Despite the reported efficacy of methylphenidate (MET) against Alzheimer’s disease (AD)–associated apathy, a recent larger clinical trial was not included in pooled analysis.
This study aimed at investigating the efficacy of MET for attenuating apathy in patients diagnosed with AD.
The PubMed, Cochrane Library, and EMBASE databases were searched from inception until March, 2022 to identify randomized controlled trials (RCTs). The primary outcome was apathy improvement assessed with the Neuropsychiatric Inventory (NPI) apathy subscale, Apathy Evaluation Scale (AES), or Clinical Global Impressions of Change scale (CGI-C apathy).
Meta-analysis of four RCTs revealed an improvement in apathy among patients receiving MET compared to placebo (MD = − 5.12, p = 0.04, three trials, 144 participants) at follow-ups of 1–3 months assessed with AES score. Despite the absence of improvement on NPI-apathy subscale at follow-ups of 1–2 months (MD = − 0.74, p = 0.37, three trials, 265 participants), significant improvement was noted at follow-ups of 6 months (MD = − 1.4, p = 0.02, one trial, 180 participants). Assessment with CGI-C apathy revealed no significant association between improvement in apathy with MET use (RR = 1.38, p = 0.05, three trials, 265 participants). No significant differences in global cognitive function (using the Mini Mental State Exam) or adverse events were noted between the two groups.
While AES score suggested an early attenuation effect of MET on apathy in different domains, the NPI-apathy subscale did not show early improvement in apathy until the 6-month follow-up. Further studies with longer follow-ups are needed to elucidate the efficacy of MET for relieving caregiver burden and improving global functional performance.
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Andrade C (2022) Methylphenidate and other pharmacologic treatments for apathy in Alzheimer's disease. J Clin Psychiatry 83
Apostolova LG, Akopyan GG, Partiali N, Steiner CA, Dutton RA, Hayashi KM, Dinov ID, Toga AW, Cummings JL, Thompson PM (2007) Structural correlates of apathy in Alzheimer’s disease. Dement Geriatr Cogn Disord 24:91–97
Arevalo-Rodriguez I, Smailagic N, Roqué IFM, Ciapponi A, Sanchez-Perez E, Giannakou A, Pedraza OL, BonfillCosp X, Cullum S (2015) Mini-Mental State Examination (MMSE) for the detection of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2015:Cd010783
Azhar L, Kusumo RW, Marotta G, Lanctôt KL, Herrmann N (2022) Pharmacological management of apathy in dementia. CNS Drugs 36:143–165
Bruen PD, McGeown WJ, Shanks MF, Venneri A (2008) Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain 131:2455–2463
Chen Y, Dang M, Zhang Z (2021) Brain mechanisms underlying neuropsychiatric symptoms in Alzheimer’s disease: a systematic review of symptom-general and -specific lesion patterns. Mol Neurodegener 16:38
Clarke DE, Reekum R, Simard M, Streiner DL, Freedman M, Conn D (2007) Apathy in dementia: an examination of the psychometric properties of the apathy evaluation scale. J Neuropsychiatry Clin Neurosci 19:57–64
Drevon D, Fursa SR, Malcolm AL (2017) Intercoder reliability and validity of WebPlotDigitizer in extracting graphed data. Behav Modif 41:323–339
Fauth EB, Gibbons A (2014) Which behavioral and psychological symptoms of dementia are the most problematic? Variability by prevalence, intensity, distress ratings, and associations with caregiver depressive symptoms. Int J Geriatr Psychiatry 29:263–271
Fazio L, Logroscino G, Taurisano P, Amico G, Quarto T, Antonucci LA, Barulli MR, Mancini M, Gelao B, Ferranti L, Popolizio T, Bertolino A, Blasi G (2016) Prefrontal activity and connectivity with the basal ganglia during performance of complex cognitive tasks is associated with apathy in healthy subjects. PLoS One 11:e0165301
Galasko D (2013) The diagnostic evaluation of a patient with dementia. Continuum (minneap Minn) 19:397–410
Gauthier S, Feldman H, Hecker J, Vellas B, Ames D, Subbiah P, Whalen E, Emir B (2002) Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr 14:389–404
