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Adjunctive memantine for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials

Published online by Cambridge University Press:  22 May 2017

W. Zheng ,
X-H. Li ,
X-H. Yang ,
D-B. Cai ,
G. S. Ungvari ,
C. H. Ng ,
S-B. Wang ,
Y-Y. Wang ,
Y-P. Ning  and
Y-T. Xiang
W. Zheng
Affiliation:
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
X-H. Li
Affiliation:
The National Clinical Research Center for Mental Disorders, China Center of Depression, Beijing Institute for Brain Disorders & Mood Disorders Center, Beijing Anding Hospital, Capital Medical University, Beijing, China
X-H. Yang
Affiliation:
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
D-B. Cai
Affiliation:
Clinics of Chinese Medicine, the First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
G. S. Ungvari
Affiliation:
The University of Notre Dame Australia/Marian Centre, Perth, Australia School of Psychiatry & Clinical Neurosciences, University of Western Australia, Perth, Australia
C. H. Ng
Affiliation:
Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
S-B. Wang
Affiliation:
Faculty of Health Sciences, Unit of Psychiatry, University of Macau, Macao SAR, China
Y-Y. Wang
Affiliation:
Faculty of Health Sciences, Unit of Psychiatry, University of Macau, Macao SAR, China
Y-P. Ning*
Affiliation:
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
Y-T. Xiang*
Affiliation:
Faculty of Health Sciences, Unit of Psychiatry, University of Macau, Macao SAR, China
*
*Address for correspondence: Dr Y-T. Xiang, M.D., Ph.D., Faculty of Health Sciences, University of Macau, Avenida da Universidade, 3/F, Building E12, Taipa, Macau SAR, China. (Email: xyutly@gmail.com) Or Dr Y-P. Ning, M.D., Ph.D., The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China. (Email: ningjeny@126.com)
*Address for correspondence: Dr Y-T. Xiang, M.D., Ph.D., Faculty of Health Sciences, University of Macau, Avenida da Universidade, 3/F, Building E12, Taipa, Macau SAR, China. (Email: xyutly@gmail.com) Or Dr Y-P. Ning, M.D., Ph.D., The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China. (Email: ningjeny@126.com)
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Abstract

Background

Dysfunction of N-methyl-D-aspartate receptor (NMDAR) is involved in the pathophysiology of schizophrenia. A meta-analysis of randomized controlled trials (RCTs) was conducted to examine the efficacy and safety of memantine, a non-competitive NMDAR antagonist, in the treatment of schizophrenia.

Methods

Standardized/weighted mean differences (SMDs/WMDs), risk ratio (RR), and their 95% confidence intervals (CIs) were calculated and analyzed.

Results

Included in the meta-analysis were eight RCTs (n = 452) of 11.5 ± 2.6 weeks duration, with 229 patients on memantine (20 mg/day) and 223 patients on placebo. Adjunctive memantine outperformed placebo in the measures of Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale negative symptoms [SMD: −0.63 (95% CI −1.10 to −0.16), p = 0.009, I2 = 77%], but not in the total, positive and general symptoms [SMD: −0.46 to −0.08 (95% CI −0.93 to 0.22), p = 0.06–0.60, I2 = 0–74%] or the Clinical Global Impression Severity Scale [WMD: 0.04 (95% CI −0.24 to 0.32), p = 0.78]. The negative symptoms remained significant after excluding one outlying RCT [SMD: −0.41 (95% CI −0.72 to −0.11), p = 0.008, I2 = 47%]. Compared with the placebo group, adjunctive memantine was associated with significant improvement in neurocognitive function using the Mini-Mental State Examination (MMSE) [WMD: 3.09, (95% CI 1.77–4.42), p < 0.00001, I2 = 22%]. There was no significant difference in the discontinuation rate [RR: 1.34 (95% CI 0.76–2.37), p = 0.31, I2 = 0%] and adverse drug reactions between the two groups.

