Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of great importance, since apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress.
Design:
Within this context, we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies that have investigated the effect of pharmacological and nonpharmacological treatments of apathy in AD.
Results:
Acetylcholinesterase inhibitors, gingko biloba, methylphenidate, and a variety of nonpharmacological interventions were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity of the studies and the small amount of studies where apathy was a primary outcome measure are limiting factors to evaluate for group effects.
Conclusion:
Treatment of apathy in AD is a complicated and an underexplored field. Standardized and systematic efforts primarily focused on the study of apathy in AD may establish a benefit from individualized treatment for specific disease groups that would stem from a combination of both pharmacological and nonpharmacological interventions.
MegaMSCummingsJLFiorelloTGornbeinJ. The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996;46(1):130–135. doi:10.1212/WNL.46.1.130.
2.
CummingsJL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology. 1997;48(suppl 6):s10–s16. doi:10.1212/WNL.48.5_Suppl_6.10S.
3.
BenoitMDygaiIMignecoO. Behavioral and psychological symptoms in Alzheimer’s disease. Relation between apathy and regional cerebral perfusion. Dement Geriatr Cogn Disord. 1999;10(6):511–517. doi:10.1159/000017198.
4.
LyketsosCGSteinbergMTschanzJTNortonMCSteffensDCBreitnerJC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry. 2000;157(5):708–714. doi:10.1176/appi.ajp.157.5.708.
5.
LyketsosCGLopezOJonesBFitzpatrickALBreitnerJDeKoskyS. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002;288(12):1475–1483. doi:10.1001/jama.288.12.1475.
6.
LyketsosCGCarrilloMCRyanJM. Neuropsychiatric symptoms in Alzheimer’ disease. Alzheimers Dement. 2011;7(5):532–539. doi:10.1016/j.jalz.2011.05.2410.
7.
MarinRS. Differential diagnosis and classification of apathy. Am J Psychiatry. 1990;147(1):22–30. doi:10.1176/ajp.147.1.22.
8.
StarksteinSEPetraccaGChemerinskiEKremerJ. Syndromic validity of apathy in Alzheimer’s disease. Am J Psychiatry. 2001;158(6):872–877. doi:10.1176/appi.ajp.158.6.872.
9.
RobertPOnyikeCULeentjensAFG. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur Psychiatry. 2009;24(2):98–104. doi:10.1016/j.eurpsy.2008.09.001.
10.
MulinELeoneEDujardinK. Diagnostic criteria for apathy in clinical practice. Int J Geriatr Psychiatry. 2011;26(2):158–165. doi:10.1002/gps.2508.
11.
LevyRDuboisB. Apathy and the functional anatomy of the prefrontal cortex-basal Ganglia circuits. Cereb Cortex. 2006;16(7):916–928. doi:10.1093/cercor/bhj043.
TheleritisCPolitisASiarkosKLyketsosCG. A review of neuroimaging findings of apathy in Alzheimer’s disease. Int Psychogeriatr. 2014;26(2):195–207. doi:10.1017/S1041610213001725.
14.
DrijgersRLVerheyFRLeentjensAFKöhlerSAaltenP. Neuropsychological correlates of apathy in mild cognitive impairment and Alzheimer’s disease: the role of executive functioning. Int Psychogeriatr. 2011;23(8):1327–1333. doi:10.1017/S1041610211001037.
15.
ClarkeDEKoJYLyketsosCRebokGWEatonWW. Apathy and cognitive and functional decline in community-dwelling older adults: results from the Baltimore ECA longitudinal study. Int Psychogeriatr. 2010;22(5):819–829. doi:10.1017/S1041610209991402.
16.
OnyikeCUSheppardJMETschanzJT. Epidemiology of apathy in older adults: the Cache County Study. Am J Ger Psychiatry. 2007;15(5):365–375. doi:10.1097/01.JGP.0000235689.42910.0d.
17.
LandesAMSperrySDStraussMEGeldmacherDS. Apathy in Alzheimer’s disease. J Am Geriatr Soc. 2001;49(12):1700–1707. doi:10.1046/j.1532-5415.2001.49282.x.
18.
PolitisAMMayerLSPassaMMaillisALyketsosCG. Validity and reliability of the newly translated Hellenic Neuropsychiatric Inventory (H-NPI) applied to Greek outpatients with Alzheimer’s disease: a study of disturbing behaviors among referrals to a memory clinic. Int J Geriatr Psychiatry. 2004;19(3):203–208. doi:10.1002/gps.1045.
