Medication alternatives for behavioural disturbance

Neurology 13 Medication alternatives for behavioural disturbance Many patients with dementia will in the later stages develop distressing behavioural symptoms. Antipsychotics are commonly used to treat this; however, as a class have been associated with serious adverse events in this vulnerable population. In this article we provide an overview of alternative medications. Dr Sean Carrivick* Foundation Year 2, Victoria Centre, 53 Downs Way, Swindon Dr Simon Manchip Consultant Old Age Psychiatrist Victoria Centre, 53 Downs Way, Swindon Email sean.carrivick@doctors.org.uk Patients with dementia commonly develop symptoms such as delusions, hallucinations, depression, agitation and aggression. Tese can be distressing for both patient and carer and are collectively known as behavioural and psychological symptoms in dementia (BPSD) the point prevalence is between 60 80%. 1 Various medications have been used to reduce these symptoms including antipsychotics. A conservative estimate of use is that one quarter (180,000) of people with dementia are treated with antipsychotics on the NHS. 2 Antipsychotics are sometimes prescribed for psychosis although the levels of psychosis are much lower than the prescribing levels recorded. Antipsychotics are used in a more general approach for BPSD. Given the vulnerable population, concern was raised regarding the safety of antipsychotics for this use during drug trials, which reported a higher level of cerebrovascular adverse events (CVAEs). Over the typical 6 12 week period of these studies a suggested number needed to harm for a CVAE was 58 and for one additional death was 100. An independent analysis of 17 pooled randomised controlled trials (RCT) showed an increase in all-cause mortality by 1.7 times with atypical antipsychotic use in patients with dementia compared with placebo. 3 Te 2008 Cochrane review on the use of atypical antipsychotics for aggression and psychosis in Alzheimer s disease concluded that both risperidone and olanzapine are useful to reduce aggression and risperidone also for psychosis although there is potential for extrapyramidal symptoms but no increased risk of falls. 4 It should be considered that in the UK only risperidone (Risperdal) has a license to be used for aggression in Alzheimer s dementia for up to six weeks but all other antipsychotic use would be off licence. Only aripiprazole (Abilify) has shown a clinically significant improvement in psychosis in dementia. 3,5 Overall, antipsychotics show minimal efficacy in treating BPSD effect sizes for most atypicals are only between 0.1 to 0.2 with a number needed to treat for clinically significant improvement of 5 to 11. In 2009, the Department of Health commissioned a report on antipsychotic use in dementia which has concluded that a proportion of antipsychotic prescriptions may be unnecessary if appropriate support were available and targeted a large reduction in their use. 2 Cholinesterase inhibitors (Aricept, Exelon, Reminyl) and memantine (Ebixa) are licensed for mild-moderate and moderatesevere Alzheimer s disease, respectively. There is some evidence that both groups may delay the onset of BPSD, providing additional benefit to using these currently available treatment options. 6 General approach to management Good practice includes thorough assessment and managing March 2012 Midlife and Beyond GM

14 Neurology Box 1: Cornell Scale items for depression in dementia A. Mood related signs 1. Anxiety: anxious expression, ruminations, worrying 2. Sadness: sad expression, sad voice, tearfulness 3. Lack of reactivity to pleasant events 4. Irritability: easily annoyed, short tempered B. Behavioural disturbance 5. Agitation: restlessness, hand wringing, hair pulling 6. Retardation: slow movement, slow speech, slow reactions 7. Multiple physical complaints (score 0 if GI symptoms only) 8. Loss of interest: less involved in usual activities (score only if change acutely, ie less than 1 month) C. Physical signs 9. Appetite loss: eating less than usual 10. Weight loss (score 2 if greater than 5lb in one month) 11. Lack of energy: fatigues easily, unable to sustain activities (Score only if occurred acutely, ie. in less than one month) D. Cyclic functions 12. Diurnal variation of mood: symptoms worse in the morning 13. Difficulty falling asleep: later than usual for this individual 14. Multiple awakenings during sleep 15. Early morning awakening: earlier than usual for this individual E. Ideational disturbance 16. Suicide: feels life is not worth living, has suicidal wishes or makes suicide attempt 17. Poor self esteem: self blame, self depreciation, feelings of failure 18. Pessimism: anticipation of the worst 19. Mood congruent delusions: delusions of poverty, illness or loss Scoring system: A=unable to evaluate, 0=absent, 1=mild or intermittent, 2=severe Based on symptoms and signs during the week prior to interview with no score given if symptoms result from physical disability or illness. Reproduced from: Cornell Institute for Geriatric Psychiatry, Weill Medical College of Cornell University. specific treatable causes such as delirium, infection, constipation and pain. Given the above issues, consideration of risk and benefit is essential NICE recommend that antipsychotics are only considered for severe BPSD causing significant distress or an immediate risk of harm to the person with dementia or others. 