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Management of agitation and aggression associated with Alzheimer diseaseClive G. Ballard, Serge Gauthier, Jeffrey L. Cummings, Henry Brodaty, George T. Grossberg, Philippe Robert and Constantine G. Lyketsos Abstract Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia (BPsD). These symptoms are disturbing for individuals with Alzheimer disease, commonly confer risk to the patient and others, and present a major management challenge for clinicians. The most widely prescribed pharmacological treatments for these symptoms—atypical antipsychotics—have a modest but significant beneficial effect in the short-term treatment (over 6–12 weeks) of aggression but limited benefits in longer term therapy. Benefits are less well established for other symptoms of agitation. in addition, concerns are growing over the potential for serious adverse outcomes with these treatments, including stroke and death. A detailed consideration of other pharmacological and nonpharmacological approaches to agitation and aggression in patients with Alzheimer disease is, therefore, imperative. This article reviews the increasing evidence in support of psychological interventions or alternative therapies (such as aromatherapy) as a first-line management strategy for agitation, as well as the potential pharmacological alternatives to atypical antipsychotics—preliminary evidence for memantine, carbamazepine, and citalopram is encouraging.
King's College London, London, UK Ballard, C. G. et al. Nat. Rev. Neurol. 5, 245–255 (Cg Ballard). Alzheimer's Disease and related Disorders Unit, McGill Center for studies in Aging, worldwide, almost 25 million people have dementia, than 90% of people with dementia develop at least one Douglas Mental Health 50–75% of whom have alzheimer disease (aD).1 aD is BPsD,2 with around 85% of cases having serious clinical University institute, a devastating illness that results in a progressive decline implications.3 these symptoms are frequently distressing Montreal, QC, Canada (S gauthier). University in cognitive ability and functional capacity, causes for the patient,4 and problema tic for the carer,5 in whom of California, Los immense distress to patients, their carers, and their fami­ they can result in clinical depression.6 in addition, BPsD Angeles, Alzheimer's Disease Center, lies, and has an enormous effect on society. numerous are often the precipitant for transfer of the patient to Los Angeles, CA, UsA issues surround this disease in terms of research priori­ institutional care.7 (Jl Cummings). Primary ties and the clinical treatments used; such issues include BPsD present as three main syndromes—agitation, Dementia Collaborative research Centre, the develop ment of disease­modifying treatments, the psychosis, and mood disorders8—and these syndromes school of Psychiatry, discovery of diagnostic biomarkers, and the identifica­ frequently co­exist. almost all BPsD increase in fre­ University of New south wales, sydney, Nsw, tion of effective disease­ prevention strategies. although quency and severity over time.2 in the common scenario Australia (H Brodaty). these are crucial long­term goals, the most frequent of a patient who presents with simultaneous and multi ple issue for people with aD who present to clinical services symptoms, clinicians should not group together dispar ate Neurology and Psychiatry, st Louis remains the manage ment of behavioral and psycho­ symptom clusters that could have different bio logical and University school of logical symptoms of dementia (BPsD), also known as psychosocial triggers. For example, apathy and depres­ Medicine, st Louis, MO, UsA (gT grossberg). neuro psychiatric symptoms. over a 5­year period, more sion are very different from aggression and paranoid Memory Center for delusions, and an appreciation of such complexity is Care and research, Centre Hospitalier Competing interests vital to determine the appropriate treatment for BPsD Universitaire de Nice, C. G. Ballard has declared associations with the following syndromes. this review focuses on treatment strategies Hôpital Pasteur, Nice, companies: Arcadia, esai, Lundbeck A/s, Novartis, shire and for agitation and aggression. these symptoms become France (P robert). wyeth. s. Gauthier has declared associations with the increasingly evident as aD progresses (Figure 1), are following companies: Lundbeck and Merz Pharmaceuticals. Psychiatry, The Johns J. L. Cummings has declared associations with the following the most likely symptoms to require pharmacological companies: Forest, Janssen, Lundbeck, Merz Pharmaceuticals, intervention, and often present considerable treatment Baltimore, MD, UsA Novartis and Pfizer. H. Brodaty has declared an association di lemmas for clinicians. Common symptoms of aggres­ (Cg lyketsos).
with the following company: Lundbeck. G. T. Grossberg has sion in people with aD include verbal insults and shout­ declared associations with the following companies: elan, Forest, Medivation, Novartis, PAM Labs, Pfizer and wyeth. ing, as well as physical aggression such as hitting and CG Ballard, wolfson P. robert has declared associations with the following biting others, and throwing objects. these symptoms Centre for Age related companies: esai Pharma, Janssen, Lundbeck A/s, Novartis most commonly manifest when people with aD are and wyeth. C. G. Lyketsos has declared associations with the being assisted with personal care. Common symptoms following companies: Forest, Lilly, Novartis, Pfizer and wyeth. London se1 1UL, UK see the article online for full details of the relationships. of agitation include restlessness and pacing, excessive nature reviews neurology volume 5 maY 2009 245
2009 Macmillan Publishers Limited. All rights reserved Key points
group of patients. when specific data are not available on the treatment of agitation and aggression, data on the ■ Agitation and aggression are frequent and distressing symptoms that present major management problems in people with Alzheimer disease (AD) overall treatment of BPsD will be presented if thought to be of particular importance. we will also briefly discuss ■ Atypical antipsychotics are widely used in the pharmacological treatment of emerging biological findings that should inform further agitation and aggression, but their benefit is primarily limited to short-term management of aggression development of pharmacological treatments for agitation and aggression. where the evidence is incomplete, this serious adverse events are associated with atypical antipsychotics in AD, including increased risk of stroke and death review provides the consensus opinion of the authors to help guide clinical decision­making.