Gauthier S, Feldman H, Hecker J, Vellas B, Emir B, Subbiah P (2002) Functional, cognitive and behavioral effects of donepezil in patients with moderate Alzheimer’s disease. Curr Med Res Opin 18:347–354
Geda YE, Roberts RO, Knopman DS, Petersen RC, Christianson TJ, Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, Tangalos EG, Rocca WA (2008) Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry 65:1193–1198
Grossman HT, Sano M, Aloysi A, Elder GA, Neugroschl J, Schimming C, Soleimani L, Zhu CW (2021) Prevalent, persistent, and impairing: longitudinal course and impact of apathy in Alzheimer’s disease. Alzheimers Dement (amst) 13:e12169
Herrmann N, Rothenburg LS, Black SE, Ryan M, Liu BA, Busto UE, Lanctôt KL (2008) Methylphenidate for the treatment of apathy in Alzheimer disease: prediction of response using dextroamphetamine challenge. J Clin Psychopharmacol 28:296–301
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring Inconsistency in Meta-Analyses. Bmj 327:557–560
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, Pandita-Gunawardena ND, Hogg F, Clare C, Damms J (2004) The efficacy of donepezil in the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology 63:214–219
Hung KC, Hung CT, Poon YY, Wu SC, Chen KH, Chen JY, Chang YJ, Chen IW, Sun CK, Chiang MH (2021) The effect of cricoid pressure on tracheal intubation in adult patients: a systematic review and meta-analysis. Can J Anaesth 68:137–147
Hung KC, Lin YT, Chen KH, Wang LK, Chen JY, Chang YJ, Wu SC, Chiang MH, Sun CK (2020) The effect of perioperative Vitamin C on postoperative analgesic consumption: a meta-analysis of randomized controlled trials. Nutrients 12
Johansson M, Stomrud E, Lindberg O, Westman E, Johansson PM, van Westen D, Mattsson N, Hansson O (2020) Apathy and anxiety are early markers of Alzheimer’s disease. Neurobiol Aging 85:74–82
Kishi T, Sakuma K, Iwata N (2020) Efficacy and safety of psychostimulants for Alzheimer’s disease: a systematic review and meta-analysis. Pharmacopsychiatry 53:109–114
Lanctôt KL, Agüera-Ortiz L, Brodaty H, Francis PT, Geda YE, Ismail Z, Marshall GA, Mortby ME, Onyike CU, Padala PR, Politis AM, Rosenberg PB, Siegel E, Sultzer DL, Abraham EH (2017) Apathy associated with neurocognitive disorders: recent progress and future directions. Alzheimers Dement 13:84–100
Le Heron C, Holroyd CB, Salamone J, Husain M (2019) Brain mechanisms underlying apathy. J Neurol Neurosurg Psychiatry 90:302–312
Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 16:916–928
Li T, Yu T, Hawkins BS, Dickersin K (2015) Design, analysis, and reporting of crossover trials for inclusion in a meta-analysis. PLoS One 10:e0133023
Marin RS (1990) Differential diagnosis and classification of apathy. Am J Psychiatry 147:22–30
Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL (2006) Neuropathologic correlates of apathy in Alzheimer’s disease. Dement Geriatr Cogn Disord 21:144–147
Miller DS, Robert P, Ereshefsky L, Adler L, Bateman D, Cummings J, DeKosky ST, Fischer CE, Husain M, Ismail Z, Jaeger J, Lerner AJ, Li A, Lyketsos CG, Manera V, Mintzer J, Moebius HJ, Mortby M, Meulien D, Pollentier S, Porsteinsson A, Rasmussen J, Rosenberg PB, Ruthirakuhan MT, Sano M, Zucchero Sarracini C, Lanctôt KL (2021) Diagnostic criteria for apathy in neurocognitive disorders. Alzheimers Dement 17:1892–1904
Mintzer J, Lanctôt KL, Scherer RW, Rosenberg PB, Herrmann N, van Dyck CH, Padala PR, Brawman-Mintzer O, Porsteinsson AP, Lerner AJ, Craft S, Levey AI, Burke W, Perin J, Shade D (2021) Effect of methylphenidate on apathy in patients with Alzheimer disease: the ADMET 2 randomized clinical trial. JAMA Neurol 78:1324–1332
Moretti R, Signori R (2016) Neural correlates for apathy: frontal-prefrontal and parietal cortical- subcortical circuits. Front Aging Neurosci 8:289
Mori T, Shimada H, Shinotoh H, Hirano S, Eguchi Y, Yamada M, Fukuhara R, Tanimukai S, Zhang MR, Kuwabara S, Ueno S, Suhara T (2014) Apathy correlates with prefrontal amyloid β deposition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 85:449–455