19.
TrifiròGSpinaEGambassiG. Use of antipsychotics in elderly patients with dementia: do atypical and conventional agents have a similar safety profile?Pharmacol Res. 2009;59(1):1–12. doi:10.1016/j.phrs.2008.09.017.
20.
TrifiróGSultanaJSpinaE. Are the safety profiles of antipsychotic drugs used in dementia the same? An updated review of observational studies. Drug Saf. 2014;37(7):501–520. doi:10.1007/s40264-014-0170-y.
MaherCSherringtonCHerbertRMoseleyAElkinsM. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. 2003;83(8):713–721. http://ptjournal.apta.org/content/83/8/713.long.
23.
HarveyLHerbertRCrosbieJ. Does stretch induce lasting increases in joint ROM? A systematic review. Physiother Res Int. 2002;7(1):1–13. doi:10.1002/pri.236.
24.
TariotPNCummingsJLKatzIR. A randomized, double blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001;49(12):1590–1599. doi:10.1111/j.1532-5415.2001.49266.x.
25.
FeldmanHGauthierSHeckerJVellasBSubbiahPWhalenE; Donepezil MSAD Study Investigators Group. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57(4):613–620. doi:10.1212/WNL.57.4.613.
26.
GauthierSFeldmanHHeckerJ; Donepezil MSAD Study Investigators Group. Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr. 2002;14(4):389–404. doi:10.1017/S104161020200858X.
27.
WeinerMFMartin-CookKFosterBMSaineKFontaineCSSvetlikDA. Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 2000;61(7):487–492. doi:10.4088/JCP.v61n0705.
28.
FeldmanHGauthierSHeckerJ; Donepezil MSAD Study Investigators Group. Efficacy and safety of donepezil in patients with more severe Alzheimer’s disease: a subgroup analysis from a randomized placebo-controlled trial. Int J Geriatr Psychiatry. 2005;20(6):559–569. doi:10.1002/gps.1325.
29.
HolmesCWilkinsonDDeanC. The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 2004;63(2):214–219. doi:10.1212/01.WNL.0000129990.32253.7B.
30.
SeltzerBZolnouniPNunezM; Donepezil “402” Study Group. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61(12):1852–1856. doi:10.1001/archneur.61.12.1852.
31.
CummingsJLMcRaeTZhangR; Donepezil-Sertraline Study Group. Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry. 2006;14(7):605–612. doi:10.1097/01.JGP.0000221293.91312.d3.
32.
WinbladBEngedalKSoininenH; Donepezil Nordic Study Group. A 1-year, randomized, placebo controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57(3):489–495. doi:10.1212/WNL.57.3.489.
33.
TariotPNSolomonPRMorrisJCKershawPLilienfeldSDingC. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology. 2000;54(12):2269–2276. doi:10.1212/WNL.54.12.2269.
34.
RockwoodKMintzerJTruyenLWesselTWilkinsonD. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry. 2001;71(5)589–595. doi:10.1136/jnnp.71.5.589.
35.
ErkinjunttiTKurzAGauthierSBullockRLilienfeldSDamarajuCV. Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 2002;359(9314):1283–1290. doi:10.1016/S0140-6736(02)08267-3.
36.
CummingsJLSchneiderLTariotPNKershawPRYuanW. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry. 2004;161(3):532–538. doi:10.1176/appi.ajp.161.3.532.
37.
BullockRMouliasRSteinwachsKCCicin-SainASpiegelR. Effects of rivastigmine on behavioural symptoms in nursing home patients with Alzheimer’s disease. Int Psychogeriatr. 2001;13(suppl 2):242. doi:10.1017/S1041610202008207.
38.
PantevMRitterRGortelmeyerR. Clinical and behavioural evaluation in long-term care patients with mild to moderate dementia under memantine treatment. Zeitschrt für Gerontopsychologie Und-Psychiatrie. 1993;6(2):S103–S117.
39.
WinbladBPoritisN. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999;14(2):135–146. doi:10.1002/(SICI)1099-1166(199902).
40.
CummingsJLSchneiderETariotPNGrahamSM; Memantine MEM-MD-02 Study Group. Behavioral effects of memantine in Alzheimer disease patients receiving donepezil treatment. Neurology. 2006;67(1):57–63. doi:10.1212/01.wnl.0000223333.42368.f1.
41.