An evidence base is emerging to support a variety of practical and easy-to-implement nonpharmacological treatments for the first-line treatment of agitation and aggression in AD ■ Further clinical trials of pharmacotherapy for agitation and aggression in AD are antipsychotic drugs (usual y now referred to as ‘typical urgently needed, but preliminary data indicate that memantine, citalopram and antipsychotics') were introduced as a treatment for schizo­ carbamazepine could be promising alternatives to atypical antipsychotics phrenia in the 1950s and 1960s, and by the 1970s these drugs were in frequent clinical use as an ‘off­licence' treat­ ment for agitation, aggression, and other BPsD. in the early 1990s, atypical antipsychotics such as ris peridone, olanzapine, and quetiapine were introduced for the treat­ ment of schizophrenia. the adverse­effect profiles of atypical agents are general y favorable in comparison to those of typical agents, and consequently atypical anti­ psychotics became the preferred option for the treatment of agitation and aggression (and other BPsD) in patients with aD by the mid­1990s. However, several important issues relate to the use of these agents in patients with aD, which we outline in the following sections.
Typical antipsychotics Frequency (% of patients) 11 randomized, placebo­controlled trials have been carried out of typical antipsychotics for the treatment Socially unacceptable behavior of BPsD, which mostly involved small sample sizes and were performed over periods of between 4 and 12 weeks Sexually inappropriate behavior (see table 1).9–12 with a good outcome defined as a 30% improvement on standardized behavioral rating scales, Time before/after diagnosis (months) as per convention, a significant but modest advantage Figure 1 Peak frequency of behavioral symptoms as Alzheimer disease
of typical antipsychotics over placebo (59% versus 41%) progresses. Permission obtained from Blackwell Publishing Jost, B. C. & has been reported, albeit in the context of a high placebo Grossberg, G. T. J. Am. Geriatr. Soc. 44, 1078–1081 (1996).
response.9 the most comprehensive evidence within this drug class on treatment of agitation and aggression pertains to haloperidol, in which four randomized con­ fidgeting, motor activities associated with anxiety (such trolled trials (rCts) have been completed. these trials as hand wringing and following a carer around the indicated a significant improvement in symptoms of house), and abnormal vocalizations.
aggression with haloperidol compared with placebo, Given the limited evidence base to guide treatment but showed no substantial improvement with the drug decisions, the management of agitation and aggression in other symptoms of agitation.13 very little clinical trial is often based on clinical judgment. such management is evidence is available on other typical antipsychotics in becoming a progressively more challenging and contro­ the treatment of agitation or aggression.
versial area of clinical practice because of increasing typical antipsychotics are, however, associated with evidence that, in people with dementia, the use of anti­ several severe adverse effects in patients with aD. these psychotic drugs—which have traditional y been used as a effects include parkinsonism,13 dystonia, tardive dys­ first­line management approach for these symptoms—is kinesia,14 and Qtc­interval prolongation.15 the last of associated with serious adverse effects. in this review, these effects has been demonstrated with several previ­ we present a summary of the evidence for benefit and ously widely prescribed typical antipsychotics, including harm related to the use of antipsychotic drugs for the thiori dazine and droperidol;15 both have now either been treatment of agitation and aggression in patients with withdrawn or are prescribed infrequently to people with aD, followed by a review of the evidence for alternative dementia. Furthermore, a significant increase in mor­ nonpharmacological and pharmacological approaches tality associated with typical anti psychotics compared for the management of agitation and aggression in this with atypical antipsychotics has been identified in people 246 MAY 2009 voluMe 5
2009 Macmillan Publishers Limited. All rights reserved Table 1 Pharmacological treatment of agitation and aggression in people with dementia
Major adverse effects significant but modest advantage over placebo for Parkinsonism, dystonia, Adverse events associated with placebo-control ed behavioral symptoms in early meta-analysis tardive dyskinesias; typical antipsychotics make their trials, mostly small Thioridazine: only one placebo-control ed trial showed QTc-interval prolongation; use inadvisable in people with sample sizes and of significant benefit in recent meta-analysis significant increase in Alzheimer disease 4–12 weeks' duration; mortality compared with one up to 16 weeks' Thiothixine: a smal study suggested efficacy at low atypical antipsychotics doses but that symptoms return after discontinuation (administered for Haloperidol: meta-analysis indicated improvement in ≤180 days, relative risk aggression but not in other symptoms of agitation 18 placebo-controlled significant benefit in the treatment of aggression over Parkinsonism; sedation; Probably stil the best option for trials over 6–12 increased mortality short-term (6–12 weeks) treatment weeks; only three Limited benefit for other symptoms and lack of (1.5–1.7-fold); increased of aggression that is severe, trials of 6–12 months benefit over treatment periods longer than 12 weeks cerebrovascular adverse persistent, and treatment events (threefold) resistant, but serious adverse events are a major contraindication to long-term therapy More than 30 rCTs No benefit in agitation over 12–24 weeks in two of General y wel tolerated; evidence from the total pool of over 6–12 months, the three trials that focused on patients with clinical y gastrointestinal symptoms, trials suggests an overal effect on relevant agitation including nausea and neuropsychiatric symptoms over specifically in people vomiting, are the most 6 months, but the main benefits with clinically relevant frequent adverse effects are probably for anxiety and apathy rather than agitation Benefit in irritability, lability, agitation, aggression and very wel tolerated; low risk Promising treatment, but a 3–6 months, none psychosis over 3–6 months in individual studies, prospective study in patients specifical y in patients meta-analysis and pooled analyses with clinical y significant