7 An atypical antipsychotic (eg. risperidone) is preferred over a typical (eg. haloperidol). If the immediate safety concerns allow, a period of watchful waiting may be useful as there is a high rate of spontaneous recovery. A Norwegian nursing home study has shown remission rates of delusions, depression and aggression/agitation of about 50% at one year independently of pharmacological treatment and this is in line with other outpatient studies. 8 Psychological and behavioural approaches should be used first such as structured social interaction or aromatherapy. However, if medication is considered the patient and carers should be involved in discussions especially as the patient may lack capacity to consent themselves. In general, the lowest effective dose of medication should be used with frequent reviews aiming for reduction or cessation where possible. Medication alternatives The consideration of non antipsychotic medications is indicated in the long and short term management which may replace the need for antipsychotics. Antidepressants Persons with dementia GM Midlife and Beyond March 2012

commonly have symptoms of depression and at a higher rate than the control population. 9 Older people are often susceptible to drug side effects and the anticholinergic effect of tricyclic antidepressants including delirium and cognitive dysfunction have put them out of favour. With negligible effects on cholinergic transmission, the selective serotonin reuptake inhibitors (SSRIs) do not produce these side effects and with less effect on histaminergic and adrenergic neurotransmission they also produce less sedation and postural hypotension. Due to the safety and tolerability factors of SSRIs they have been more widely studied. Patients with dementia do not report a higher rate of adverse events than those without. 10 Box 1 shows the Cornell Scale which is a useful tool for diagnosing depression in dementia. Citalopram has had positive reports including showing a significant decrease in agitation and a similar improvement in psychotic symptoms compared with risperidone over 12 weeks. Psychotic side effects such as sedation, tension and apathy were significantly lower with citalopram but interestingly a comparable increase in extrapyramidal side effects was seen with both drugs. 11 Sertraline was shown to improve dementia related agitation (DRA) particularly for aggression, irritability and motor disturbance in a relatively small treatment group of 22 people and may not be widely generalisable. 12 The 2004 Cochrane review on the use of trazodone was inconclusive due to insufficient evidence and could not therefore recommend its use, 13 and their 2009 review on using antidepressants to treat depression in dementia highlights only weak evidence to support their use. 14 The 2011 Cochrane review which included nine studies (692 individuals) suggests that from these few studies sertraline and citalopram were associated with a modest reduction in symptoms of agitation and psychosis when compared to placebo (in two studies) but few other significant differences for SSRIs or trazodone in measures of tolerability when compared to placebo or haloperidol. 15 Antidepressants are however widely used especially where behavioural difficulties may be secondary to depression or anxiety. SSRIs are usually first line as they have a favourable risk benefit ratio and are equally effective as other classes. However, there is an increased risk of bleeding especially in older people with concomitant use of non-steroidal GM Midlife and Beyond March 2012

Neurology 17 anti-inflammatories and warfarin or aspirin. Gastroprotection with a proton pump inhibitor and considering switching to mirtazapine would therefore be advised. 16 Cholinesterase inhibitors In the 2006 Cochrane review of 10 randomised, double blind, placebo controlled trials six months of treatment with donepezil (Aricept), galantamine (Reminyl) or rivastigmine (Exelon) in Alzheimer s disease produced a small treatment effect on behaviour disturbance as well as activities of daily living and cognitive function. 17 Donepezil in Alzheimer s disease was reviewed and showed benefits in behavioural disturbance 18 however these pivotal trials were based on patients being able to give full informed consent and attend clinic appointments. Tey presented with a low baseline of BPSD and benefits were primarily in apathy not aggression which limits translation to severe cases. Tere was only one suitable trial included in the 2003 Cochrane review of cholinesterase inhibitors in Dementia with Lewy bodies although this does suggest there is weak evidence of a benefit in behavioural disturbance with rivastigmine if tolerated. 