Original Article

The Effect of Memantine Versus Folic Acid on Cognitive Impairment in Patients with Schizophrenia: A Randomized Clinical Trial

Abstract

Objective: Schizophrenia, as one of the most severe psychiatric diseases, has a chronic and debilitating process. The majority of patients with schizophrenia do not respond adequately to treatment with common antipsychotic drugs. Therapeutic problems induced by drug side effects as well as undesired results are major challenging issues regarding this disease. This study aimed at evaluating the effect of memantine supplementation on the improvement of cognitive symptoms in patients with schizophrenia.

Method: The present clinical trial was performed on 50 patients with acute schizophrenia who were admitted to Kargarnejad Psychiatric Hospital in Kashan in 2022 and who were diagnosed as schizophrenia cases at least three months ago. Patients were randomly divided into either the intervention group (n = 25) or the placebo group (n = 25). The intervention group received 5 mg of memantine per day for three months. The dose of memantine in this group was increased to the maximum of 20 mg per day. The placebo group received 1 mg of folic acid per day for three months. Moreover, an identical routine schizophrenia therapeutic regimen was administered to all patients. The effectiveness of memantine was evaluated using the Wechsler Adult Intelligence Scale (WAIS-III), which assessed cognitive ability in older adults over a 12-week follow-up period.

Results: The WAIS-III score in the 12th week of the study was significantly different between the placebo and intervention groups (P = 0.004), such that the score of the memantine group was higher than that of the placebo group. No significant difference was observed between the two groups in terms of drug side effects.

Conclusion: Memantine can be supplemented in the treatment of schizophrenia so as to improve the cognitive symptoms of this disorder. However, subsequent studies involving larger sample sizes and different doses seem to be necessary to provide more accurate results in this respect.

