Pharmacological Management of Apathy in Dementia

Abstract

Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer’s disease [AD], Huntington’s disease [HD] and Parkinson’s disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics—such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)—that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs.

Appendix

Quality assessment risk of bias summary

Study	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Binding of participant and personnel (performance bias)	Binding of outcome assessments (detection bias)	Incomplete outcome data (attrition bias)	Selective outcome reporting (reporting bias)	Other bias
Åhlin et al. [66]	+	+	+	+	+	+	+
Araki et al. [103]	+	+	−	?	+	+	+
Bachinskaya et al. [159]	+	+	+	+	+	+	+
Ban et al. [157]	+	+	+	+	+	+	+
Barone et al. [42]	+	+	+	+	+	−	+
Bayer et al. [160]	+	+	+	+	+	+	+
Callegari et al. [162]	+	+	+	+	+	+	?
Castrioto et al. [41]	+	+	+	+	+	+	+
Cummings et al. [58]	?	?	?	?	+	+	+
Cummings et al. [53]	+	+	+	+	+	+	?
De Deyn et al. [37]	+	+	+	+	+	+	?
De Deyn et al. [36]	+	+	+	+	+	−	?
Devos et al. [67]	+	+	+	+	+	+	+
Dubois et al. [56]	+	+	+	+	+	+	+
Erkinjuntti et al. [69]	+	+	+	+	+	+	+
Feldman et al. [63]	+	+	+	+	+	+	+
Finger et al. [161]	+	+	+	+	+	+	+
Frakey et al. [33]	+	+	+	+	+	+	+
Gauthier et al. [61]	+	+	+	+	+	+	+
Gauthier et al. [60]	+	+	+	+	+	+	+
Gauthier et al. [104]	?	?	?	?	+	+	?
Gelderblom et al. [89]	+	+	+	+	+	+	+
Hauser et al. [40]	+	+	+	+	+	+	+
Herrmann et al. [52]	+	+	+	+	+	+	?
Herrmann et al. [29]	+	+	+	+	+	+	?
Holmes et al. [62]	+	+	+	+	+	+	+
Kaufer et al. [54]	+	+	+	+	+	+	?
Kim et al. [156]	+	+	+	+	+	+	+
Lanctôt et al. [77]	+	+	+	+	+	+	+
Lawlor et al. [76]	+	+	+	+	+	+	?
Lebert et al. [81]	+	+	+	+	+	+	+
Leonpacher et al. [79]	+	+	+	+	+	−	?
Maier et al. [88]	+	+	+	+	+	+	+
McKeith et al. [68]	+	+	+	+	+	+	+
Mintzer et al. [32]	+	+	+	+	+	+	+
Moreau et al. [39]	+	+	+	+	+	+	+
Morris et al. [55]	+	+	+	+	+	+	+
Nave et al. [34]	+	+	+	+	+	+	+
Nyth and Gottfries [80]	+	+	+	+	+	+	+
Padala et al. [30]	+	+	+	+	+	+	+
Pollock et al. [35]	+	+	+	+	+	−	?
Raskind et al. [57]	+	+	+	+	+	+	+
Rea et al. [65]	+	+	+	+	−	−	+
Rosenberg et al. [31]	+	+	+	+	+	+	+
Rosenberg et al. [154]	+	+	+	+	+	+	+
Scripnikov et al. [158]	+	+	+	+	−	−	?
Seltzer et al. [64]	+	+	+	+	+	+	+
Sival et al. [97]	+	+	+	+	+	+	+
Tariot et al. [59]	+	+	+	+	+	+	+
Trzepacz et al. [155]	+	+	+	+	+	+	+
Winblad and Poritis [107]	+	+	+	+	+	+	+
Zhou et al. [78]	+	+	+	+	+	+	+

1. + indicates low risk of bias; – indicates high risk of bbias; ? indicates unclear risk of bias