Are memantine, methylphenidate and donepezil effective in sparing cognitive functioning after brain irradiation?

Abstract

One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication. To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics: memantine, methylphenidate and donepezil. The use of memantine after brain irradiation showed a delay in cognitive deterioration, although at 24 weeks this did not reach significance (P = 0.059). Lack of significance is likely to be the result of the limited statistical power of 35% and memantine did show significant differences in secondary outcomes. The study on methylphenidate was not conclusive. Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found. In addition, larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.

Keywords

Memantine / donepezil / methylphenidate / brain irradiation / neuroprotection / whole brain irradiation / neuroprotective agent / lung cancer

References

[1] Greene-Schloesser D,Robbins ME.Molecular pathways: radiation-induced cognitive impairment..Clin Cancer Res2013;19:2294-300 PMCID:PMC3642233

[2] Welzel G,Schaefer J,Kraus-Tiefenbacher U.Memory function before and after whole brain radiotherapy in patients with and without brain metastases..Int J Radiat Oncol Biol Phys2008;72:1311-8

[3] Makale MT,Hattangadi-Gluth JA.Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours..Nat Rev Neurol2017;13:52-64 PMCID:PMC5805381

[4] Pereira Dias G,Bevilaqua MC,Hindges R.Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms..Neuro Oncol2014;16:476-92 PMCID:PMC3956361

[5] Monje ML,Fike JR.Irradiation induces neural precursor-cell dysfunction..Nat Med2002;8:955-62

[6] Brown PD,Laack NN,Khuntia D.Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial..Neuro Oncol2013;15:1429-37 PMCID:PMC3779047

[7] Rogawski MA.The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease..CNS Drug Rev2003;9:275-308

[8] Petersen RC,Grundman M,Doody R.Vitamin E and donepezil for the treatment of mild cognitive impairment..N Engl J Med2005;352:2379-88

[9] Rosenberg PB,Drye LT,Scherer RW.Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial..J Clin Psychiatry2013;74:810-6 PMCID:PMC3902018

[10] Mulhern RK,Kaplan S,Christensen R.Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer..J Clin Oncol2004;22:4795-803

[11] Rapp SR,Peiffer A,Chan MD.Donepezil for irradiated brain tumor survivors: a phase III randomized placebo-controlled clinical trial..J Clin Oncol2015;33:1653-9 PMCID:PMC4429174

[12] Levels of evidence..BJU Int2011;107:870

[13] Butler JM Jr,Atkins J,Sanders G.A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCI in brain tumor patients receiving radiation therapy..Int J Radiat Oncol Biol Phys2007;69:1496-501

[14] Meyers CA,Valentine AD.Methylphenidate therapy improves cognition, mood, and function of brain tumor patients..J Clin Oncol1998;16:2522-7

[15] Shaw EG,D’Agostino RB Jr,Naughton MJ.Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life..J Clin Oncol2006;24:1415-20

[16] Correa DD,Baser RE,DeAngelis LM.Cognitive effects of donepezil therapy in patients with brain tumors: a pilot study..J Neurooncol2016;127:313-9 PMCID:PMC4966618

[17] Castellino SM,Flowers L,McMullen KP.Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: a pilot study..Pediatr Blood Cancer2012;59:540-7 PMCID:PMC3345166

[18] Jatoi A,Frytak S,Foote RL.Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: preliminary results and suggestions for future study designs..Support Care Cancer2005;13:66-9

[19] Attia A,Lesser GJ.Treatment of radiation-induced cognitive decline..Curr Treat Options Oncol2014;15:539-50