Off-label Use of Memantine as Adjunctive Treatment in Schizophrenia: A Retrospective Case Series Study

Abstract

Introduction: Memantine, an uncompetitive N-methyl D-aspartate receptor (NMDAR) open-channel blocker holds great promise for its potential clinical effectiveness as add-on therapy to on-going treatment with antipsychotics.

Methods: We report here the results of a chart review-based retrospective case series study that examined the effectiveness of off-label use of memantine in patients with schizophrenia when used as adjunctive therapy to standard neuroleptic therapy.

Results: 17 of the 26 patients, whose case files were reviewed using a study-specific proforma showed clinical improvement in positive and/or negative psychopathology as well as in cognitive and/or functional domains. The doses of on-going antipsychotic medications could be reduced in a sizeable number of responders. None of the subjects reported serious adverse events.

Discussion: Memantine holds great promise as adjunctive therapy for treatment of schizophrenia. Randomized controlled trials, wherein memantine is administered at adequate doses for an adequate period of time to ongoing antipsychotic treatment are required to confirm its efficacy in alleviating symptoms of schizophrenia.

Key words

augmentation therapy - add-on treatment - NMDAR open-channel blocker - glutamatergic hypothesis - neuroprotection

• References

• 1 Carlsson A, Waters N, Waters S et al. Network interactions in schizophrenia – therapeutic implications. Brain research Brain research reviews 2000; 31: 342-349
• 2 Duncan GE, Zorn S, Lieberman JA. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Molecular psychiatry 1999; 4: 418-428
• 3 Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. International review of neurobiology 2007; 78: 69-108
• 4 Gunduz-Bruce H. The acute effects of NMDA antagonism: from the rodent to the human brain. Brain research reviews 2009; 60: 279-286
• 5 Lindsley CW, Shipe WD, Wolkenberg SE et al. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Current topics in medicinal chemistry 2006; 6: 771-785
• 6 Krystal JH, Karper LP, Seibyl JP et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of general psychiatry 1994; 51: 199-214
• 7 Malhotra AK, Pinals DA, Weingartner H et al. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 1996; 14: 301-307
• 8 Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature reviews Drug discovery 2006; 5: 160-170
• 9 Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. Journal of neurochemistry 2006; 97: 1611-1626
• 10 Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx: the journal of the American Society for Experimental NeuroTherapeutics 2004; 1: 101-110
• 11 Xia P, Chen HS, Zhang D et al. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. The Journal of neuroscience: the official journal of the Society for Neuroscience 2010; 30: 11246-11250
• 12 Rands GS. Memantine as a neuroprotective treatment in schizophrenia. The British journal of psychiatry: the journal of mental science 2005; 186: 77 author reply -8
• 13 Carpenter SS, Hatchett AD, Fuller MA. Catatonic schizophrenia and the use of memantine. The Annals of pharmacotherapy 2006; 40: 344-346
• 14 Thomas C, Carroll BT, Maley RT et al. Memantine and catatonic schizophrenia. The American journal of psychiatry 2005; 162: 626
• 15 Sleeper RB. Antipsychotic dose-sparing effect with addition of memantine. The Annals of pharmacotherapy 2005; 39: 1573-1576
• 16 Ponde MP, Novaes CM. Aripiprazole worsening positive symptoms and memantine reducing negative symptoms in a patient with paranoid schizophrenia. Rev Bras Psiquiatr 2007; 29: 92
• 17 Krivoy A, Weizman A, Laor L et al. Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: A preliminary study. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 2008; 18: 117-121
• 18 Rezaei F, Mohammad-Karimi M, Seddighi S et al. Memantine add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-blind, placebo-controlled study. Journal of clinical psychopharmacology 2013; 33: 336-342
• 19 Lieberman JA, Papadakis K, Csernansky J et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 2009; 34: 1322-1329
• 20 Lee JG, Lee SW, Lee BJ et al. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. Psychiatry investigation 2012; 9: 166-173
• 21 de Lucena D, Fernandes BS, Berk M et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. The Journal of clinical psychiatry 2009; 70: 1416-1423
• 22 Matsuda Y, Kishi T, Iwata N. Efficacy and safety of NMDA receptor antagonists augmentation therapy for schizophrenia: An updated meta-analysis of randomized placebo-controlled trials. Journal of psychiatric research. 2013
• 23 Cerullo MA, Adler CM, Strakowski SM et al. Memantine normalizes brain activity in the inferior frontal gyrus: a controlled pilot fMRI study. Schizophrenia research 2007; 97: 294-296
• 24 Surman CB, Hammerness PG, Petty C et al. A pilot open label prospective study of memantine monotherapy in adults with ADHD. The world journal of biological psychiatry: the official journal of the World Federation of Societies of Biological Psychiatry 2013; 14: 291-298
• 25 Zdanys K, Tampi RR. A systematic review of off-label uses of memantine for psychiatric disorders. Progress in neuro-psychopharmacology & biological psychiatry 2008; 32: 1362-1374
• 26 Sani G, Serra G, Kotzalidis GD et al. The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence. CNS drugs 2012; 26: 663-690
• 27 Stafford RS. Regulating off-label drug use – rethinking the role of the FDA. The New England journal of medicine 2008; 358: 1427-1429
• 28 Mello MM, Studdert DM, Brennan TA. Shifting terrain in the regulation of off-label promotion of pharmaceuticals. The New England journal of medicine 2009; 360: 1557-1566
• 29 Walton SM, Schumock GT, Lee KV et al. Prioritizing future research on off-label prescribing: results of a quantitative evaluation. Pharmacotherapy 2008; 28: 1443-1452
• 30 Tsutsumi C, Uchida H, Suzuki T et al. The evolution of antipsychotic switch and polypharmacy in natural practice – a longitudinal perspective. Schizophrenia research 2011; 130: 40-46
• 31 Marcus MM, Jardemark K, Malmerfelt A et al. Augmentation by escitalopram, but not citalopram or R-citalopram, of the effects of low-dose risperidone: behavioral, biochemical, and electrophysiological evidence. Synapse 2012; 66: 277-290
• 32 Porcelli S, Balzarro B, Serretti A. Clozapine resistance: augmentation strategies. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 2012; 22: 165-182
• 33 Tiihonen J, Hallikainen T, Ryynanen OP et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biological psychiatry 2003; 54: 1241-1248
• 34 Gama CS, Antunes P, Moser C et al. Memantine as an adjunctive therapy for schizophrenia negative symptoms. Rev Bras Psiquiatr 2005; 27: 257-258
• 35 John JP, Halahalli HN. Role of aberrant glutamatergic neurotransmission in psychiatric disorders: Focus on schizophrenia. In: Avasthi A. ed. Neurobiology of Psychiatric Disorders. Jaipur: Indian Psychiatric Society publication; 2010: 11-31
• 36 Lewis DA, Moghaddam B. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Archives of neurology 2006; 63: 1372-1376
• 37 Uhlhaas PJ, Haenschel C, Nikolic D et al. The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophrenia bulletin 2008; 34: 927-943
• 38 Correll CU, Kishimoto T, Kane JM. Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives. Dialogues in clinical neuroscience 2011; 13: 155-172