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. 2018 May;32(5):509-523.
doi: 10.1177/0269881117744996. Epub 2018 Jan 17.

Sequential drug treatment algorithm for agitation and aggression in Alzheimer's and mixed dementia

Simon Jc Davies  1   2   3 , Amer M Burhan  3   4 , Donna Kim  1   2   3 , Philip Gerretsen  1   2   3   5 , Ariel Graff-Guerrero  1   2   3   5 , Vincent L Woo  1   2   3 , Sanjeev Kumar  1   2   3 , Sarah Colman  1   2   3 , Bruce G Pollock  1   2   3 , Benoit H Mulsant  1   2   3 , Tarek K Rajji  1   2   3
Affiliations

Sequential drug treatment algorithm for agitation and aggression in Alzheimer's and mixed dementia

Simon Jc Davies et al. J Psychopharmacol. 2018 May.

Abstract

Introduction: Behavioural and psychological symptoms of dementia (BPSD) include agitation and aggression in people with dementia. BPSD is common on inpatient psychogeriatric units and may prevent individuals from living at home or in residential/nursing home settings. Several drugs and non-pharmacological treatments have been shown to be effective in reducing behavioural and psychological symptoms of dementia. Algorithmic treatment may address the challenge of synthesizing this evidence-based knowledge.

Methods: A multidisciplinary team created evidence-based algorithms for the treatment of behavioural and psychological symptoms of dementia. We present drug treatment algorithms for agitation and aggression associated with Alzheimer's and mixed Alzheimer's/vascular dementia. Drugs were appraised by psychiatrists based on strength of evidence of efficacy, time to onset of clinical effect, tolerability, ease of use, and efficacy for indications other than behavioural and psychological symptoms of dementia.

Results: After baseline assessment and discontinuation of potentially exacerbating medications, sequential trials are recommended with risperidone, aripiprazole or quetiapine, carbamazepine, citalopram, gabapentin, and prazosin. Titration schedules are proposed, with adjustments for frailty. Additional guidance is given on use of electroconvulsive therapy, optimization of existing cholinesterase inhibitors/memantine, and use of pro re nata medications.

Conclusion: This algorithm-based approach for drug treatment of agitation/aggression in Alzheimer's/mixed dementia has been implemented in several Canadian Hospital Inpatient Units. Impact should be assessed in future research.

Keywords: Dementia; agitation; algorithm; drug treatment.

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Conflict of interest statement

Declaration of grant support and conflicting interests: S Davies receives grant support from the Centre for Addiction and Mental Health (CAMH)/University of Toronto, National Institute for Health Research (NIHR) (UK), Canadian Centre for Ageing and Brain Health Innovation, Canadian Consortium for Neurodegeneration in Aging (CCNA) and Medical-Psychiatry Alliance. A Burhan has been a co-investigator over the last two years on two funded Canadian Institutes of Health Research (CIHR) and CCNA team projects related to prevention of neuropsychiatric symptoms of dementia and cognition and mobility, a sub-investigator on a National Institutes of Health (NIH) funded trial on Citalopram in agitation of Alzheimer’s disease (completed 2015) and site principal investigator on NIH funded trial of S-citalopram in agitation of Alzheimer’s disease (to begin recruitment September 2017), the principal investigator on a St Joseph’s Health Care London funded project on actigraphy as a measure of agitation in dementia, and a co-investigator on a Schulich School of Medicine Dean Innovation funded trial of trans-cranial magnetic stimulation on executive functioning in seniors with cognitive disorders. He states that no direct conflict of interest is perceived given that all the studies are peer-funded and manuscripts use generic medication names and rely on published literature and guidelines. P Gerretsen reports receiving fellowship awards and grant support from CIHR, Ontario Mental Health Foundation and CAMH. A Graff-Guerrero has received support from the US NIH, CIHR, Ontario Mental Health Foundation, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain and Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, W. Garfield Weston Foundation and Brain Canada. S Kumar currently receives grant support from NIH, USA, Brain and Behavior Foundation, USA, Brain Canada, Weston Brain Institute, Ontario Brain Institute, Canadian Centre for Ageing and Brain Health Innovation and CCNA. B Pollock receives research support from the NIH, CIHR, American Psychiatric Association and CAMH Foundation. He has been a faculty member of the Lundbeck International Neuroscience Foundation (last meeting was April 2010). B Mulsant currently receives research support from Brain Canada, CIHR, CAMH Foundation, Patient-Centered Outcomes Research Institute (PCORI), US NIH, Eli Lilly (medications for a NIH-funded clinical trial), Pfizer (medications for a NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). Within the past five years he has also received research support from Bristol-Myers Squibb (medications for a NIH-funded clinical trial) and Pfizer/Wyeth (medications for a NIH-funded clinical trial). He directly owns stocks of General Electric (less than $5,000). T Rajji has received research support from Brain Canada, Brain and Behavior Research Foundation, Canadian Foundation for Innovation, CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, NIH, and W. Garfield Weston Foundation. The remaining authors have no interests to declare.

Figures

Figure 1.
Figure 1.
Summary of drugs, illustrating main pathway, pro re nata (PRN) drugs and Alzheimer’s disease treatments. ECT: electroconvulsive therapy.
Figure 2.
Figure 2.
Assessment of sequential drug treatment algorithm medications in five domains. Key: Five domains are listed in descending order of importance in their contribution for ranking the drugs in the sequential medication algorithm. Efficacy: strength of evidence for efficacy in agitation/aggression in Alzheimer’s or mixed Alzheimer’s/vascular dementia. Time to onset: time to onset of clinical effect. Tolerability: tolerability/side effect profile. Ease of use: potential for interactions/disruption of co-prescribed medication. Efficacy/other: evidence in other relevant conditions beyond behavioural and psychological symptoms of dementia (BPSD), including anxiety disorders. Green indicates that the drug was given the highest rating, yellow intermediate rating and red the lowest rating. For instance, risperidone is rated “green” for efficacy due to the existence of multiple successful randomized trials, while gabapentin is rated “red” as evidence relies on case reports/case series only. The remaining drugs are rated “yellow” or intermediate on efficacy since positive randomized controlled trials are more limited, or evidence is based on meta-analysis of randomized trials.
Figure 3.
Figure 3.
Drug clean-up principles. AchEI: acetycholinesterase inhibitor; BPSD: behavioural and psychological symptoms of dementia; PRN: pro re nata.
Figure 4.
Figure 4.
Flow chart illustrating sequential medication algorithm. AV: atrioventricular; BPSD: behavioural and psychological symptoms of dementia; CGI; Clinical Global Impression; ECT: electroconvulsive therapy; EPSE: extrapyramidal side effect; PO: per os (oral); RCT: randomized controlled trial; SE: side effect; SSRI: selective serotonin reuptake inhibitor.
See this image and copyright information in PMC

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