ScripnikovAKhomenkoANapryeyenkoO, GINDEM-NP Study Group. Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial. Wien Med Wochenschr. 2007;157(13-14):295–300. doi:10.1007/s10354-007-0427-5.
42.
BachinskayaNHoerrRIhlR. Alleviating neuropsychiatric symptoms in dementia: the effects of ginkgo biloba extract EGb 761. Findings from a randomized controlled trial. Neuropsychiatr Dis Treat. 2011;7:209–215. doi:10.2147/NDT.S18741.
43.
IhlRBachinskayaNKorczynAD; GOTADAY Study Group. Efficacy and safety of a once-daily formulation of ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial. Int J Geriatr Psychiatry. 2011;26(11):1186–1194.doi:10.1002/gps.2662.
44.
KaplitzSE. Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc. 1975;23(6):271–276. doi:10.1111/j.1532-5415.1975.tb00317.x.
45.
HerrmannNRothenburgLSBlackS. Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine. J Clin Psychopharmacol. 2008;28(3):296–301. doi:10.1097/JCP.0b013e318172b479.
46.
RosenbergPBLanctôtKLDryeLT; ADMET Investigators. Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. J Clin Psychiatry. 2013;74(8):810–816. doi:10.4088/JCP.12m08099.
47.
LanctôtKLChauSAHerrmannN. Effect of methylphenidate on attention in apathetic AD patients in a randomized, placebo-controlled trial. Int Psychogeriatr. 2014;26(2):239–246. doi:10.1017/S1041610213001762.
48.
FrakeyLLSallowaySBuelowMMalloyP. A randomized, double-blind, placebo-controlled trial of modafinil for the treatment of apathy in individuals with mild-to-moderate Alzheimer’s disease. J Clin Psychiatry. 2012;73(6):796–801. doi:10.4088/JCP.10m06708.
49.
PorsteinssonAPDryeLTPollockBG; CitAD Research Group. Effect of citalopram on agitation in Alzheimer’s disease—the CitAD randomized controlled trial. JAMA. 2014;311(7):682–691. doi:10.1001/jama.2014.93.
50.
ReaRCarotenutoATrainiEFasanaroAMManzoVAmentaF. Apathy treatment in Alzheimer’s disease: interim results of the ASCOMALVA trial. J Alzheimers Dis. 2015;48:377–383. Doi:10.3233/JAD-141983.
51.
AhlinANybackHJuntheTOhmanGNordgrenI. Tetrahydroaminoacridine in Alzheimer’s dementia: clinical and biochemical results of a double-blind crossover trial. Hum Psychopharmacol. 1991;6(2):109–118. doi:10.1002/hup.470060205.
52.
KauferD. Beyond the cholinergic hypothesis: the effect of metrifonate and other cholinesterase inhibitors on neuropsychiatric symptoms in Alzheimer’s disease. Dement Geriatr Cogn Disord. 1998;9(suppl 2):8–14. doi:10.1159/000051193.
53.
DuboisBMcKeithIOrgogozoJMCollinsOMeulienD. A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer’s disease: the MALT study. Int J Geriatr Psychiatry. 1999;14(11):973–982. doi:10.1002/(SICI)1099-1166(199911).
54.
SuemotoCKApolinarioDNakamura-PalaciosEM. Effects of a non-focal plasticity protocol on apathy in moderate Alzheimer’s disease: a randomized, double-blind, sham-controlled trial. Brain Stimul. 2014;7(2):308–313. doi:10.1016/j.brs.2013.10.003.
55.
MegaMSMastermanDMO’ConnorSMBarclayTRCummingsJL. The spectrum of behavioral responses to cholinesterase inhibitor therapy in Alzheimer disease. Arch Neurol. 1999;56(11):1388–1393. doi:10.1001/archneur.56.11.1388.
56.
MatthewsHPKorbeyJWilkinsonDGRowdenJ. Donepezil in Alzheimer’s disease: eighteen month results from Southampton Memory Clinic. Int J Geriatr Psychiatry. 2000;15(8):713–720. doi:10.1002/1099-1166(200008).
57.
BarakYBodnerEZemishlaniHMireckiIAizenbergD. Donepezil for the treatment of behavioral disturbances in Alzheimer’s disease: a 6-month open trial. Arch Gerontol Geriatr. 2001;33(3):237–241. doi:10.1016/S0167-4943(01)00187-X.
TanakaMNamikiCThuyDH. Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer’s disease. J Neurol Sci. 2004;225(1-2):135–141. doi:10.1016/j.jns.2004.07.009.
