participants receiving active memantine than among those receiving placebo.


Memantine at a 20-mg daily dose is a well tolerated drug that can improve BPD symptomatology and may be a promising novel therapeutic for its treatment. Further studies are needed to explore the efficacy of memantine versus placebo, as well as in comparison with other potential treatments for BPD. identifier: NCT02097706.



Author Kulkarni participated in the conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Author Thomas participated in the acquisition of data, analysis and interpretation of data, drafting of the manuscript and significantly contributed to the writing and editing of this review. Author Hudaib undertook the analyses and writing of the study results. Author Gavrilidis provided assistance in the setup of the study including ethics and budget as well as acquisition of data. Author Grigg contributed to the initial stages of this research including protocol development and data acquisition. Authors Cheng, Tan and Arnold recruited patients, provided clinical assistance and assisted with data acquisition. Author Gurvich participated in the interpretation of data and critical revision of the manuscript. All authors contributed to and have approved the final manuscript. We would like to thank the participants and their families for their generous involvement in the study.

Compliance with Ethical Standards

Conflict of interest

The authors (Jayashri Kulkarni, Natalie Thomas, Abdul- Rahman Hudaib, Emorfia Gavrilidis, Jasmin Grigg, Raelene Tan, Jacinta Cheng, Amelia Arnold and Caroline Gurvich) have no conflicts of interest to declare.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.


National Health and Medical and Research Council (NHMRC) Project Grant: 1129815 and Private Philanthropic Grant provided by Dr. Jeff Wolinski, C/o Monash University Fundraising Department, Faculty of Medicine, Nursing and Health Sciences.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

Supplementary material

40263_2018_506_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 18 kb)