1. Di Iorio G, Baroni G, Lorusso M, Montemitro C, Spano MC, di Giannantonio M. Efficacy of Memantine in Schizophrenic Patients: A Systematic Review. J Amino Acids. 2017;2017:7021071.
2. Czarnecka K, Chuchmacz J, Wójtowicz P, Szymański P. Memantine in neurological disorders - schizophrenia and depression. J Mol Med (Berl). 2021;99(3):327-34.
3. van Os J, Kenis G, Rutten BP. The environment and schizophrenia. Nature. 2010;468(7321):203-12.
4. Castle D, Wessely S, Der G, Murray RM. The incidence of operationally defined schizophrenia in Camberwell, 1965-84. Br J Psychiatry. 1991;159:790-4.
5. Martel JC, Gatti McArthur S. Dopamine receptor subtypes, physiology and pharmacology: new ligands and concepts in schizophrenia. Front Pharmacol. 2020;11:1003.
6. Gaebel W, Stricker J, Riesbeck M. The long-term antipsychotic treatment of schizophrenia: A selective review of clinical guidelines and clinical case examples. Schizophr Res. 2020;225(6):4-14.
7. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative Efficacy and Tolerability of 32 Oral Antipsychotics for the Acute Treatment of Adults With Multi-Episode Schizophrenia: A Systematic Review and Network Meta-Analysis. Focus (Am Psychiatr Publ). 2020;18(4):443-55.
8. Yang AC, Tsai SJ. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int J Mol Sci. 2017;18(8):1689.
9. Balu DT. The NMDA receptor and schizophrenia: from pathophysiology to treatment. Adv Pharmacol. 2016;76:351-82.
10. Pagano J, Giona F, Beretta S, Verpelli C, Sala C. N-methyl-d-aspartate receptor function in neuronal and synaptic development and signaling. Curr Opin Pharmacol. 2021;56:93-101.
11. McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020;19(1):15-33.
12. Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020;205:107426.
13. Plitman E, Nakajima S, de la Fuente-Sandoval C, Gerretsen P, Chakravarty MM, Kobylianskii J, et al. Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol. 2014;24(10):1591-605.
14. Kikuchi T. Is Memantine Effective as an NMDA-Receptor Antagonist in Adjunctive Therapy for Schizophrenia? Biomolecules. 2020;10(8):1134.
15. de Bartolomeis A, Sarappa C, Buonaguro EF, Marmo F, Eramo A, Tomasetti C, et al. Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:1-12.
16. Parsons CG, Stöffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse. Neuropharmacology. 2007;53(6):699-723.
17. Danysz W, Parsons CG. Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. Br J Pharmacol. 2012;167(2):324-52.
18. Alam S, Lingenfelter KS, Bender AM, Lindsley CW. Classics in Chemical Neuroscience: Memantine. ACS Chem Neurosci. 2017;8(9):1823-9.
19. John JP, Lukose A, Manjunath S. Off-label use of memantine as adjunctive treatment in schizophrenia: a retrospective case series study. Pharmacopsychiatry. 2014;47(6):202-9.
20. Lee JG, Lee SW, Lee BJ, Park SW, Kim GM, Kim YH. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. Psychiatry Investig. 2012;9(2):166-73.
21. Kishi T, Matsuda Y, Iwata N. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis. Psychopharmacology (Berl). 2017;234(14):2113-25.
22. Roffman JL, Lamberti JS, Achtyes E, Macklin EA, Galendez GC, Raeke LH, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70(5):481-9.
23. Wechsler D. Wechsler Memory Scale Revised. Psychological Corp.: Harcourt Brace Jovanovich, 1987.
24. Movahedi Y, Khodadadi M, Mohammadzadegan R. A Comparison of Neuropsychological Functioning and Theory of Mind in People with Symptoms of Obsessive-Compulsive Disorder and in Normal People. J Cogn Psychol. 2014;2(3):29-36.
25. Mazinani R, Nejati S, Khodaei M. Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial. Psychiatry Res. 2017;247:291-5.
26. Kishi T, Iwata N. NMDA receptor antagonists interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled trials. J Psychiatr Res. 2013;47(9):1143-9.
27. de Bartolomeis A, Barone A, Vellucci L, Mazza B, Austin MC, Iasevoli F, et al. Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review. Mol Neurobiol. 2022;59(10):6460-501.
28. Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73(5):204-15.
29. Stansley BJ, Conn PJ. The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia. Curr Opin Pharmacol. 2018;38:31-6.
30. Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK. Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA psychiat. 2016;73(7):665-74.
31. de Bartolomeis A, Sarappa C, Magara S, Iasevoli F. Targeting glutamate system for novel antipsychotic approaches: relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur J Pharmacol. 2012;682(1-3):1-11.
32. Benarroch EE. Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms. Neurology. 2018;91(3):125-32.
33. Stepanenko YD, Boikov SI, Sibarov DA, Abushik PA, Vanchakova NP, Belinskaia D, et al. Dual action of amitriptyline on NMDA receptors: enhancement of Ca-dependent desensitization and trapping channel block. Sci Rep. 2019;9(1):19454.
34. Kulkarni J, Thomas N, Hudaib AR, Gavrilidis E, Grigg J, Tan R, et al. Effect of the Glutamate NMDA Receptor Antagonist Memantine as Adjunctive Treatment in Borderline Personality Disorder: An Exploratory, Randomised, Double-Blind, Placebo-Controlled Trial. CNS Drugs. 2018;32(2):179-87.
35. 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.
36. 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.
37. Lisoway AJ, Chen CC, Zai CC, Tiwari AK, Kennedy JL. Toward personalized medicine in schizophrenia: Genetics and epigenetics of antipsychotic treatment. Schizophr Res. 2021;232:112-24.
Files
IssueVol 18 No 3 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijps.v18i3.13002
Keywords
Cognitive Symptoms Folic Acid Memantine Schizophrenia

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Hosseini SA, Sepehrmanesh Z, Gilasi H, Ghoraishi‬FS. The Effect of Memantine Versus Folic Acid on Cognitive Impairment in Patients with Schizophrenia: A Randomized Clinical Trial. Iran J Psychiatry. 2023;18(3):258-265.