19 Box 2: Alternative medications Antidepressants Citalopram (10 20mg/day) Sertraline (25 200mg/day) Cholinesterase inhibitors Galantamine (8 24mg/day) Donepezil (5 10mg/day) Rivastigmine (3 9mg/day) Assessed in multiple RCTs Reduces agitation associated with comorbid depression SSRIs are preferred. Adverse effects include hyponatraemia Assessed in multiple RCTs Benefits in behaviour, cognition and activities of daily living Side effects include GI disturbance. Over alertness may add to BPSD NMDA-glutamate receptor antagonist Memantine (10 20mg/day) Assessed in multiple RCT s Effect size small to medium. Can stabilise agitation, cognition and function. Usually well tolerated Antiepileptics Valproic acid Carbamazepine Benzodiazepines Lorazepam (0.5 4mg/day) Clonazepam(0.5 1mg) Clonazepam for REM sleep disorder. Others Lavender oil Melatonin Concern regarding multiple adverse effects Useful in the short term for agitation with severe anxiety Some success but the literature is mixed overall Memantine Memantine is an NMDAglutamate receptor antagonist. In 2006 the Cochrane group reviewed its use in dementia and concluded that in moderate to severe Alzheimer s disease, memantine has a small beneficial effect on behaviour as well as cognition and activities of daily living, and is well tolerated. Where agitation was already present there was no evidence to suggest it had an effect but in those without agitation they were slightly less likely to develop it. 20 A pooled analysis of three studies has shown a significant treatment advantage with memantine at 12 and 24/28 weeks from baseline agitation and aggression as well as improvement in cognitive, functional and global outcomes. 21 Clinical experience has shown memantine to be particularly useful for clinically driven behaviour and problems with verbal fluency (for example in primary progressive aphasia). NICE recommend memantine as an option for managing Alzheimer s disease for people with severe illness, or moderate illness who are intolerant or March 2012 Midlife and Beyond GM

18 Neurology have a contraindication to acetylcholinesterase inhibitors. 22 Accessibility is variable around the UK and it is usually only a secondary care prescribed drug. Antiepileptics Individual case reports with sodium valproate have been positive and it is still widely used clinically. However in 2009, Cochrane updated their review to include more recent trials and drew the same conclusion that valproate preparations were not effective for agitation and were associated with unacceptable levels of adverse events they do not therefore recommend it for BPSD. 23 Carbamazepine has been used for intermittent aggression but is limited by its potential for drug interactions and side effects. We await the outcome of a review on carbamazepine and oxcarbazepine (Trileptal) for BPSD. 24 Benzodiazepines Benzodiazepines are often used in primary and secondary care particularly for agitation with severe anxiety but should be considered for short term management only. However, they should be used with additional caution in the elderly due to the risk of adverse events including increasing falls risk, respiratory side effects and the development of tolerance. Tose with a short halflife such as lorazepam are preferable to minimise accumulation. The suggested dose of benzodiazepines in the elderly with dementia would be a quarter of the usual adult dose, non-specialists often start benzodiazepines at too high a dose. Clonazepam (Klonopin) is the treatment of choice for persisting and problematic REM Figure 1. Factors influencing behavioural problems in dementia sleep behaviour disorder. It is effective in controlling both dreams and behaviours with good evidence for safety and a sustained benefit. 25 Table 2 summarises the pharmacological alternatives to antipsychotics. Finally, Cochrane s systematic review of Special Care Units (these are usually part of a nursing home with trained staff, a modified environment and family involvement) finds no strong evidence of a benefit although there are no RCTs. Tey comment that implementing best practice is likely to be more important than a specialist unit itself. 26 Conclusion Dementia has a profound impact on a patient s life and additional symptoms such as agitation or aggression can be very distressing for both the patient and family/ carers. It can also lead to an increased likelihood of transfer to an Elderly Mental Illness (EMI) home. Te greatest evidence as an alternative to antipsychotic use exists for cholinesterase inhibitors and SSRI antidepressants although their slower onset and minimal effect with severe symptoms still leaves a place for antipsychotics. As part of a complete biopsychosocial assessment (see figure 1) and bearing in mind potentially serious adverse events, antipsychotics could be considered sparingly for severe cases in the short term with the longer term use of cholinesterase inhibitors, an SSRI or memantine. Excellent nursing care with behavioural interventions can however delay or stop the need for their use in many cases. Other medications such as lithium, analgesics, betaadrenoreceptor antagonists, cannabinoid receptor agonists and hormonal agents require further studies to determine a useful and GM Midlife and Beyond March 2012

