Pharmacopsychiatry 2020; 53(01): 21-29
DOI: 10.1055/a-0970-9310
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Acute and Long-term Memantine Add-on Treatment to Risperidone Improves Cognitive Dysfunction in Patients with Acute and Chronic Schizophrenia

Martin Schaefer
1   Department of Psychiatry, Psychotherapy, Psychosomatics and Addiction Medicine, Kliniken Essen-Mitte, Essen, Germany
2   Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
,
Susanne Sarkar
2   Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
,
Ines Theophil
2   Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
,
Karolina Leopold
3   Department of Psychiatry and Psychotherapy, Wenckebachklinikum, Berlin, Germany
,
Andreas Heinz
2   Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
,
Jürgen Gallinat
2   Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany
4   Department of Psychiatry and Psychotherapy, Center of Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Germany
› Author Affiliations
Further Information

Publication History

received 09 November 2018
revised 25 June 2019

accepted 01 July 2019

Publication Date:
07 August 2019 (online)

Abstract

Introduction Patients with schizophrenia are mainly characterized by negative symptoms and cognitive dysfunction. In this proof-of-concept study we tested effects on cognition and negative symptoms of a 6- or 24-week memantine add-on treatment to risperidone in patients with acute or chronic schizophrenia.

Materials and Methods Patients with an acute episode of schizophrenia (n=11) and predominating positive symptoms were randomized to a 6-week add-on treatment with memantine (10 mg twice a day) versus placebo and patients with chronic schizophrenia (n=13) and negative symptoms were randomized to a 24-week add-on treatment with memantine (10 mg twice a day) versus placebo. All patients received antipsychotic medication with risperidone (2–8 mg/day). Psychopathological changes were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and after 2, 4, 6, 12, and 24 weeks. Cognitive function was measured at baseline, after 6 weeks, and 24 weeks.

Results Patients with acute schizophrenia who received add-on treatment with memantine showed a significantly higher performance in attention intensity (p=0.043), problem-solving (p=0.043), verbal learning (p=0.050), and flexibility (p=0.049). Patients with chronic schizophrenia showed a significantly higher immediate memory in the memantine group compared to the placebo group (p=0.033) and a significantly greater reduction of the PANSS sum score if compared to the placebo group.

Discussions Our study gives further evidence that memantine add-on treatment to risperidone may have neuroprotective effects and improve cognitive function in patients with schizophrenia. ClinicalTrials.gov Number: NCT00148590 and NCT00148616.