agitation significant benefit in a pooled analysis of patients important agitation with at least one symptom of aggression, agitation One comparative trial Trazodone: meta-analysis concluded insufficient Generally well tolerated evidence base for ssris is and one paral el-group evidence of efficacy encouraging but preliminary; large rCT of trazodone; Citalopram: equivalence to other active treatments in placebo-control ed trials of long one small placebo- active-comparator trials, with efficacy over placebo duration are urgently needed; control ed rCT and in one small placebo-controlled trial further work is needed to one active-comparator establish whether a differential rCT of citalopram; sertaline: significant benefits for agitation in response is shown by genotype or one rCT of sertaline a post hoc analysis in placebo-controlled rCT in patients with affective and/or psychotic symptoms Two small, short, Carbamazepine: significant improvement in behavioral Carbamazepine Promising treatment option; placebo-control ed symptoms in one of the two rCTs, with overall benefit demonstrated good a larger and longer clinical trial is confirmed in a meta-analysis of the two trials tolerability over short term needed; long-term safety also sodium valproate: Cochrane review concluded cannot in the rCTs, but drug–drug needs to be established; further mainly open trials or be tolerated in clinically effective doses interactions are a potential work is needed to determine case series with other concern; have the whether a preferential response is anticonvulsants such Gabapentin: evidence very preliminary potential to impair balance shown in agitated patients with as sodium valproate and increase risk of falls; concurrent affective symptoms mortality does not seem Abbreviations: rCT, randomized controlled trial; ssris, selective serotonin reuptake inhibitors.
with dementia (relative risk 1.37 over ≤180 days).16 Conse­ haloperidol were all widely used in the clinical setting; quently, despite the modest benefits of short­term therapy however, prescription practice has changed substantial y with typical antipsychotics, serious concerns have arisen following specific concerns related to the cardiac safety of over the use of these agents in the treatment of people thioridazine, and general concerns regarding the side­effect with dementia. until 2000, thioridazine , promazine and profile of typical antipsychotics. atypical antipsychotics nature reviews neurology volume 5 maY 2009 247
2009 Macmillan Publishers Limited. All rights reserved are now more widely prescribed than typical agents, and because the category of ‘serious cerebrovascular events' in thioridazine is prescribed very infrequently—although a these trials was broad and was not operational y defined. 2007 study that investigated antipsychotic prescriptions in However, summary data suggest that the increase in the care homes revealed that of patients with dementia who incidence of cerebrovascular adverse events with ris­ were receiving an anti psychotic, 28% were prescribed a peridone was similar to that seen in placebo­controlled trials of olanzapine in aD (1.3% for olanzapine at all doses versus 0.4% for placebo),20 and the general consen­ Atypical antipsychotics sus seems to be that this association is probably a class since 1995, 18 placebo­controlled trials have examined effect for atypical antipsychotics. evidence is insufficient the efficacy of atypical antipsychotics in patients with aD, to determine whether the increased risk also applies to mainly over treatment periods of 6–12 weeks (see table 1). only nine of these studies are in the public domain—four two other key issues have emerged from meta­analyses compared risperidone with placebo, one com pared ris­ that have combined the results of trials with al atypical peri done and olanzapine with placebo, one com pared antipsychotics. Firstly, schneider's meta­analysis highlights olanza pine with placebo, one compared quetia pine with a significant acceleration in the rate of cognitive decline placebo, and two compared aripiprazole with placebo. in people who received atypical antipsychotics compared these studies are reviewed in full by Bal ard and Howard18 with those treated with placebo over 12 weeks; cognitive and schneider et al.19 decline as measured by the mini­mental state examination one key study of olanzapine and several key studies of (mmse) was 0.73 points greater in the drug group (all quetiapine are not in the public domain, which has made atypical antipsychotic trials at all doses: 95% Ci 0.38–1.09; meta­analysis of these agents' effects impossible. on the P <0.0001).19 this measured decline was approxi mately basis of published evidence, neither agent has a significant double that expected. secondly, and of even greater impor­ beneficial effect on agitation overal .18 meta­analyses have, tance, several meta­analyses indicate a signifi cant increase however, been conducted of risperidone and aripipra zole, in mortality associated with anti psychotic prescription. as al trials of these agents are ful y in the public domain. the FDa conducted an analysis based on data from 17 these meta­analyses highlight the efficacy of these agents of the placebo­controlled trials of atypical antipsychotics, in the short­term management (6–12 weeks) of aggres­ which identified a 1.6–1.7­fold increase in mortality for sion.18,19 the magnitude of benefit is similar for both agents, people taking atypical anti psychotics compared with those although these findings are based on a substantial y larger taking placebo over the 12 weeks of the trials.21 on the evidence base for risperidone, for which the effect size basis of these findings, the FDa published a warning notice compared with placebo on the BeHav­aD (Behavioral of the significant increase in mortality risk for people Pathology in alzheimer Disease) rating scale is −0.84 with aD treated with atypical antipsychotics. schneider points (95% Ci −1.28 to −0.40 points) for a dose of 1 mg reviewed the evidence from 15 of these trials, confirm­ daily, and −1.50 points (95% Ci −2.05 to −0.95 points) for ing the significant increase in mortality (or 1.54, 95% Ci a dose of 2 mg daily, over 12 weeks of treatment.18 no trials 1.06–2.23; P = 0.02), but he found no difference between that have investi gated the use in aD of other widely used specific atypical antipsychotic drugs.22 atypical anti psychotics (such as amisulpride, sertindole , evidence for the medium­term to long­term effi­ clozapine, or zotepine) have been reported.