60.
RockwoodKBlackSBedardMATranTLussierI; TOPS Study Investigators. Specific symptomatic changes following donepezil treatment of Alzheimer’s disease: a multicentre, primary care, open label study. Int J Geriatr Psychiatry. 2007;22(4):312–319. doi:10.1002/gps.1675.
61.
LopezOLMackellJASunY. Effectiveness and safety of donepezil in Hispanic patients with Alzheimer’s disease: a 12-week open-label study. J Natl Med Assoc. 2008;100(11):1350–1358.
62.
MatsuzonoKHishikawaNOhtaY. Combination therapy of cholinesterase inhibitor (donepezil or galantamine) plus memantine in the Okayama Memantine Study. J Alzheimers Dis. 2015;45:771–780. doi:10.3233/JAD-143084.
63.
MatsuzonoKYamashitaTOhtaY. Clinical benefits for older Alzheimer’s disease patients: Okayama Late Dementia Study (OLDS). J Alzheimers Dis. 2015;46(3):687–693. doi:10.3233/JAD-150175.
64.
MonschAUGiannakopoulosP; GAL-SUI Study Group. Effects of galantamine on behavioural and psychological disturbances and caregiver burden in patients with Alzheimer’s disease. Curr Med Res Opin. 2004;20(6):931–938. doi:10.1185/030079904125003890.
65.
BrodatyHWoodwardMBoundyKBarnesNAllenG; NATURE Investigators. A naturalistic study of galantamine for Alzheimer’s disease. CNS Drugs. 2006;20(11):935–943. doi:10.2165/00023210-200620110-00006.
ClericiFVanacoreNEliaA; Memantine Lombardy Study Group. Memantine effects on behaviour in moderately severe to severe Alzheimer’s disease: a post-marketing surveillance study. Neurol Sci. 2012;33(1):23–31. doi:10.1007/s10072-011-0618-0.
68.
KauferDCummingsJLChristineD. Effect of tacrine on behavioral symptoms in Alzheimer’s disease: an open-label study. J Geriatr Psychiatry Neurol. 1996;9(1):1–6. doi:10.1177/089198879600900101.
69.
KauferDCummingsJLChristineD. Differential neuropsychiatric symptom responses to tacrine in Alzheimer’s disease: relationship to dementia severity. J Neuropsychiatry Clin Neurosci. 1998;10(1):55–63. doi:10.1176/jnp.10.1.55.
70.
DartiguesJGoulleyFBourdeixIPéréJJBarberger-GateauP. Rivastigmine in current clinical practice in patients with mild to moderate Alzheimer’s disease [in French]. Rev Neurol. 2002;158(8-9):807–812. doi:RN-09-2002-158-8-9-0035-3787-101019-ART4.
71.
HatoumHTLinSJArconaSThomasSKKoumarasBMirskiD. The use of the occupational disruptiveness scale of the neuropsychiatric inventory-nursing home version to measure the impact of rivastigmine on the disruptive behavior of nursing home residents with Alzheimer’s disease. J Am Med Dir Assoc. 2005;6(4):238–245. doi:10.1016/j.jamda.2005.04.003.
72.
CummingsJLKoumarasBChenMMirskiD; Rivastigmine Nursing Home Study Team. Rivastigmine Nursing Home Study Team. Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer’s disease: a 26-week, multicenter, open-label study. Am J Geriatr Pharmacother. 2005;3(3):137–148. doi:10.1016/S1543-5946(05)80020-0.
73.
AupperlePMKoumarasBChenMRabinowiczAMirskiD. Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer’s disease: results of a 52-week open-label study. Curr Med Res Opin. 2004;20(10):1605–1612. doi:10.1185/030079904125004204.
74.
EdwardsKKoumarasBChenMGunayIMirskiD; the Rivastigmine Nursing Home Study Team. Long-term effects of rivastigmine treatment on the need for psychotropic medications in nursing home patients with Alzheimer’s disease: results of a 52-week open-label study. Clin Drug Investig. 2005;25(8):507–515. doi:10.2165/00044011-200525080-00003.
75.
GauthierSJubyAMorelliLRehelBSchecterR; EXTEND Investigators. A large, naturalistic, community-based study of rivastigmine in mild-to-moderate AD: the EXTEND Study. Curr Med Res Opin. 2006;22(11):2251–2265. doi:10.1185/030079906X132749.
76.