Neurology 21 effective role in the management of behavioural and psychological symptoms in dementia. Conflict of interest: Dr Manchip has sat on advisory boards and lectured for Shire, Pfizer, Eisai, Lundbeck and Novartis. References 1. Parnetti L, Amici S, Lanari A, et al. Pharmacological treatment of non-cognitive disturbances in dementia disorders. Mechanisms of Ageing and Development 2001; 122(16): 2063 9 2. Banerjee S. The use of antipsychotic medication for people with dementia: Time for action. A report for the Minister of State for Care Services. Department of Health, London, 2009. 3. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: metaanalysis of randomized placebocontrolled trials. Journal of American Medical Association 2005; 294(15): 1934 43 4. Ballard CG, Waite J, Birks J. Atypical antipsychotics for aggression and psychosis in Alzheimer s disease. Cochrane Database of Systematic Reviews 2006, Issue 1 5. Schneider LS, Dagerman K, Insel, PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. American Journal of Geriatric Psychiatry 2006; 14: 191 210 6 Optimising treatment and care for behavioural and psychological symptoms of dementia. http://alzheimers.org. uk/site/scripts/documents_info. php?documentid=1657 7. NICE/SCIE. Dementia Supporting People with Dementia and Their Carers in Health and Social Care. London: NICE/SCIE, 2006. 8. Geir Selbæk, Øyvind Kirkevold, Knut Engedal. The Course of Psychiatric and Behavioral Symptoms and the Use of Psychotropic Medication in patients with Dementia in Norwegian Nursing Homes-a 12 month Follow up study. The American Journal of Geriatric Psychiatry 2008; 16(7): 528 36 9. Allen H, Jolley D, Comish J, Burns A. Depression in dementia: a study of mood in a community sample and referrals to a community service. International Journal of Geriatric Psychiatry 1997; 12: 513 18 10. Solai, LalithKumar K, Mulsant, Benoit H, Pollock, Bruce G. Selective Serotonin Reuptake Inhibitors for Late-Life Depression - A Comparative Review. Drugs & Aging 2001; 18 (5): 355 68 11. Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007; 15(11): 942 52 12. Lanctot KL, Herrmann N, van Reekum R, et al. Gender, aggression and serotonergic function are associated with response to sertraline for behavioural disturbances in Alzheimer s disease. Int J Geriatr Psychiatry 2002; 17 (6): 531 41 13. Martinón-Torres G, Fioravanti M, Grimley Evans J. Trazodone for agitation in dementia. Cochrane Database of Systematic Reviews 2004, Issue 3 14. Bains J, Birks J, Dening T. Antidepressants for treating depression in dementia. Cochrane Database of Systematic Reviews 2009 15. Seitz DP, Adunuri N, Gill S, Gruneir A, Herrmann N, Rochon P. Antidepressants for agitation and psychosis in dementia. Cochrane Database of Systematic Reviews 2011, Issue 2 16.NICE. Depression-Treatment and management of depression in adults, including adults with a chronic physical health problem. NICE clinical guidelines CG90. London: NICE, 2009 17. Birks J. Cholinesterase inhibitors for Alzheimer s disease. Cochrane Database of Systematic Reviews 2006, Issue 1 18. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer s disease. Cochrane Database of Systematic Reviews 2006, Issue 1 19. Wild R, Pettit TACL, Burns A. Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database of Systematic Reviews 2003, Issue 3 20. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database of Systematic Reviews 2006, Issue 2 21. Wilcock GK, Ballard CG, Cooper JA, Loft H. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer s disease: a pooled analysis of 3 studies. J Clin Psychiatry 2008; 69(3): 341 48 22. NICE. Dementia-Supporting people with dementia and their carers in health and social care. NICE clinical guidelines CG42. London: NICE, November 2006 revised March 2011 23. Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database of Systematic Reviews 2009, Issue 3 24. Tampi R, Aziz R, Kantrowitz J, et al. Carbamazepine and oxcarbazepine for the treatment of behavioural and psychological symptoms of dementia (BPSD) (Protocol). Cochrane Database of Systematic Reviews 2009, Issue 2 25. Carlos H. Schenck MD, Mark W. Mahowald MD. REM Sleep Behavior Disorder: Clinical, Developmental, and Neuroscience Perspectives 16 Years After its Formal Identification in SLEEP. Sleep 2002; 25(02): 120 138 26. Lai CKY, Yeung JHM, Mok V, Chi I. Special care units for dementia individuals with behavioural problems. Cochrane Database of Systematic Reviews 2009, Issue 4 March 2012 Midlife and Beyond GM