  1. 1.
    Leichsenring F, Leibing E, Kruse J, New AS, Leweke F. Borderline personality disorder. Lancet (London, England). 2011;377(9759):74–84.CrossRefGoogle Scholar
  2. 2.
    National Health and Medical Research Council. Clinical practice guideline for the management of borderline personality disorder. Melbourne: National Health and Medical Research Council; 2012.Google Scholar
  3. 3.
    van den Bosch LM, Sinnaeve R, Hakkaart-van Roijen L, van Furth EF. Efficacy and cost-effectiveness of an experimental short-term inpatient dialectical behavior therapy (DBT) program: study protocol for a randomized controlled trial. Trials. 2014;15(1):1–9.CrossRefGoogle Scholar
  4. 4.
    Barnicot K, Katsakou C, Marougka S, Priebe S. Treatment completion in psychotherapy for borderline personality disorder—a systematic review and meta-analysis. Acta Psychiatrica Scandinavica. 2011;123(5):327–38.CrossRefPubMedGoogle Scholar
  5. 5.
    Owen RR, Drummond KL, Viverito KM, Marchant K, Pope SK, Smith JL, et al. Monitoring and managing metabolic effects of antipsychotics: a cluster randomized trial of an intervention combining evidence-based quality improvement and external facilitation. Implement Sci IS. 2013;8(8):120.CrossRefPubMedGoogle Scholar
  6. 6.
    Abosi O, Lopes S, Schmitz S, Fiedorowicz JG. Cardiometabolic effects of psychotropic medications. Horm Mol Biol Clin Investig. 2018. Scholar
  7. 7.
    Commonwealth of Australia. Clinical practice guideline for the management of borderline personality disorder. In: Council NHaMR, editor. Canberra: NHMRC; 2012.Google Scholar
  8. 8.
    Lieb K, Vollm B, Rucker G, Timmer A, Stoffers JM. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J Psychiatry J Ment Sci. 2010;196(1):4–12.CrossRefGoogle Scholar
  9. 9.
    Grosjean B, Tsai GE. NMDA neurotransmission as a critical mediator of borderline personality disorder. J Psychiatry Neurosci. 2007;32(2):103.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Battle CL, Shea MT, Johnson DM, Yen S, Zlotnick C, Zanarini MC, et al. Childhood maltreatment associated with adult personality disorders: findings from a Collaborative Longitudinal Personality Disorders Study. J Personal Disord. 2004;18(2):193–211.CrossRefGoogle Scholar
  11. 11.
    Stern A. Psychoanalytic investigation and therapy in the borderline group of neuroses. Psychoanal Q. 1938;7:467–89.Google Scholar
  12. 12.
    Fonagy P, Target M, Gergely G. Attachment and borderline personality disorder: a theory and some evidence. Psychiatr Clin N Am. 2000;23(1):103–22.CrossRefGoogle Scholar
  13. 13.
    Zanarini MC, Williams AA, Lewis RE, Reich RB. Reported pathological childhood experiences associated with the development of borderline personality disorder. Am J Psychiatry. 1997;154(8):1101.CrossRefPubMedGoogle Scholar
  14. 14.
    Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2012;13(1):22–37.CrossRefGoogle Scholar
  15. 15.
    Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5(2):160–70.CrossRefPubMedGoogle Scholar
  16. 16.
    La Spada AR. Memantine strikes the perfect balance. Nat Med. 2009;15(12):1355–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 2000;57:925–35.CrossRefPubMedGoogle Scholar
  18. 18.
    Driessen MHJ, Stahl K, et al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch Gen Psychiatry. 2000;57:1115–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Gereau RW, Swanson G. The glutamate receptors. Berlin: Springer Science and Business Media; 2008.CrossRefGoogle Scholar
  20. 20.
    Nakamura T, Lipton SA. Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: possible pharmacological strategies. Cell Calcium. 2010;47(2):190–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984–97.CrossRefPubMedGoogle Scholar
  22. 22.
    Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cognit Sci. 2000;4(6):215–22.CrossRefGoogle Scholar
  23. 23.
    Hoerst M, Weber-Fahr W, Tunc-Skarka N, et al. Correlation of glutamate levels in the anterior cingulate cortex with self-reported impulsivity in patients with borderline personality disorder and healthy controls. Arch Gen Psychiatry. 2010;67(9):946–54.CrossRefPubMedGoogle Scholar
  24. 24.
    Pittenger C, Krystal JH, Coric V. Initial evidence of the beneficial effects of glutamate-modulating agents in the treatment of self-injurious behavior associated with borderline personality disorder. J Clin Psychiatry. 2005;66(11):1492.CrossRefPubMedGoogle Scholar
  25. 25.
    Muehlmann AM, Devine DP. Glutamate-mediated neuroplasticity in an animal model of self-injurious behaviour. Behav Brain Res. 2008;189(1):32–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Rammes G, Danysz W, Parsons CG. Pharmacodynamics of memantine. Curr Neuropharmacol. 2008;6(1):55–78.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gilling KE, Jatzke C, Hechenberger M, Parsons CG. Potency, voltage-dependency, agonist concentration-dependency, blocking kinetics and partial untrapping of the uncompetitive N-methyl-d-aspartate (NMDA) channel blocker memantine at human NMDA (GluN1/GluN2A) receptors. Neuropharmacology. 2009;56(5):866–75.CrossRefPubMedGoogle Scholar
  29. 29.
    Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev. 2003;9(3):275–308.CrossRefPubMedGoogle Scholar
  30. 30.
    Koukopoulos A, Serra G, Koukopoulos AE, Reginaldi D, Serra G. The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: findings from a 12-month naturalistic trial. J Affect Disord. 2012;136(1):163–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Glasgow NG, Povysheva NV, Azofeifa AM, Johnson JW. Memantine and ketamine differentially alter NMDA receptor desensitization. J Neurosci Off J Soc Neurosci. 2017;37(40):9686–704. Scholar
  32. 32.
    Amin SN, El-Aidi AA, Ali MM, Attia YM, Rashed LA. Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress. Neuromol Med. 2015;17(2):121–36.CrossRefGoogle Scholar
  33. 33.
    Battista MA, Hierholzer R, Khouzam HR, Barlow A, O’Toole S. Pilot trial of memantine in the treatment of posttraumatic stress disorder. Psychiatry. 2007;70(2):167–74.CrossRefPubMedGoogle Scholar
  34. 34.
    Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PloS One. 2015;10(4):e0123289.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kishi T, Matsunaga S, Iwata N. The effects of memantine on behavioral disturbances in patients with Alzheimer’s disease: a meta-analysis. Neuropsychiatr Dis Treat. 2017;13:1909–28.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zanarini MC. Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD): a continuous measure of DSM-IV borderline psychopathology. J Personal Disord. 2003;17(3):233–42.CrossRefGoogle Scholar
  37. 37.
    West SG, Finch JF, Curran PJ. Structural equation models with non normal variables: problems and remedies. In: Hoyle RH, editor. Structural equation modelling: concepts, issues, and applications. Thousand Oaks: SAGE; 1995. p. 56–75.Google Scholar
  38. 38.
    Bollen K, Curran P. Latent curve models: a structural equation perspective. Hoboken: Wiley; 2006.Google Scholar
  39. 39.
    Zeger SL, Liang K-Y, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44:1049–60.CrossRefPubMedGoogle Scholar
  40. 40.
    Hu LT, Bentler PM. Fit indices in covariance structure modelling: Sensitivity to under parameterized model misspecification. Psychol Methods. 1998;3:424.CrossRefGoogle Scholar
  41. 41.
    Ramaswamy S, Madabushi J, Hunziker J, Bhatia SC, Petty F. An open-label trial of memantine for cognitive impairment in patients with posttraumatic stress disorder. J Aging Res. 2015;2015:934162.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kishi T MS, Oya K, Nomura I, Ikuta T, Iwata N. Memantine for Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis. 2017;60(2):401–25.CrossRefPubMedGoogle Scholar
  43. 43.
    Koukopoulos A, Serra G, Koukopoulos AE, Reginaldi D, Serra G. The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: findings from a 12-month naturalistic trial. J Affect Disord. 2012;136(1–2):163–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Keck PE, Hsu HA, Papadakis K, Russo J. Memantine efficacy and safety in patients with acute mania associated with bipolar I disorder: a pilot evaluation. Clin Neuropharmacol. 2009;32:199–204.CrossRefPubMedGoogle Scholar
  45. 45.
    Anand A, Gunn AD, Barkay G, Karne HS, Nurnberger JI, Mathew SJ, Ghosh S. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord Bipolar Disord. 2012;14:64–70.CrossRefPubMedGoogle Scholar
  46. 46.
    Noetzli M, Guidi M, Ebbing K, Eyer S, Wilhelm L, Michon A, et al. Population pharmacokinetic study of memantine: effects of clinical and genetic factors. Clin Pharmacokinet. 2013;52(3):211–23.CrossRefPubMedGoogle Scholar
  47. 47.
    Forest Laboratories I. Memantine HCI (NDA 21-487) briefing document. Food and Drug Administration Peripheral and Central Nervous System Drugs Advisory Committee; 2003.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Monash Alfred Psychiatry Research Centre, Central Clinical SchoolMonash University and The Alfred HospitalMelbourneAustralia

Personalised recommendations