cacy of any of the atypical antipsychotics in aD is very adverse effects such as extrapyramidal symptoms, limited; the rCts that were conducted over periods of drowsiness, and peripheral edema are commonly associ­ 6–12 months either found that atypical anti psychotics ated with all atypical antipsychotics. these effects have conferred no significant benefit in the treatment of been best quantified with regard to risperidone because aggression and agitation, or found that any advantages of rigorous adverse­event reporting and a large number of were offset by adverse effects.23–25 in addition, none of the trials with this agent. meta­analyses of the trials that have studies that focused on randomized withdrawal of anti­ compared risperidone against placebo in aD demon strate psychotic drugs in patients in nursing homes or with a significant increase in extra pyramidal symptoms (1 mg dementia (who had been receiving medium­term to long­ odds ratio [or] 1.78, 95% Ci 1.00–3.17; 2 mg or 3.39, term treatment with these agents) indicated a significant 95% Ci 1.69–6.80), drowsiness (1 mg or 2.38, 95% Ci exacerbation of agitation and aggression, or other BPsD, 1.76–3.20; 2 mg or 4.46, 95% Ci 2.30–8.64), and periph­ after antipsychotics were stopped.26–28 Further to these eral edema (1 mg or 2.75, 95% Ci 1.51–5.03; 2 mg or findings, it seems that the effect of some severe adverse 3.80, 95% Ci 1.74–8.29) over 12 weeks of treatment.18 a events, such as accelerated cognitive decline and mor tality, more serious potential concern pertains to cerebro vascular could be exacerbated with prolonged treatment.23,29 For events. Pooled data from the placebo­controlled trials of example, in the Dementia antipsychotic withdrawal trial risperidone in aD showed that risperidone was associated (Dart­aD), survival at 24 months was 46% in patients with a threefold increased risk of serious cerebro vascular randomly assigned to continue antipsychotics, compared adverse events compared with placebo (or 3.43, 95% Ci with 71% in patients assigned to placebo.29 1.60–7.32; P = 0.001).19 although extremely worrying, Despite the safety concerns over atypical anti psychotics, these data are difficult to interpret in a clinical context these agents do have the best documented evidence for 248 MAY 2009 voluMe 5
2009 Macmillan Publishers Limited. All rights reserved short­term efficacy in the treatment of aggression, aggression, and other BPsD, fluctuate greatly in sever­ although the meta­analyses conducted to date have not ity and often resolve or improve spontaneously over indicated significant benefit for the treatment of non­ 4–6 weeks. For mild to moderate symptoms, therefore, a aggressive symptoms of agitation.18,19 use of these drugs period of monitoring wherein relatives or care staff keep should probably be restricted to short­term manage­ a diary of symptoms can often provide valuable insights and ment (up to 12 weeks) of severe physical aggression. can help to avoid premature and unnecessary treatment Detailed clinical recommendations are provided later in for symptoms that might resolve spontaneously. sometimes, this review.
however, additional treatment will be required.
The alternatives to antipsychotics
the treatment of agitation and aggression associated with aD is discussed here in the context of increasing concerns emerging evidence confirms that a variety of psycho­ over the widespread use of antipsychotics in people with logical or psychosocial interventions confer benefit in the aD. Firstly, we outline general principles for assessment treatment of agitation and aggression and other BPsD and treatment of BPsD, with the aim of highlighting the (see table 2). we suggest that these alternative therapies means by which premature or unnecessary administration should be considered before pharmacological therapies are of treatments for agitation and aggression can be avoided. prescribed. a systematic review, conducted by livingston secondly, we consider the role of nonpharmacological and and colleagues, identified 162 studies of specific psycho­ alternative therapies for agitation and aggression. Final y, logical interventions that satisfied the authors' inclusion we discuss the most promising pharmacological alterna­ criteria; selected trials analyzed "quantitative outcome tives to antipsychotics for the treatment of agitation and measures that were either direct or proxy measures of aggression in aD.