Conclusions

This meta-analysis showed that adjunctive memantine appears to be an efficacious and safe treatment for improving negative symptoms and neurocognitive performance in schizophrenia. Higher quality RCTs with larger samples are warranted to confirm these findings.

Keywords

Memantinemeta-analysisnegative symptomsNMDA receptor antagonistsschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 1 , January 2018 , pp. 72 - 81
Copyright
Copyright © Cambridge University Press 2017 

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Footnotes

†

These authors contributed equally to this work.

References

Atkins, D, Best, D, Briss, PA, Eccles, M, Falck-Ytter, Y, Flottorp, S, Guyatt, GH, Harbour, RT, Haugh, MC, Henry, D, Hill, S, Jaeschke, R, Leng, G, Liberati, A, Magrini, N, Mason, J, Middleton, P, Mrukowicz, J, O'Connell, D, Oxman, AD, Phillips, B, Schunemann, HJ, Edejer, T, Varonen, H, Vist, GE, Williams, JW Jr., Zaza, S (2004). Grading quality of evidence and strength of recommendations. British Medical Journal 328, 1490.Google ScholarPubMed
Balshem, H, Helfand, M, Schunemann, HJ, Oxman, AD, Kunz, R, Brozek, J, Vist, GE, Falck-Ytter, Y, Meerpohl, J, Norris, S, Guyatt, GH (2011). GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 64, 401–406.CrossRefGoogle ScholarPubMed
Carroll, BT, Goforth, HW, Thomas, C, Ahuja, N, McDaniel, WW, Kraus, MF, Spiegel, DR, Franco, KN, Pozuelo, L, Munoz, C (2007). Review of adjunctive glutamate antagonist therapy in the treatment of catatonic syndromes. Journal of Neuropsychiatry and Clinical Neurosciences 19, 406–412.Google Scholar
de Lucena, D, Fernandes, BS, Berk, M, Dodd, S, Medeiros, DW, Pedrini, M, Kunz, M, Gomes, FA, Giglio, LF, Lobato, MI, Belmonte-de-Abreu, PS, Gama, CS (2009). 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. Journal of Clinical Psychiatry 70, 1416–1423.Google Scholar
DerSimonian, R, Laird, N (1986). Meta-analysis in clinical trials. Controlled Clinical Trials 7, 177–188.Google Scholar
Egger, M, Davey Smith, G, Schneider, M, Minder, C (1997). Bias in meta-analysis detected by a simple, graphical test. British Medical Journal 315, 629–634.Google Scholar
Field, JR, Walker, AG, Conn, PJ (2011). Targeting glutamate synapses in schizophrenia. Trends in Molecular Medicine 17, 689–698.Google Scholar
Folstein, MF, Folstein, SE, McHugh, PR (1975). ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 12, 189–198.CrossRefGoogle Scholar
Gama, CS, Andreazza, AC, Kunz, M, Berk, M, Belmonte-de-Abreu, PS, Kapczinski, F (2007). Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder. Neuroscience Letters 420, 45–48.Google Scholar
Gama, CS, Antunes, P, Moser, C, Belmonte-de-Abreu, PS (2005). Memantine as an adjunctive therapy for schizophrenia negative symptoms. Revista Brasileira de Psiquiatria 27, 257–258.Google Scholar
Gu, J, Wu, Y, Tang, L (2012). A controlled study of clozapine plus memantine in schizophrenia negative symptoms [In Chinese]. Journal of Clinical Psychiatry 22, 261–263.Google Scholar
Guy, W (1976). Clinical global impressions. In ECDEU Assessment Manual for Psychopharmacology (Revised) (ed. Guy, W.), pp. 217–221. National Institute of Mental Health: Rockville.Google Scholar
Higgins, J, Higgins, J (2008). Cochrane Handbook for Systematic Reviews of Interventions. J. Wiley & Sons: Chichester, UK.CrossRefGoogle Scholar
Jadad, AR, Moore, RA, Carroll, D, Jenkinson, C, Reynolds, DJ, Gavaghan, DJ, McQuay, HJ (1996). Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 17, 1–12.Google Scholar