Supporting Information

 
  • References

  • 1 Reichenberg A, Harvey PD. Neuropsychological impairments in schizophrenia: Integration of performance-based and brain imaging findings. Psychol Bull 2007; 133: 833-858
  • 2 Schaefer J, Giangrande E, Weinberger DR. et al. The global cognitive impairment in schizophrenia: Consistent over decades and around the world. Schizophr Res 2013; 150: 42-50
  • 3 Barnes SA, Der-Avakian A, Markou A. Anhedonia, avolition, and anticipatory deficits: Assessments in animals with relevance to the negative symptoms of schizophrenia. Eur Neuropsychopharmacol 2014; 24: 744-758
  • 4 Elvevag B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev in Neurobiol 2000; 14: 1-21
  • 5 Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: Implications for MATRICS. Schizophr Res 2004; 72: 41-51
  • 6 Koola MM, Buchanan RW, Pillai A. et al. Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia. Schizophr Res 2014; 157: 84-89
  • 7 Vita A, De Peri L, Deste G. et al. Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry 2012; 2: e190
  • 8 Andreasen NC, Liu D, Ziebell S. et al. Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: A prospective longitudinal MRI study. Am J Psychiatry 2013; 170: 609-615
  • 9 Kubota M, van Haren NE, Haijma SV. et al. Association of IQ changes and progressive brain changes in patients with schizophrenia. JAMA Psychiatry 2015; 72: 803-812
  • 10 Moncrieff J, Leo J. A systematic review of the effects of antipsychotic drugs on brain volume. Psychol Med 2010; 40: 1409-1422
  • 11 Kremen WS, Seidman LJ, Faraone SV. et al. The paradox of normal neuropsychological function in schizophrenia. J Abnorm Psychol 2000; 109: 743-752
  • 12 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: 2113-2125
  • 13 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. J Psychiatr Res 2013; 47: 2018-2020
  • 14 Leucht S, Corves C, Arbter D. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet 2009; 373: 31-41
  • 15 Németh G, Laszlovszky I, Czobor P. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: A randomised, double-blind, controlled trial. Lancet 2017; 389: 1103-1113
  • 16 Bugarski-Kirola D, Blaettler T, Arango C. et al. Bitopertin in negative symptoms of schizophrenia – results from the Phase III FlashLyte and DayLyte studies. Biol Psychiatry 2017; 82: 8-16
  • 17 Anderson KK, Voineskos A, Mulsant BH. et al. The role of untreated psychosis in neurodegeneration: A review of hypothesized mechanisms of neurotoxicity in first-episode psychosis. Can J Psychiatr 2014; 59: 513-517
  • 18 Kochunov P, Hong LE. Neurodevelopmental and neurodegenerative models of schizophrenia: White matter at the center stage. Schizophr Bull 2014; 40: 721-728
  • 19 Genius J, Geiger J, Dölzer A. Glutamatergic dysbalance and oxidative stress in in vivo and in vitro models of psychosis based on chronic NMDA receptor antagonism. PLoS One 2013; 8: e59395
  • 20 Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: Implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997; 41: 135-144
  • 21 Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat Rev Drug Discov 2006; 5: 160-170
  • 22 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. J Clin Psychopharmacol 2013; 33: 336-342
  • 23 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders Text Revision. 4th ed Washington: American Psychiatric Press; 1994
  • 24 First MB, Williams Janet BW, Spitzer RL. et al. Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV). Washington: American Psychiatric Press; 1996
  • 25 Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276
  • 26 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62
  • 27 Guy W. ECDEU Assessment for Psychopharmacology, Revised Edition. Rockville: NIMH Publication; 1976
  • 28 Endicott J, Spitzer RL, Fleiss JL. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 1976; 33: 766-771
  • 29 Helmstaedter C, Lendt M, Lux S. Verbaler Lern- und Merkfähigkeitstest. Göttingen: Beltz Test GmbH; 2001
  • 30 Härting C, Markowitsch HJ, Neufeld H. WMS-R. Wechsler Gedächtnistest – Revidierte Fassung. Deutsche Adaptation der revidierten Fassung der Wechsler Memory Scale. Bern: Hans Huber; 2000
  • 31 Lezak MD. Neuropsychological Assessment. 3rd ed New York: Oxford University Press; 1995
  • 32 Bäumler G. Farbe-Wort-Interferenztest (FWIT) nach J. R. Stroop. Göttingen: Hogrefe; 1985
  • 33 Reitan RM, Wolfson D. The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. Tucson: Neuropsychology Press; 1995
  • 34 Aschenbrenner S, Tucha O, Lange KW. Regensburger Wortflüssigkeits-Test. Göttingen: Hogrefe; 2000
  • 35 Heaton RK. Wisconsin Card Sorting Test Manual. Inc. Odessa: Psychological Assessment Resources; 1981
  • 36 Rosvold HE, Mirsky A, Sarason M. et al. A continuous performance test of brain damage. J. Consult Psychol 1956; 343-350
  • 37 Conners CK. Conners’ Continuous Performance Test 3.0. Toronto: MHS; 2000
  • 38 Lehrl S. Der Mehrfachwortwahlschatz-Intelligenztest MWT-B. 5. Auflage Balingen: Spitta; 2005
  • 39 Horn W. Leistungsprüfsystem L-P-S. Göttingen: Hogrefe; 1983
  • 40 Lieberman JA, Papadakis K, Csernansky J. et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 2009; 34: 1322-1329
  • 41 Lee JG, Lee SW, Lee BJ. et al. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: A placebo-controlled pilot study. Psychiatry Investig 2012; 9: 166-173
  • 42 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. J Clin Psychiatry 2009; 70: 1416-1423
  • 43 Kishi T, Iwata N. NMDA receptor antagonists interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled trials. J Psychiatr Res 2013; 47: 1143-1149
  • 44 Zheng W, Li XH, Yang XH. et al. Adjunctive memantine for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials. Psychol Med 2018; 48: 72-81
  • 45 Kantrowitz JT, Woods SW, Petkova E. et al. D-serine for the treatment of negative symptoms in Individuals at clinical high risk of schizophrenia: A pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. Lancet Psychiatry 2015; 2: 403-412
  • 46 Marsman A, van den Heuvel MP, Klomp DW. et al. Glutamate in schizophrenia: A focused review and meta-analysis of ¹H-MRS studies. Schizophr Bull 2013; 39: 120-129