neuro psychiatric symptoms".31 the majority of studies were small and the evidence base for each specific inter­ general management principles vention was modest. therapeutic approaches used in the Before any specific treatments are considered for patients trials that met the review criteria included six trials of with aD who present with agitation and aggression, or reality orientation, two trials of validation therapy, four other BPsD, a broad and detailed clinical assessment is trials of reminiscence therapy, two trials of snoezelen essential. Physical health problems such as infection, therapy or multisensory stimulation, six trials of simulated­ pain or dehydration are common in patients with aD presence therapy, six trials of structured activity, six trials of and can often precipitate agitation and aggression. Pain music therapy, and three trials of environmental manipu­ can be difficult to assess in people with dementia and is lation. For many of these interventions the benefits were often under­diagnosed. urinary tract infections and chest unclear or were limited to the period during the inter­ infections are frequent triggers for agitation and aggres­ vention.31 in addition, several of these therapies fol ow a sion, but dental infections are also common and are often very structured intervention format and might, therefore, not recognized. treatment of concurrent physical health be difficult to implement in routine practice without the problems will frequently result in the resolution of agita­ local avail ability of specifical y trained practitioners. of tion and aggression, and other BPsD, without recourse the therapies identified in the livingston review, we high­ to any therapies aimed specifical y at targeting the BPsD. light validation therapy as a practical therapy with at least visual and auditory impairment can also precipitate some evidence of efficacy. this therapy is a pragmatic inter­ BPsD, which should be assessed for, and treated if pos­ vention based on principles of providing empathy for the sible. treatment may be as simple as changing the patient's patient and respecting the individual's reality. this therapy spectacles or hearing aid, or encouraging regular use of is usual y delivered in a group format, with involvement of such equipment. the degree of environmental stimula­ elements such as communication, reminiscence, and activi­ tion can also be an important trigger for certain BPsD ties that involve music and movement.32 a specific system­ syndromes, including agitation. For example, low light­ atic review identified three trials of validation therapy,32 ing and extreme noise levels (high or very low) can be each of which employed very different methods and com­ important precipitants of agitation and are often modifi­ parison groups, which precludes formal meta­analysis. the able. these principles are outlined in detail by lyketsos only study identified that compared validation therapy and colleagues.30 with usual care indicated a significant benefit for validation Consideration of the severity and consequences of any therapy on BPsD at 6 weeks. validation therapy seemed to behavioral or psychiatric symptoms is also important. For have similar efficacy to social interaction.32 example, symptoms might occur very inter mittently, might Cohen­mansfield and colleagues developed a ‘tool box' arise only in specific situations, or might not result in dis­ of simple and practical psychological interventions, such tress or risk to the individual or others. symptoms that as structured social interaction and meaningful activities, are infrequent or do not result in distress or risk might which can be individualized to the needs of a particular not require any specific therapy, or might be preferential y individual. a recent trial demonstrated a significant treated with a nonpharmacological approach, such as a decrease in agitation in patients with dementia with this psychological therapy (see next section). agitation and method, in comparison with usual care augmented by nature reviews neurology volume 5 maY 2009 249
2009 Macmillan Publishers Limited. All rights reserved Table 2 Non-pharmacological treatment of agitation and aggression in people with dementia
Two rCTs examined whether staff robust evidence from two large rCTs emerging evidence indicates that several training can reduce antipsychotic use indicates that staff training in nursing methods of training and psychological Two rCTs of individualized homes can reduce use of atypical interventions work well, but these approaches psychological intervention, one rCT antipsychotics without worsening are only effective if implemented and one open trial of ‘tool box' patients' behavior systematically by appropriately trained The rCTs of individualized psychological staff—which could limit potential availability Three rCTs of validation therapy, intervention and ‘tool box' intervention Probably the preferred first-line treatment several trials of other specific suggest significant benefit option when no high level of risk or extreme therapies such as reminiscence in small preliminary rCTs, validation therapy distress is present seems to be better than treatment as usual but comparable to social interaction Aromatherapy or herbal remedies38,40,43,85 Three short (all ≤4 weeks) placebo- All three trials demonstrated significant None—extremely safe and popular treatment approach controlled rCTs, two with lavender oil, benefits, but only the trial with melissa oil with encouraging emerging evidence one with melissa oil was included in the Cochrane meta-analysis because of methodological issuesOne additional trial that used oral melissa also indicated benefit Abbreviation: rCT, randomized controlled trial.
education. although this was a wel ­conducted and com­ psycho logical interventions) is, in the view of the authors, pelling study, treatment assignment could not be fully for aromatherapy.
randomized, and some caution must, therefore, be exer­ evidence is accumulating that aromatherapy with laven­ cised in the interpretation of the results.33 nevertheless, der oil, and therapy with Melissa of icinalis (lemon balm; this study probably provides the best evidence available as oil used for aromatherapy or extract used as a herbal for a relatively simple and straightforward psychosocial remedy) are efficacious at reducing agitation in demen­ treatment. in addition, an open trial has been conducted tia.38,40,42 the few rCts that have been conducted in this of brief psychosocial therapy,34 a simplified version of the area are summarized in table 2; all studies were small and Cohen­mansfield approach that focuses on structured were conducted over periods of 4 weeks or fewer.43 the social interaction between the person with aD and a care largest study, which focused on melissa oil aromatherapy, assistant for 10–15 min. the initial results were promising, randomly assigned 72 patients with severe dementia to but an rCt is needed.34 melissa oil or placebo.40 the oil was mixed into a base cream rCts have provided evidence that comprehensive and that was applied to participants' hands and arms twice daily. individualized interventions delivered by mental health the treatment resulted in a highly significant improve­ nurses, clinical psychologists or nursing home staff are ment in agitation, without any increase in adverse events, also effective; such interventions can be based on assess­ compared with placebo.40 the trials of lavender oil used an ment methods such as ‘antecedent behavior consequence' aroma­stream or similar approach to deliver the therapy.42,43 charts, or the ‘tool box' approach.35,36 rCts also indicate Both of the described methods are straightforward and can that intensive 6–12­month programs to educate staff in easily be implemented in clinical practice. larger, longer­ person­centered care can reduce the use of psycho tropic duration studies are needed, but the preliminary evidence medication in nursing homes, without a negative influence does indicate some efficacy for lavender or melissa oil on levels of agitated or disruptive behavior.36,37 aroma therapy in the treatment of agitation. aromatherapy with these agents has not been widely adopted in clinical Other nonpharmacological interventions practice, but we believe this approach should be seriously a variety of other nonpharmacological treatments have considered as an alternative to pharmaco logical therapy been investigated, including multisensory interventions in situations in which no immediate high level of risk is (such as those reviewed by livingston et al.31), herbal present for the individual or others.