John, JP, Lukose, A, Manjunath, S (2014). Off-label use of memantine as adjunctive treatment in schizophrenia: a retrospective case series study. Pharmacopsychiatry 47, 202–209.Google Scholar
Kay, SR, Fiszbein, A, Opler, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276.Google Scholar
Kishi, T, Iwata, N (2013). NMDA receptor antagonists interventions in schizophrenia: meta-analysis of randomized, placebo-controlled trials. Journal of Psychiatric Research 47, 1143–1149.Google Scholar
Koch, HJ, Uyanik, G, Fischer-Barnicol, D (2005). Memantine: a therapeutic approach in treating Alzheimer's and vascular dementia. Current Drug Targets CNS and Neurological Disorders 4, 499–506.CrossRefGoogle ScholarPubMed
Krivoy, A, Weizman, A, Laor, L, Hellinger, N, Zemishlany, Z, Fischel, T (2008). Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: a preliminary study. European Neuropsychopharmacology 18, 117–121.Google Scholar
Lee, JG, Lee, SW, Lee, BJ, Park, SW, Kim, GM, Kim, YH (2012). Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. Psychiatry Investigation 9, 166–173.Google Scholar
Lelorier, J, Grégoire, G, Benhaddad, A, Lapierre, J, Derderian, F (1997). Discrepancies between meta-analyses and subsequent large randomized, controlled trials. New England Journal of Medicine 337, 536–542.Google Scholar
Leucht, S, Cipriani, A, Spineli, L, Mavridis, D, Orey, D, Richter, F, Samara, M, Barbui, C, Engel, RR, Geddes, JR, Kissling, W, Stapf, MP, Lassig, B, Salanti, G, Davis, JM (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962.Google Scholar
Leucht, S, Corves, C, Arbter, D, Engel, RR, Li, C, Davis, JM (2009 a). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41.Google Scholar
Leucht, S, Komossa, K, Rummel-Kluge, C, Corves, C, Hunger, H, Schmid, F, Asenjo Lobos, C, Schwarz, S, Davis, JM (2009 b). A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. American Journal of Psychiatry 166, 152–163.CrossRefGoogle ScholarPubMed
Lieberman, JA, Papadakis, K, Csernansky, J, Litman, R, Volavka, J, Jia, XD, Gage, A (2009). A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 34, 1322–1329.Google Scholar
Lipton, SA (2004). Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders. Journal of Alzheimers Disease 6, S61–S74.Google Scholar
Marder, SR, Fenton, W (2004). Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophrenia Research 72, 5–9.CrossRefGoogle ScholarPubMed
Matsuda, Y, Kishi, T, Iwata, N (2013). Efficacy and safety of NMDA receptor antagonists augmentation therapy for schizophrenia: an updated meta-analysis of randomized placebo-controlled trials. Journal of Psychiatric Research 47, 2018–2020.Google Scholar
Mazinani, R, Nejati, S, Khodaei, M (2016). Effects of memantine added to risperidone on the symptoms of schizophrenia: a randomized double-blind, placebo-controlled clinical trial. Psychiatry Research 247, 291–295.Google Scholar
Moghaddam, B, Javitt, D (2012). From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 4–15.Google Scholar
Moher, D, Liberati, A, Tetzlaff, J, Altman, DG (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine 151, 264–269, W64.CrossRefGoogle ScholarPubMed
Omranifard, V, Rajabi, F, Mohammadian-Sichani, M, Maracy, M (2015). The effect of add-on memantine on global function and quality of life in schizophrenia: a randomized, double-blind, controlled, clinical trial. Advanced Biomedical Research 4, 2277–9175.Google ScholarPubMed
