Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer’s Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial

Schneider, Lon S.; Frangakis, Constantine; Drye, Lea T.; Devanand, Devangere P.; Marano, Christopher; Mintzer, J.; Mulsant, Benoit H.; Munro, Cynthia A.; Newell, Jeffery; Pawluczyk, Sonia; Pelton, Gregory H.; Pollock, Bruce G.; Porsteinsson, Anton P.; Rabins, Peter V.; Rein, Lisa; Rosenberg, Paul B.; Shade, David M.; Weintraub, Daniel; Yesavage, Jerome A.; Lyketsos, Constantine G.

doi:10.1176/appi.ajp.2015.15050648

Cited by 79 publications

(41 citation statements)

References 23 publications

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“…Like other SSRIs, citalopram can cause akathisia and other extra-pyramidal symptoms (440), although they do so less commonly than antipsychotics. An analysis to assess heterogeneity of response showed that it was not effective for those with more severe agitation, with more impaired cognition and in patients who resided in long-term care (441). It showed no efficacy on the agitation scale of the neuropsychiatric inventory (442).…”

Section: Other Drugs For Agitationmentioning

confidence: 98%

Dementia prevention, intervention, and care

et al. 2017

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People with dementia are usually older, often have co-morbidities and may need help in coping with these illnesses. A third of older people now die with dementia and all professionals working in endof-life care need to make this a central part of their planning and communication. In this commission, we have detailed evidence-based approaches to dementia and its symptoms. Services should be available, scalable and give value. As there are limited resources, professionals and services need to use what works, not use what is ineffective, and be aware of the difference. Overall, there is good potential for prevention and, once someone develops dementia, for care to be high-quality, accessible, and give value to an under-served, growing population. Effective dementia prevention and care could transform the future for society and vastly improve living and dying for individuals with dementia and their families. Acting now on what we already know can make this difference happen. Key Messages 1 There are increasing numbers of people with dementia globally although incidence in some countries has decreased. 2 Be ambitious about prevention: We recommend energetically treating hypertension in middle aged and older people without dementia to reduce dementia incidence. Interventions for other risk factors, including more childhood education, exercise, maintaining social engagement, reducing smoking, and management of hearing loss, depression, diabetes and obesity; may have the potential of delaying or preventing a third of dementias. 3 Treat cognitive symptoms: To maximise cognition, people with Alzheimer's dementia or Dementia with Lewy Bodies should be offered Cholinesterase Inhibitors (ChEIs)at all stages, or memantine for severe dementia. ChEIs are not effective in Mild Cognitive Impairment. 4 Individualise dementia care: Good dementia care spans medical, social and supportive care, should be tailored to unique individual and cultural needs, preferences, priorities, and should incorporate support for the family carers 5 Care for family carers. Family carers are at high risk of depression. Effective interventions reduce the risk and treat the symptoms, include START (Strategies for Relatives) or REACH (Resources for Enhancing Alzheimer's Caregiver Health intervention) and should be made available. 6 Plan for the future. People with dementia and their families value discussions about the future and decisions about possible attorneys to make decisions. Clinicians should consider capacity to make different types of decisions at diagnosis. 7 Protect people with dementia. People with dementia and society require protection from possible risks of the condition, including self-neglect, vulnerability including to exploitation, managing money, driving or using weapons. Risk assessment and management at all stages of the disease is essential but it should be balanced against the persons' right to autonomy. 8 Manage neuropsychiatric symptoms. Management of the neuropsychiatric symptoms of dementia including agitation, low mood or psyc...

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Section: Other Drugs For Agitationmentioning