GauthierSJubyARehelBSchecterR; EXTEND Investigators. EXACT: rivastigmine improves high prevalence of attention deficits and mood and behavior symptoms in Alzheimer’s disease. Int J Clin Pract. 2007;61(6):886–895. doi:10.1111/j.1742-1241.2007.01387.x.
77.
GauthierSJubyADalzielWRéhelBSchecterR; EXPLORE Investigators. Effects of rivastigmine on common symptomatology of Alzheimer’s disease (EXPLORE). Curr Med Res Opin. 2010;26(5):1149–1160. doi:10.1185/03007991003688888.
78.
GalynkerIIeronimoCMinerCRosenblumJVilkasNRosenthalR. Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatry Clin Neurosci. 1997;9(2):231–239. doi:10.1176/jnp.9.2.2.
79.
PadalaPRBurkeWJShostromVK. Methylphenidate for apathy and functional status in dementia of the Alzheimer type. Am J Geriatr Psychiatry. 2010;18(4):371–374. doi:10.1097/JGP.0b013e3181cabcf6.
BenoitMAndrieuSLechowskiLGillette-GuyonnetSRobertPHVellasB; REAL-FR Group. Apathy and depression in Alzheimer’s disease are associated with functional deficit and psychotropic prescription. Int J Geriatr Psychiatry. 2008;23(4):409–414. doi:10.1002/gps.1895.
82.
SiddiqueHHynanLSWeinerMF. Effect of a serotonin reuptake inhibitor on irritability, apathy and psychotic symptoms in patients with Alzheimer’s disease. J Clin Psychiatry. 2009;70(6):915–918. doi:10.4088/JCP.08m04828.
83.
LyketsosCGDelCampoLSteinbergM. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry. 2003;60(7):737–746. doi:10.1001/archpsyc.60.7.737.
84.
PollockBGMulsantBHRosenJ. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry. 2002;159(3):460–465. doi:10.1176/appi.ajp.159.3.460.
85.
NythALGottfriesCGLybyK. A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia. Acta Psychiatr Scand. 1992;86(2):138–145. doi:10.1111/j.1600-0447.1992.tb03242.x.
86.
TariotPNCohenRMSunderlandT. L-deprenyl in Alzheimer’s disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition. Arch Gen Psychiatry. 1987;44(5):427–433. doi:10.1001/archpsyc.1987.01800170041007.
87.
FreedmanMRewilakDXerriT. L-deprenyl in Alzheimer’s disease: cognitive and behavioral effects. Neurology. 1998;50(3):660–668. doi:10.1212/WNL.50.3.660: 1526-632X.
88.
WongpakaranNvan ReekumRWongpakaranTClarkeD. Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-control study. Ann Gen Psychiatry. 2007;6:7. doi:10.1186/1744-859X-6-7.
89.
OberholzerAFHendriksenCMonschAUHeierliBStähelinHB. Safety and effectiveness of low-dose clozapine in psychogeriatric patients: a preliminary study. Int Psychogeriatr. 1992;4(2):187–195. doi:10.1017/S1041610292001017.
90.
NegronAEReichmanWE. Risperidone in the treatment of patients with Alzheimer’s disease with negative symptoms. Int Psychogeriatr. 2000;12(4):527–536. doi:10.1017/S1041610200006633.
91.
De DeynPPCarrascoMMDeberdtW. Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 2004;19(2):115–126. doi:10.1002/gps.1032.
92.
OnorMLSainaMTrevisiolMCristanteTAgugliaE. Clinical experience with risperidone in the treatment of behavioural and psychological symptoms of dementia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):205–209. doi:10.1016/j.pnpbp.2006.09.001.
93.
Food and Drug Administration. Deaths with antipsychotics in elderly patients with behavioral disturbances. US Food and Drug Administration, FDA Public Health Advisory, Centre for Drug Evaluation and Research. 2005.
94.
WaldemarGGauthierSJonesR. Effect of donepezil on emergence of apathy in mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry. 2011;26(2):150–157. doi:10.1002/gps.2507.
95.
HerrmannNRabheruKWangJBinderC. Galantamine treatment of problematic behavior in Alzheimer’s disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry. 2005;13(6):527–534. doi:10.1097/00019442-200506000-00012.
96.
GauthierSLoftHCummingsJ. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry. 2008;23(5):537–545. doi:10.1002/gps.1949.
97.
PeskindERPotkinSGPomaraN; the Memantine MEM-MD-10 Study Group. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry. 2006;14(8):704–715. doi:10.1097/01.JGP.0000224350.82719.83.