Overall, JE, Gorham, DR (1962). The brief psychiatric rating-scale. Psychological Reports 10, 799–812.Google Scholar
Pieta Dias, C, Martins de Lima, MN, Presti-Torres, J, Dornelles, A, Garcia, VA, Siciliani Scalco, F, Rewsaat Guimaraes, M, Constantino, L, Budni, P, Dal-Pizzol, F, Schroder, N (2007). Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats. Neuroscience 146, 1719–1725.Google Scholar
Puangthong, U, Hsiung, GYR (2009). Critical appraisal of the long-term impact of memantine in treatment of moderate to severe Alzheimer's disease. Neuropsychiatric Disease and Treatment 5, 553–561.Google Scholar
Rezaei, F, Mohammad-Karimi, M, Seddighi, S, Modabbernia, A, Ashrafi, M, Salehi, B, Hammidi, S, Motasami, H, Hajiaghaee, R, Tabrizi, M, Akhondzadeh, S (2013). 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 33, 336–342.Google Scholar
Singh, SP, Singh, V (2011). Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs 25, 859–885.CrossRefGoogle ScholarPubMed
Sterne, JA, Sutton, AJ, Ioannidis, JP, Terrin, N, Jones, DR, Lau, J, Carpenter, J, Rucker, G, Harbord, RM, Schmid, CH, Tetzlaff, J, Deeks, JJ, Peters, J, Macaskill, P, Schwarzer, G, Duval, S, Altman, DG, Moher, D, Higgins, JP (2011). Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. British Medical Journal 343, d4002.Google Scholar
Tsai, G, Coyle, JT (2002). Glutamatergic mechanisms in schizophrenia. Annual Review of Pharmacology and Toxicology 42, 165–179.CrossRefGoogle ScholarPubMed
Tsai, GE, Lin, PY (2010). Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Current Pharmaceutical Design 16, 522–537.CrossRefGoogle ScholarPubMed
Veerman, SR, Schulte, PF, Smith, JD, de Haan, L (2016). Memantine augmentation in clozapine-refractory schizophrenia: a randomized, double-blind, placebo-controlled crossover study. Psychological Medicine 46, 1909–1921.Google Scholar
Wu, EQ, Birnbaum, HG, Shi, L, Ball, DE, Kessler, RC, Moulis, M, Aggarwal, J (2005). The economic burden of schizophrenia in the United States in 2002. Journal of Clinical Psychiatry 66, 1122–1129.Google Scholar
Xiang, YQ, Zheng, W, Wang, SB, Yang, XH, Cai, DB, Ng, CH, Ungvari, GS, Kelly, DL, Xu, WY, Xiang, YT (2017). Adjunctive minocycline for schizophrenia: a meta-analysis of randomized controlled trials. European Neuropsychopharmacology 27, 8–18.Google Scholar
Zdanys, K, Tampi, RR (2008). A systematic review of off-label uses of memantine for psychiatric disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32, 1362–1374.Google Scholar
Zheng, W, Li, Q, Lin, JX, Xiang, YQ, Guo, T, Chen, Q, Cai, DB, Xiang, YT (2016 a). Tai Chi for schizophrenia: a systematic review. Shanghai Archives of Psychiatry 28, 185–194.Google Scholar
Zheng, W, Wang, SB, Ungvari, GS, Ng, CH, Yang, XH, Gu, YH, Li, M, Xiang, YQ, Xiang, YT (2017). Amantadine for antipsychotic-related weight Gain: meta-analysis of randomized placebo-controlled trials. Journal of Clinical Psychopharmacology 37, 341–346.Google Scholar
Zheng, W, Xiang, YT, Xiang, YQ, Li, XB, Ungvari, GS, Chiu, HF, Correll, CU (2016 b). Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatrica Scandinavica 134, 385–398.CrossRefGoogle ScholarPubMed
Zheng, W, Zheng, YJ, Li, XB, Tang, YL, Wang, CY, Xiang, YQ, de Leon, J (2016 c). Efficacy and safety of adjunctive aripiprazole in schizophrenia: meta-analysis of randomized controlled trials. Journal of Clinical Psychopharmacology 36, 628–636.Google Scholar
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