reme dies,38 bright light therapy39 and aromatherapy.40 while some evidence shows that bright light therapy and related treatments such as melatonin might improve For agitation and aggression and other BPsD of sufficient or stabilize sleep and rest–activity rhythms,41 evidence severity to require a specific therapy, the majority of best­ that such therapy specifically influences symptoms of practice guidelines suggest that psychological inter ventions agitation is limited. the best evidence for alternative should be the first­line approach for most individuals with treatment approaches to agitation in aD (other than aD, a recommendation that seems reasonable on the basis 250 MAY 2009 voluMe 5
2009 Macmillan Publishers Limited. All rights reserved of the available evidence. validation therapy and structured of 2.2 points was shown for rivastigmine compared with social interaction are simple, practical treatments that are placebo in the treatment of agitation.23 this difference straightforward to admini ster. reasonable evidence is was not statistical y significant, but it perhaps indicates also available to support the value of other nonpharmaco­ the need for further studies with a focus on the long­term logical treatments, including aromatherapy. For persistent treatment of agitation with Cheis.
or severe symptoms, a more comprehensive intervention by a clinical psychologist might be a valuable alternative to individual studies, meta­analyses and pooled analyses in situations in which the risk to the individual or others indicate that memantine confers benefit in the treatment of is high, or when the patient is extremely distressed, initial agitation and aggression over 3–6 months in patients with treatment with an atypical antipsychotic might still be aD.52–56 the best evidence probably comes from a retro­ the best approach. However, in such circumstances, we spective analysis of all patients with at least one symptom strongly advise that antipsychotic treatment should not of aggression, agitation or psychosis, from pooled data continue for longer than 12 weeks. the introduction of of three placebo­controlled trials of memantine in mod­ nonpharmacological treatments could also enable the erate to severe aD (total 593 patients).56 in the patients withdrawal of antipsychotic drugs.
on memantine, agitation and aggression improved in 55.3% of patients by week 12, and in 61.0% by week 24. By comparison, the proportions of patients who improved the serious adverse events associated with the use of anti­ on placebo were 43.1% at week 12, and 45.0% at week 24. psychotic drugs in people with dementia have produced a a significant difference in favor of memantine was seen strong imperative to develop improved, safer pharmaco­ at both time points, with an effect size at 12 weeks that logical treatments for these patients. in current clinical was very similar to that seen in placebo­controlled trials practice, the key questions are whether other available of atypical antipsychotics for the treatment of aggression licensed compounds can provide useful pharmaco logical in aD. memantine was well tolerated, and, compared alternatives to atypical antipsychotics, and when the use of with individuals who received placebo, significantly these drugs should be considered. this section reviews the fewer memantine­treated patients withdrew from the evidence for the best candidate compounds and suggests study (22.9% versus 32.3%; P <0.01), or withdrew due to some recommendations for the use of these treatments in adverse events (10.3% versus 17.3%; P <0.05). rates of the clinical setting (see also table 1).
treatment­emergent adverse events were similar in the two groups (82.6% versus 79.9%). Benefits in cognition and function were also evident in memantine­treated patients rCts have provided evidence for the use of donepezil in compared with those who received placebo.56 the positive aD,44,45 rivastigmine in dementia with lewy bodies,46 and interpretation of this pooled analysis is that it provides galantamine in vascular dementia and in aD with con­ preliminary evidence for a beneficial influence of meman­ comitant cerebrovascular disease,47 but the be havioral tine on agitation and aggression over 12 and 24 weeks of effects of cholinesterase inhibitors (Cheis) have been treatment. the results do, however, need to be interpreted little recognized. Consideration of such effects could with great care as the data were analyzed retrospectively have positively contributed to the debate about the and the severity of agitation and aggression was general y useful ness of this class of drugs in the management of mild. the potential beneficial effects of memantine in the aD.48 a meta­analysis demonstrated a small but signifi­ treatment of agitation and aggression in aD are, however, cant overall advantage of Cheis over placebo with regard supported by several other preliminary pieces of evidence. to the treatment of BPsD.49 additional support for the in an observational discontinuation study, withdrawal of benefits of Cheis in the treatment of BPsD comes from memantine was associated with increased use of psycho­ a ran domized withdrawal study, in which cessation of tropic drugs,57 and a further 2008 observational study donepezil was associated with a significant worsening suggested that treatment with memantine was associated of the total neuropsychiatric inventory (nPi) score within with decreased use of psychotropic medication.58 whilst 6 weeks.50 However, no short­term benefit was found for this evidence is very encouraging with respect to meman­ treatment of clinical y important agitation with donepezil tine, no rCts have been performed specifical y to assess over 12 weeks in a large rCt,51 which suggests that Cheis this agent in patients with aD who have clinical y relevant do not seem to be useful in the management of acute agita­ agitation or aggression. Prospective rCts in patients with tion. in the treatment of BPsD syndromes, Cheis seem to aD who have clinical y significant agitation are needed be most effective against depression, dysphoria, apathy (or to support the findings. ongoing rCts in Canada and in indifference), and anxiety,44 and these agents are probably the uK will hopeful y clarify the role of memantine in the not effective for clinical y relevant agitation or aggression, treatment of agitation and aggression in aD.