98.
PorsteinssonAPGrossbergGTMintzerJOlinJT; Memantine MEM-MD-12 Study Group. Memantine treatment in patients with mild to moderate Alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res2008;5(1):83–89. doi:10.2174/156720508783884576.
van DyckCHTariotPNMeyersBMalca ResnickE; Memantine MEM-MD-01 Study Group. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord. 2007;21(2):136–143. doi:10.1097/WAD.0b013e318065c495.
101.
TariotPNFarlowMRGrossbergGTGrahamSMMcDonaldSGergelI; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317–324. doi:10.1001/jama.291.3.317.
102.
ReisbergBDoodyRStofflerASchmittFFerrisSMöbiusHJ; Memantine Study Group. Memantine in moderate-to severe Alzheimer’s disease. New Engl J Med. 2003;348(14):1333–1341. doi:10.1056/NEJMoa013128.
103.
CummingsJLNadelAMastermanDCyrusPA. Efficacy of metrifonate in improving the psychiatric and behavioral disturbances of patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol. 2001;14(2):101–108. doi:10.1177/089198870101400211.
104.
MorrisJCCyrusPAOrazemJ. Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer’s disease. Neurology. 1998;50(5):1222–1230. doi:10.1212/WNL.50.5.1222.
105.
RaskindMACyrusPARuzickaBBGulanskiBI. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer’s disease patients. Metrifonate Study Group. J Clin Psychiatry. 1999;60(5):318–325. doi:10.4088/JCP.v60n0510.
106.
GauthierSWirthYMobiusHJ. Effects of memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies. Int J Geriatr Psychiatry. 2005;20(5):459–464. doi:10.1002/gps.1341.
107.
AmievaHRobertPHGrandoulierAS. Group and individual cognitive therapies in Alzheimer’s disease: the ETNA3 randomized trial. Int Psychogeriatr. 2016;28(5):707–717. doi:10.1017/S1041610215001830.
108.
TreuschYMajicTPageJGutzmannHHeinzARappMA. Apathy in nursing home residents with dementia: results from a cluster-randomized controlled trial. Eur Psychiatry. 2015;30(2):251–257. doi:10.1016/j.eurpsy.2014.02.004.
109.
Ferrero-AriasJGoñi-ImízcozMGonzález-BernalJLara-OrtegaFda Silva-GonzalezADıez-LopezM. The efficacy of non pharmacological treatment for dementia-related apathy. Alzheimer Dis Assoc Disord. 2011;25(3):213–219.doi:10.1097/WAD.0b013e3182087dbc.
110.
LeoneEDeudonABauchetM. Management of apathy in nursing homes using a teaching program for care staff: the STIM-EHPAD study. Int J Geriatr Psychiatry. 2013;28(4):383–392. doi:10.1002/gps.3836.
111.
BakerRBellSBakerE. A randomized controlled trial of the effects of multi-sensory stimulation (MSS) for people with dementia. Br J Clin Psychol. 2001;40(pt 1):81–96. doi:10.1348/014466501163508.
112.
BakerRHollowayJHoltkampCC. Effects of multi-sensory stimulation for people with dementia. J Adv Nurs. 2003;43(5):465–477. doi:10.1046/j.1365-2648.2003.02744.x.
113.
SánchezAMarante-MoarMPSarabiaC. Multisensory stimulation as an intervention strategy for elderly patients with severe dementia: a pilot randomized controlled trial. Am J Alzheimers Dis Other Demen. 2016;31(4):341–350. doi:10.1177/1533317515618801.
114.
NiuYXTanJPGuanJQZhangZQWangLN. Cognitive stimulation therapy in the treatment of neuropsychiatric symptoms in Alzheimer’s disease: a randomized controlled trial. Clin Rehabil. 2010;24(12):1102–1111. doi:10.1177/0269215510376004.
115.
MaciTPiraFLQuattrocchiGDi NuovoSPerciavalleVZappiaM. Physical and cognitive stimulation in Alzheimer disease. The GAIA project: a pilot study. Am J Alzheimers Dis Other Demen. 2012;27(2):107–113. doi:10.1177/1533317512440493.
116.
PolitisAMVozzellaSMayerLSOnyikeCUBakerASLyketsosCG. A randomized, controlled, clinical trial of activity therapy for apathy in patients with dementia residing in long-term care. Int J Geriatr Psychiatry. 2004;19(11):1087–1094. doi:10.1002/gps.1215.