confidence: 98%

Dementia prevention, intervention, and care

et al. 2017

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“…Interestingly, serotonin is phylogenetically the oldest neurotransmission system present involved in cognition and memory in both vertebrate and invertebrate species, and pathological alterations in 5-HT metabolism and/or down-regulation of serotonergic signaling have been associated with various pathophysiological conditions in the CNS including amyloidogenesis and SP formation, hyper-phosphorylation of tau and NFT formation, two classical aggregates that in part characterize AD brain neuropathology (McClam et al, 2015; Panza et al, 2015; Butzlaff and Ponimaskin, 2016; Wirth et al, 2016). Due to the extensive serotonergic denervation observed in AD and the important roles played by serotonin in both behavior and cognition, this neurotransmitter system has become a focus of dedicated research efforts to identify novel pathways in Aβ peptide or NFT assembly and/or aggregation (Butzlaff and Ponimaskin, 2016; Schneider et al, 2016; Wirth et al, 2016). Serotonin has been found to increase by 4-fold, respectively in AD raphe cell bodies over controls, while in amygdala synaptic terminals 5-HT was decreased to 0.4-fold in the same AD cases; the accumulation of TPH and its products in the raphe perikarya in AD as the result of diminished transport of TPH to axon terminals and the accumulation of oxidative metabolites of serotonin may contribute to the degeneration of serotonergic neurons in AD (Burke et al, 1990; Wirth et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…For example, SSRI such as the antianxiety/ antidepressant citalopram hydrobromide (Celexa) has been used in AD with varying success while antipsychotics remain the pharmacological agents with most evidence to support their use (Gallagher and Herrmann, 2015). On the other hand other recent investigations, as part of the recent Citalopram for Agitation in Alzheimer Disease (CitAD) study, indicate that higher doses of SSRIs such as citalopram actually may trigger aggression especially in patients with more severe cognitive impairment encountered in the more advanced stages of AD (Schneider et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Genetics of Aggression in Alzheimer’s Disease (AD)

Lukiw

Rogaev

2017

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype.

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“…13 The modest benefits provided by anxiolytics or typical/atypical antipsychotics that clinicians prescribe to mitigate hallucinations and delusions in ADP are associated with considerable adverse effects, such as accelerated cognitive decline and increased short-term mortality in elderly populations. [14][15][16] Disruptive behaviors and significant impairments in interpersonal relationships and social functioning make agitation and aggression one of the most difficult symptoms to treat. 17,18 However, the underlying causes and mechanisms of agitation and aggression are multifaceted and not well understood.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the efficacy of pimavanserin in the treatment of agitation and aggression in patients with Alzheimer's disease psychosis: A post hoc analysis

Ballard

Coate

Abler

et al. 2020

Int J Geriat Psychiatry

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Funding information ACADIA Pharmaceuticals Inc Objectives: Patients with Alzheimer's disease psychosis (ADP) commonly experience concomitant agitation and aggression. We investigated whether a reduction in ADP following pimavanserin treatment conferred a reduction in associated agitation and aggression. Methods: ACP-103-019 was a 12-week, randomized, double-blind, placebocontrolled study that evaluated the efficacy of pimavanserin (34 mg) in reducing psychotic symptoms in patients with ADP. The primary endpoint was change from baseline in Neuropsychiatric Inventory-Nursing Home Version-Psychosis Score (NPI-NH-PS) at week six. A post hoc analysis examined whether there was a greater reduction in agitation and aggression (NPI-NH domain C [agitation/aggression] and Cohen-Mansfield Agitation Inventory-Short Form [CMAI-SF]) in pimavanserintreated patients who experienced a reduction of hallucinations and delusions (psychosis responders defined as ≥50% reduction from baseline in NPI-NH-PS, week six) when compared with those who did not (nonresponders). Results: Pimavanserin-treated patients with ≥50% response in psychotic symptoms (n = 44) showed a greater improvement in agitation and aggression symptoms on the NPI-NH domain C (week six, least squares mean [LSM] difference = −3.64, t = −4.69, P < .0001) and the CMAI-SF (week six, LSM difference = −3.71, t = −2.01, P = .0483) than nonresponders (n = 32). Differences between psychosis responders and nonresponders were also observed in patients with more severe agitation and aggression at baseline on the NPI-NH domain C (responders, n = 26; nonresponders, n = 13; week six, LSM difference = −3.03, t = −2.44, P = .019). Conclusions: Patients with ADP, who show improvement in psychotic symptoms after pimavanserin treatment, also experience an improvement in concomitant agitation and aggression.

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Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer’s Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial

Cited by 79 publications

References 23 publications

Dementia prevention, intervention, and care

Dementia prevention, intervention, and care

Genetics of Aggression in Alzheimer’s Disease (AD)

Evaluation of the efficacy of pimavanserin in the treatment of agitation and aggression in patients with Alzheimer's disease psychosis: A post hoc analysis

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