at least when used for a 3­month period. in a study that investigated the treatment of agitation over 6 months in patients with dementia, a mean numerical advantage (as the use of antidepressants to treat BPsD dates back to measured by the Cohen­mansfield agitation inventory) the 1980s. Despite this fact, the literature remains limited nature reviews neurology volume 5 maY 2009 251
2009 Macmillan Publishers Limited. All rights reserved Box 1 Principles to guide pharmacological interventions
trazo done,62 but a subsequent parallel­group rCt indi­ cated no benefit of this agent compared with placebo.12 a if aggression is causing extreme distress or high risk to the patient and/or others: large, multicenter trial, with a focus on the treatment of short-term treatment (≤12 weeks) with an atypical antipsychotic is preferred; depression in patients with aD, is underway.63 the best evidence to date favors risperidone. The evidence base for benefit with extended-duration atypical antipsychotic therapy is limited and the risk of serious adverse events considerable, so treatment beyond 12 weeks should be considered only in extreme circumstances. The 12-week treatment period should be used with regard to anticonvulsants, some encouraging results to ensure optimum clinical management and to institute nonpharmacological have been reported for carbamazepine in the treatment of interventions as appropriate. if a subsequent relapse in aggression occurs agitation and aggression related to aD. a number of case and causes extreme distress and risk, we recommend that an alternative series and small crossover trials provide preliminary evi­ pharmacological therapy (citalopram, carbamazepine or memantine) is used.
dence of possible efficacy for this agent (reviewed by tariot in patients with moderate-to-severe AD with agitation causing distress but not et al.64 and Konovalov et al.65). only two, smal , parallel­ high levels of risk, in whom memantine is indicated for dementia: memantine group rCts have been conducted of carbamaze pine, both is probably the preferred treatment for agitation (and has the advantage of an over a 6­week period.66,67 a meta­analysis of the two trials excellent safety profile).
performed as part of the current review indicates signifi­ in patients with distressing, nonaggressive agitation, or aggression in the cant benefit with this agent both on the Brief Psychiatric absence of marked risk, in whom memantine is not indicated for dementia: rating scale (mean difference –5.5 points, 95% Ci –8.5 to use citalopram or carbamazepine.
–2.5 points) and on the Clinical Global impression scale in patients with AD who have distressing agitation or aggression that has not (or 10.2, 95% Ci 3.1–33.1) in comparison with placebo. responded to other interventions, who have experienced a relapse of agitation Both studies also suggest that this agent is well tolerated, or aggression after discontinuation of an atypical antipsychotic, or in whom and a subsequent case­register study of individuals aged another pharmacological agent is felt necessary to enable withdrawal of atypical 65 years or older suggested that carbamazepine confers antipsychotics: memantine, citalopram, or carbamazepine are appropriate. in less mortality risk than anti psychotic drugs do.68 studies ongoing treatment, assess the quality of clinical management and consider of sodium valproate have not shown benefits for this agent employment of concurrent nonpharmacological interventions.
in the treatment of agitation and aggression, and its toler­ No evidence is available to guide long-term prescription of pharmacological ability at thera peutic doses might not be acceptable.65,69,70 treatments other than atypical antipsychotics in patients with AD, and information Data for other anticonvulsants—such as gabapentin—are on long-term safety is limited. we recommend review of pharmacological preliminary and are largely based on small case series of treatments every 3 months and that discontinuation of the therapy is attempted patients who received open­label treatment.
after a minimum of 6 months, unless the therapy is prescribed for another indication (for example, memantine for cognition, citalopram for depression, or carbamazepine for epilepsy). in the absence of a robust, or even adequate, evidence base, recommendations for pharmacological treatment rely and few clear inferences can be drawn. the rCts that heavily on our personal interpretation. Pharmacological have been conducted examined the efficacy of sertraline, options should be considered alongside nonpharmaco­ citalopram, and trazodone in the treatment of agitation logical approaches (see earlier text for recommended in aD. in one of the rCts, sertraline was general y well approach for nonpharmacological therapies). in our tolerated.59 a subgroup analysis within the same study view, pharmacological interventions should generally that focused on patients with moderate to severe BPsD be reserved for patients who have distressing symptoms identified a significant benefit for sertraline compared of agitation and aggression that cause risk to themselves with placebo—a 50% improvement was experienced or others. except in such situations, where risk could be by 60% of patients on sertraline compared with 40% of extremely high, our opinion is that pharmaco logical treat­ patients on placebo.59 in a second, smal er, 17­day trial ments should usually only be considered after a trial of a of patients with dementia who had at least one moder­ ate to severe BPsD conducted in 2002, Pollock and col­ the best evidence for efficacy in the short­term leagues reported that citalopram was superior to placebo pharmaco logical treatment of aggression in aD remains in for the treatment of agitation and aggression. Patients in favor of the atypical antipsychotic drugs. However, in view the citalo pram group improved by a mean of one point on of the potential adverse effects of these agents, alternative the agitation subscale of the neurobehavioral rating scale pharmacological treatments are needed. on the basis of (nBrs), whereas patients in the placebo group improved this emerging evidence, our view is that the best pharmaco­ by a mean of 0.4 points (P <0.05).60 in a later study, citalo­ logical alternatives to anti psychotics for the treatment of pram was found to have comparable efficacy to the atypi­ aggression are memantine, carba mazepine, and citalo­ cal antipsychotic risperidone over 12 weeks of treatment.61 pram, all of which are currently available, licensed drugs. improvement on the agitation subscale of the nBrs was these agents possess a better evidence base than that for 1.26 points (sD 4.58) for citalopram and 0.73 points atypical antipsychotic drugs in the treatment of nonaggres­ (sD 4.91) for risperidone.61 the results of a double­blind sive agitation. other pharmacological interventions, such comparison of trazodone and haloperidol for the treatment as Cheis, might be benefi cial for other BPsD symptoms of agitation in dementia were encouraging with respect to such as apathy, mood dis orders, and visual hal ucinations; 252 MAY 2009 voluMe 5
2009 Macmillan Publishers Limited. All rights reserved however, on the basis of currently published evidence, such Table 3 reported genetic associations of agitation and related symptoms86,a
alternatives do not seem to be the preferred treatment for agitation and aggression.