117.
HolmesCKnightsADeanCHodkinsonSHopkinsV. Keep music live: music and the alleviation of apathy in dementia subjects. Int Psychogeriatr. 2006;18(4):623–630. doi:10.1017/S1041610206003887.
118.
RaglioABellelliGTraficanteD. Efficacy of music therapy treatment based on cycles of sessions: a randomised controlled trial. Aging Ment Health. 2010;14(8):900–904. doi:10.1080/13607861003713158.
119.
TadakaEKanagawaK. Effects of reminiscence group in elderly people with Alzheimer disease and vascular dementia in a community setting. Geriatr Gerontol Int. 2007;7(2):167–173. doi:10.1111/j.1447-0594.2007.00381.x.
120.
HattoriHHattoriCHokaoCMizushimaKMaseT. Controlled study on the cognitive and psychological effect of coloring and drawing in mild Alzheimer’s disease patients. Geriatr Gerontol Int. 2011;11(4):431–437. doi:10.1111/j.1447-0594.2011.00698.x.
121.
Fischer-TerworthCProbstP. Effects of a psychological group intervention on neuropsychiatric symptoms and communication in Alzheimer’s dementia. Z Gerontol Geriatr. 2012;45(5):392–397. doi:10.1007/s00391-012-0296-4.
122.
GitlinLNWinterLBurkeJChernettNDennisMPHauckWW. Tailored activities to manage neuropsychiatric behaviors in persons with dementia and reduce caregiver burden: a randomized pilot study. Am J Geriatr Psychiatry. 2008;16(3):229–239. doi:10.1097/JGP.0b013e318160da72.
123.
LamLCLuiVWLukDN. Effectiveness of an individualized functional training program on affective disturbances and functional skills in mild and moderate dementia—a randomized control trial. Int J Geriatr Psychiatry. 2010;25(2):133–141. doi:10.1002/gps.2309.
124.
StaalJASacksAMatheisR. The effects of Snoezelen (multi-sensory behavior therapy) and psychiatric care on agitation, apathy, and activities of daily living in dementia patients on a short term geriatric psychiatric inpatient unit. Int J Psychiatry Med. 2007;37(4):357–370. doi:10.2190/PM.37.4.a.
125.
ChapmanSBWeinerMFRackleyAHynanLSZientzJ. Effects of cognitive-communication stimulation for Alzheimer’s disease patients treated with donepezil. J Speech Lang Hear Res. 2004;47(5):1149–1163. doi:10.1044/1092-4388(2004/085).
126.
TeleniusEWEngedalKBerglandA. Effect of a high-intensity exercise program on physical function and mental health in nursing home residents with dementia: an assessor blinded randomized controlled trial. PLoS One. 2015;10(5):e0126102. doi:10.1371/journal.pone.0126102.
127.
TondiLRibaniLBottazziMViscomiGVulkanoV. Validation therapy (VT) in nursing home: a case-control study. Arch Gerontol Geriatr. 2007;44(suppl 1):407–411. doi:10.1016/j.archger.2007.01.057.
JohnsonDKNiedensMWilsonJRSwartzendruberLYeagerAJonesK. Treatment outcomes of a crisis intervention program for dementia with severe psychiatric complications: the Kansas bridge project. Gerontologist. 2013;53(1):102–112. doi:10.1093/geront/gns104.
130.
ManeraVPetitPDDerreumauxA. ‘Kitchen and cooking’, a serious game for mild cognitive impairment and Alzheimer’s disease: a pilot study. Front Aging Neurosci. 2015;7:24. doi:10.3389/fnagi.2015.00024. eCollection 2015.
131.
TreiberKALyketsosCGCorcoranC. Vascular factors and risk for neuropsychiatric symptoms in Alzheimer’s disease: the Cache County Study. Int Psychogeriatr. 2008;20(3):538–553. doi:10.1017/S1041610208006704.
132.
van der MastRCVinkersDJStekML. Vascular disease and apathy in old age. The Leiden 85-Plus Study. Int J Geriatr Psychiatry. 2008;23(3):266–271. doi:10.1002/gps.1872.
133.
SpaccaventoSDel PreteMCracaAFioreP. Influence of nutritional status on cognitive, functional and neuropsychiatric deficits in Alzheimer’s disease. Arch Gerontol Geriatr. 2009;48(3):356–360. doi:10.1016/j.archger.2008.03.002.