Padala PR, Padala KP, Lensing SY, Ramirez D, Monga V, Bopp MM, Roberson PK, Dennis RA, Petty F, Sullivan DH, Burke WJ (2018) Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s disease: a double-blind, randomized, placebo-controlled trial. Am J Psychiatry 175:159–168
Padala PR, Boozer EM, Lensing SY, Parkes CM, Hunter CR, Dennis RA, Caceda R, Padala KP (2020a) Neuromodulation for apathy in Alzheimer’s disease: a double-blind, randomized, sham-controlled pilot study. J Alzheimers Dis 77:1483–1493
Padala PR, Padala KP, Samant RS, James GA (2020b) Improvement of neuronal integrity with methylphenidate treatment for apathy in Alzheimer’s disease. Int Psychogeriatr 32:539–540
Robert P, Lanctôt KL, Agüera-Ortiz L, Aalten P, Bremond F, Defrancesco M, Hanon C, David R, Dubois B, Dujardin K, Husain M, König A, Levy R, Mantua V, Meulien D, Miller D, Moebius HJ, Rasmussen J, Robert G, Ruthirakuhan M, Stella F, Yesavage J, Zeghari R, Manera V (2018) Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group. Eur Psychiatry 54:71–76
Rosenberg PB, Lanctôt KL, Drye LT, Herrmann N, Scherer RW, Bachman DL, Mintzer JE, Investigators A (2013) Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. J Clin Psychiatry 74:810–816
Ruthirakuhan MT, Herrmann N, Abraham EH, Chan S, Lanctôt KL (2018) Pharmacological interventions for apathy in Alzheimer’s disease. Cochrane Database Syst Rev 5:Cd012197
Sassi KLM, Rocha NP, Colpo GD, John V, Teixeira AL (2020) Amphetamine use in the elderly: a systematic review of the literature. Curr Neuropharmacol 18:126–135
Sepehry AA, Sarai M, Hsiung GR (2017) Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. Can J Neurol Sci 44:267–275
Sharma A, Couture J (2014) A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother 48:209–225
Starkstein SE, Brockman S (2018) The neuroimaging basis of apathy: empirical findings and conceptual challenges. Neuropsychologia 118:48–53
Stella F, Radanovic M, Aprahamian I, Canineu PR, de Andrade LP, Forlenza OV (2014) Neurobiological correlates of apathy in Alzheimer’s disease and mild cognitive impairment: a critical review. J Alzheimers Dis 39:633–648
Tanaka M, Namiki C, Thuy DH, Yoshida H, Kawasaki K, Hashikawa K, Fukuyama H, Kita T (2004) Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer’s disease. J Neurol Sci 225:135–141
Theleritis C, Siarkos K, Katirtzoglou E, Politis A (2017) Pharmacological and Nonpharmacological treatment for apathy in Alzheimer disease : a systematic review across modalities. J Geriatr Psychiatry Neurol 30:26–49
Tunnard C, Whitehead D, Hurt C, Wahlund LO, Mecocci P, Tsolaki M, Vellas B, Spenger C, Kłoszewska I, Soininen H, Lovestone S, Simmons A (2011) Apathy and cortical atrophy in Alzheimer’s disease. Int J Geriatr Psychiatry 26:741–748
van Dalen JW, van Wanrooij LL, Moll van Charante EP, Brayne C, van Gool WA, Richard E (2018) Association of Apathy with risk of incident dementia: a systematic review and meta-analysis. JAMA Psychiat 75:1012–1021
van Dyck CH, Arnsten AFT, Padala PR, Brawman-Mintzer O, Lerner AJ, Porsteinsson AP, Scherer RW, Levey AI, Herrmann N, Jamil N, Mintzer JE, Lanctôt KL, Rosenberg PB (2021) Neurobiologic rationale for treatment of apathy in Alzheimer’s disease with methylphenidate. Am J Geriatr Psychiatry 29:51–62
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135
Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L, Xu W, Li JQ, Wang J, Lai TJ, Yu JT (2016) The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190:264–271
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Lee, CW., Chen, JY., Ko, CC. et al. Efficacy of methylphenidate for the treatment of apathy in patients with Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled studies. Psychopharmacology 239, 3743–3753 (2022). https://doi.org/10.1007/s00213-022-06261-y
- Apathy Evaluation Scale
- Alzheimer’s disease
- Neuropsychiatric inventory apathy