we suggest a set of principles to be used when making Agitation and/or treatment decisions with regard to pharmacological interventions (see Box 1).
an american College of neuropsychopharmacology white Paper published in 2008 drew attention to the need for further research to clarify the neurobiological basis of HTR2A (5-HT2A) BPsD, and to the search for biomarkers that might enable HTR2C (5-HT2C) individual risk:benefit prediction.71 association of agita­ tion and aggression with the related symptom of psycho­ SLC6A4 (5-HTT) VNTR sis has been reported with polymorphisms in serotonin receptors types 2a and 2C and in the serotonin trans­ The table shows the proportion of studies that have reported a significant genetic 72–74 and with polymorphisms in dopa mine recep­ association. Abbreviations: APOE4, variant of apolipoprotein e (APOE) gene; COMT, tor types D andD .75 the best available evidence supports O-methyltransferase; DRD1, dopamine receptor D DRD3, dopamine the associ ation between dopamine receptors and serotonin receptor D ; HTR2A (5-HT2A), 5-hydroxytryptamine (serotonin) receptor 2A; HTR2C transporter polymorphisms—all three studies that exam­ (5-HT2C), 5-hydroxytryptamine (serotonin) receptor 2C; 5-HTTLPR, serotonin-transporter-linked polymorphic region in solute carrier family 6 (neurotransmitter transporter, ined dopamine receptor D and D polymorphisms, and serotonin), member 4 (SLC6A4, or 5-HTT); SLC6A4 (5-HTT) VNTR, serotonin transporter four of the seven studies that examined serotonin trans­ gene variable number tandem repeat polymorphism; TPH1, tryptophan hydroxylase 1.
porter polymorphisms, identified a significant associ­ ation of these poly morphisms with agitation (see table 3). Postmortem studies suggest that certain patterns of neu­ limited with regard to the influence of vascular or other ronal loss,76 and altered adrenergic function,77 may also be comorbid pathologies on response to treatment. Future important factors associated with agitation and aggression rCts will need to address these key issues.
in aD. the consistent finding between studies of a prob­ able association between agitation in aD and serotonin transporter polymorphisms further emphasizes selective limitations are evident in our understanding of the serotonin reuptake inhibitors as a promising therapeutic biological basis of agitation and aggression (as well as approach. Biological studies also highlight the noradren­ other behavioral features) associated with aD, and the ergic system as a potential treatment target. these studies efficacy and tolerability of available drug treatments is also raise the possibility that pharmaco genetics could be a matter of debate. nevertheless, clinicians are required an attractive approach to refine the selection of optimum to treat patients on a case­by­case basis, and to make pharmacological treatments for individual patients with use of their best judgment. Careful identification of agitation and aggression in the future.
target symptoms and their consequences, initial trials of nonpharmaco logical approaches, and use of the least Interpreting the evidence
harmful medication for the shortest period of time, several factors are important to take into account when should be the guiding principles in the current manage­ the published evidence base for agitation and aggression in ment of agita tion and aggression in aD. large, prospec­ aD is considered. Firstly, a large proportion of the rCts, tive, ran domized, placebo­controlled trials are needed to particularly those that have investigated the use of atypi­ establish the role of the pharmacological alternatives cal antipsychotics, remains unpublished—the tendency to atypical anti psychotics as clinical therapies for agitation is towards publication of more­positive trials. secondly, and aggression in aD.
experience has shown that most patients with aD enrolled in rCts tend to have relatively low levels of behavioral symptoms at baseline. this factor facilitates enrollment of patients into studies and encourages their retention, but we performed a search of the PubMed and it renders the results of trials difficult to generalize with Cochrane databases for articles on the treatment respect to clinical populations and might lead to an under­ of agitation in Alzheimer disease. we used combinations of the following search terms: estimation of the potential benefit of therapy. thirdly, "Alzheimer's disease", "dementia", "agitation", agita tion and aggression often co­exist with mood dis­ "aggression", "neuropsychiatric", "BPsD", "treatment", orders or psychosis,78 but whether or not such comor bidity "aromatherapy", and the names of individual influences response to treatment is unknown. Fourthly, pharmacological and nonpharmacological treatments whether genetic polymorphisms that are associated with listed in Tables 1 and 2. we selected 47 randomized, altered risk of agitation and aggression also have an effect controlled trials for further discussion, supplemented on response to treatment is unknown. Final y, evidence is with a more general review of the background literature.
nature reviews neurology volume 5 maY 2009 253
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