134.
HishikawaNFukuiYSatoK. Cognitive and affective functions in Alzheimer’s disease patients with metabolic syndrome. Eur J Neurol. 2016;23(2):339–345. doi:10.1111/ene.12845.
135.
MegaMSCummingsJLSallowaySMalloyP. The limbic system: an anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci. 1997;9(3):315–330. doi:10.1212/WNL.46.1.130.
136.
TrinhNHHobbinJMohantySYaffeK. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a metaanalysis. JAMA. 2003;289(2):210–216. doi:10.1001/jama.289.2.210.
137.
CummingsJLMackellJKauferD. Behavioral effects of current Alzheimer’s disease treatments: a descriptive review. Alzheimers Dement. 2008;4(1):49–60. doi:10.1016/j.jalz.2007.10.011.
138.
DrijgersRLAaltenPWinogrodzkaAVerheyFRLeentjensAF. Pharmacological treatment of apathy in neurodegenerative diseases: a systematic review. Dement Geriatr Cogn Disord. 2009;28(1):13–22. doi:10.1159/000228840.
139.
BermanKBrodatyHWithallASeeherK. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 2012; 20(2):104–122. doi:10.1097/JGP.0b013e31822001a6.
140.
VerkaikRvan WeertJCFranckeAL. The effects of psychosocial methods on depressed, aggressive and apathetic behaviors of people with dementia: a systematic review. Int J Geriatr Psychiatry. 2005;20(4):301–314. doi:10.1002/gps.1279.
141.
Lane-BrownATTateRL. Apathy after acquired brain impairment: a systematic review of non-pharmacological interventions. Neuropsychol Rehabil. 2009;19(4):481–516. doi:10.1080/09602010902949207.
142.
BrodatyHBurnsK. Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry. 2012;20(7):549–564. doi:10.1097/JGP.0b013e31822be242.
DolderCRDavisLNMcKinseyJ. Use of psychostimulants in patients with dementia. Ann Pharmacother. 2010;44(10):1624–1632. doi:10.1345/aph.1P341.
145.
LanctôtKLAgüera-OrtizLBrodatyH. Apathy associated with neurocognitive disorders: recent progress and future directions [Published online June 27, 2016]. Alzheimers Dement. doi:10.1016/j.jalz.2016.05.008.
146.
RadakovicRHarleyCAbrahamsSStarrJM. A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions. Int Psychogeriatr. 2015;27(6):903–923. doi:10.1017/S1041610214002221.
147.
ClarkeDEKoJYKuhlEAvan ReekumRSalvadorRMarinRS. Are the available apathy measures reliable and valid? A review of the psychometric evidence. J Psychosom Res. 2011;70(1):73–97. doi:10.1016/j.jpsychores.2010.01.012.
148.
GitlinLNPiersolCVHodgsonN. Reducing neuropsychiatric symptoms in persons with dementia and associated burden in family caregivers using tailored activities: design and methods of a randomized clinical trial. Contemp Clin Trials. 2016;49:92–102. doi:10.1016/j.cct.2016.06.006.
149.
CummingsJFriedmanJHGaribaldiG. Apathy in neurodegenerative diseases: recommendations on the design of clinical trials. J Geriatr Psychiatry Neurol. 2015;28(3):159–173. doi:10.1177/0891988715573534.
150.
SchulzKFChalmersIHayesRJAltmanDG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408–412. doi:10.1001/jama.1995.03520290060030.
151.
LyketsosCG.Apathy and agitation: challenges and future directions. Am J Ger Psychiatry. 2007;15(5):361–364. doi:10.1097/JGP.0b013e31803d15c1.
152.
KalesHCGitlinLNLyketsosCG; Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762–769. doi:10.1111/jgs.12730.
153.
FrakerJKalesHCBlazekMKavanaghJGitlinLN. The role of the occupational therapist in the management of neuropsychiatric symptoms of dementia in clinical settings. Occup Ther Health Care. 2014;28(1):4–20. doi:10.3109/07380577.2013.867468.
154.
KalesHCGitlinLNLyketsosCG. Assessment and management of behavioral and psychological symptoms of dementia. BMJ. 2015;350:h369. doi:10.1136/bmj.h369.
155.
RosenbergPBLyketsosCG. Mild cognitive impairment: searching for the prodrome of Alzheimer’s disease. World Psychiatry. 2008;7(2):72–78. doi:10.1002/j.2051-5545.2008.tb00159.x.
