Memantine Enhances the Effect of Olanzapine in Patients With Schizophrenia: A Randomized, Placebo-Controlled Study
-
Ahmad Fakhri
,
Sirous Pakseresht
,
Mohammad Reza Haghdoost
,
Nasihat Hekmatkhah
,
Maria Torkashvand
,
Behnam Ghorbanzadeh
Abstract
Glutamate dysregulation may be involved in the neuropathology of schizophrenia. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a partial uncompetitive NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to olanzapine in patients with schizophrenia. In this double-blind, placebo-controlled studies, patients with schizophrenia according to DSM-IV clinical criteria were selected. Patients were randomly assigned to receive either memantine (week 1:10 mg/day; weeks 2-6:20 mg/day) plus olanzapine (15-20 mg/day) or olanzapine plus placebo. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. Results showed that memantine significantly improved the positive and negative PANSS score in patients maintained on olanzapine after six weeks compared to olanzapine alone (P<0.001). Furthermore, female patients showed significantly better response than males, especially in positive PANSS score. No significant changes in extrapyramidal symptoms were observed.These findings indicate that olanzapine efficacy might be augmented with memantine. Furthermore, this effect is more remarkable in female patients with schizophrenia.
Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 2004;11(3):313–27.
Toren P, Laor N, Weizman A. Use of atypical neuroleptics in child and adolescent psychiatry. J Clin Psychiatry 1998;59(12):644– 56.
Leucht S, Heres S, Kissling W, Davis JM. Evidence-based pharmacotherapy of schizophrenia. Int J Neuropsychopharmacol 2011;14(2):269–84.
Riedel M, Strassnig M, Schwarz MJ, Muller N. COX-2 inhibitors as adjunctive therapy in schizophrenia: rationale for use and evidence to date. CNS Drugs 2005;19(10):805–19.
Botts S, Hines H, Littrell R. Antipsychotic polypharmacy in the ambulatory care setting, 1993–2000. Psychiatr Serv 2003;54:1086.
Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002;88(2):199–214.
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 2003;169(3-4):215–33.
Meador-Woodruff JH, Healy DJ. Glutamate receptor expression in schizophrenic brain. Brain Res Rev 2000;31(2-3):288–94.
Lipton SA. Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurological disorders. J Alzheimer's Dis 2004;6(6 Suppl):61–74.
Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia Arch Gen Psychiatry 1995;52(12):998–1007.
Krivoy A, Weizman A, Laor L, Hellinger N, Zemishlany Z, Fischel T. Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: A preliminary study. Eur Neuropsychopharmacol 2008;18(2):117–21.
Parsons CG, Gilling K. Memantine as an example of a fast, voltage-dependent, open channel N-methyl-D-aspartate receptor blocker. Methods Mol Biol 2007;403:15–36.
Rands GS. Memantine as a neuroprotective treatment in schizophrenia. Br J Psychiatry 2005;186(77):77–8.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291(3):317–24.
Lieberman JA, Papadakis K, Csernansky J, Litman R, Volavka J, Jia XD, et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 2009;34(5):1322–9.
Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333–41.
Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res 1987;23(1):99–110.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9.
Freedman R. Schizophrenia. N Engl J Med 2003;349(18):1738-49.
Yang CR, Chen L. Targeting prefrontal cortical dopamine D1 and N-methyl-D-aspartate receptor interactions in schizophrenia treatment. Neuroscientist 2005;11(5):452–70.
Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, et al. D-Serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005;57(6):577–85.
Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007;27(43):11496–500.
De Bartolomeis A, Sarappa C, Magara S, Iasevoli F. Targeting glutamate systemfor novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol 2012;682(1-3):1-11.
Kotermanski SE, Wood JT, Johnson JW. Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol 2009;587(19):4589–604.
Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand Suppl 2000;401:3-38.
Palomero-Gallagher N, Bidmon HJ, Zilles K. AMPA, kainate, and NMDA receptor densities in the hippocampus of untreated male rats and females in estrus and diestrus. J Comp Neurol 2003;459(4):468-74.
Arbogast LA, Voogt JL. Sex-related alterations in hypothalamic tyrosine hydroxylase after neonatal monosodium glutamate treatment. Neuroendocrinology 1990;52(5):460-7.
Usall J, Suarez D, Haro JM. Gender differences in response to antipsychotic treatment in outpatients with schizophrenia. Psychiatry Res 2007;153(3):225-31.
| Files | ||
| Issue | Vol 54, No 11 (2016) | |
| Section | Articles | |
| Keywords | ||
| Memantine Schizophrenia Combination therapy Gender NMDA receptors | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
