TREATMENT OF DEMENTIA

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1 CHOLINESTERASE See end of artile for authors affiliations Correspondene to: Dr Ross Overshott, Department of Old Age Psyhiatry, 2nd Floor, Eduation and Researh Centre, Wythenshawe Hospital, Manhester, M23 9LT, UK; man.a.uk D TREATMENT OF DEMENTIA ROvershott,ABurns J Neurol Neurosurg Psyhiatry 2005; 76(Suppl V):v53 v59. doi: /jnnp ementia desribes a hroni and progressive linial syndrome haraterised by ognitive impairment (partiularly memory loss), inability to perform ativities of daily living, and neuropsyhiatri features (psyhiatri symptoms and behavioural disturbanes, also known as behavioural and psyhologial symptoms of dementia or BPSD). It affets an estimated people in the UK and four million in the USA. Alzheimer s disease (AD) is the most ommon ause of dementia (60%), followed by vasular dementia (VaD) (20%) (although 20% of people have both AD and VaD) and dementia with Lewy bodies (DLB) (15%). There have been signifiant advanes in treatments available for dementia in the last few years. INHIBITORS Cholinesterase inhibitors (ChEIs) are the mainstay of treatment of Alzheimer s disease. Randomised ontrolled trials (RCTs) have reported statistially signifiant, and linially modest, effets of ChEIs. Trials have been short, onduted over six months, although effets have been reported, in open label extensions, to last up to five years. The primary aim of the trials has been to assess the treatment response for ognitive deline. This is most often measured using the Alzheimer s disease assessment sale (ADAS-Cog), 1 whih assesses multiple ognitive outomes and is an aepted standard for measuring ognitive abilities in linial trials. The total sore of the ADAS-Cog ranges from 0 70, the higher sore indiating greater impairment. Over a six month period untreated patients with mild to moderate AD typially deteriorate as signified by an inrease of 3 4 points on the ADAS-Cog. Patients with moderate to severe AD have an inrease of 4 6 points over the same period of time. 2 The Cohrane Review of donepezil for AD found an improvement at 24 weeks of 2.9 on the ADAS-Cog ompared with plaebo. 3 Similar findings were reported in the Cohrane reviews of galantamine 4 and rivastigmine. 5 Another primary aim of trials has been to assess hanges in subjets funtional abilities. This is measured using a global assessment suh as the liniian s interview-based impression of hange plus aregiver input (CIBIC-plus). 6 A subjetive interview by a liniian with a patient and aregiver, assessing the patient s funtion, in four areas determines whether overall the patient has improved, stayed the same or deteriorated, using a 7 point sale. If an effet is deteted during the liniian s interview it is assumed that it is linially relevant. The Cohrane Reviews 3 5 dihotomised rating sale data into those who had no hange or improvement versus those who worsened and found a statistially signifiant effet in favour of treatment, with an odds ratio of approximately 2. The Cohrane Reviews also report signifiant improvements on rating sales for ativities of daily living and neuropsyhiatri symptoms. The Cohrane Review of donepezil for AD 3 reports a low dropout rate of under 20%, with similar numbers for treatment and ontrol groups within a study, exept for the treatment group taking 10 mg/day of donepezil whih had slightly higher dropout rates. Apart from Cohrane Reviews there have been several other meta-analyses that onlude there is a signifiant benefit from treatment with ChEIs. There are, however, onerns regarding the quality of evidene and the size of the benefits, whih are felt, by some, to be minimal. 7 It has been suggested that many systemati reviews have not stringently assessed the quality of studies 7 and that most, if not all, ChEIs trials have flawed methodology, whih questions their validity. There is also a shortage of evidene of improvement of quality of life using validated, dementia speifi measures, while pharmaoeonomi evaluations of ChEIs have so far been onduted in retrospet. NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE GUIDANCE Although they are not a ure, ChEIs urrently offer the best hope in treating AD. Initially the availability in the UK of ChEIs for the treatment of AD depended on where patients lived rather than their linial need, so alled post ode presribing. The National Institute for Health and Clinial Exellene (NICE) 2001 guidelines for the treatment of AD with ChEIs 8 reommended their use. v53 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. Proteted by opyright.

2 v54 The future use of ChEIs in the UK for National Health Servie (NHS) patients is, however, again in doubt following the publiation of NICE s new draft guidane. 9 They have maintained their position from 2001 that the mediations have an effet and are safe in the treatment of AD, but have now onluded that the drugs are not ost effetive and should not be reimbursed by the NHS. NICE reeived over 4000 responses, their largest ever, during the initial onsultation period of the new guidelines. NICE reported that sine the publiation of its original guidelines the linial evidene base for ChEIs has matured and that it demonstrates a onsistent gain on ognitive and global sales ompared to plaebo in mild to moderate AD. 9 They were onerned that the effets are small and there is little positive randomised evidene available on the long term gain of ChEIs. Despite these onerns, NICE onluded that ChEIs were effetive but were not ost effetive and therefore would no longer be reommended. It has been felt by many that NICE s appraisal had several shortomings whih influened their onlusions regarding ost effetiveness. They had underestimated the ost of full-time institutional are and had not fully onsidered the full benefits for arers. It has been estimated that ChEI treatment osts 2.50 a day and yet there is evidene to suggest that treatment an redue arer input by half an hour a day. 10 For a professional arer this would onstitute a saving of at least 2.50 a day: the prie of ChEI for one day. The eonomi model used by NICE also did not reflet the use of ChEIs in linial pratie, where treatment is disontinued in patients who do not respond. The NICE model, however, assumes that all patients ontinue with treatment irrespetive of response. Their analysis, therefore, inluded patients who had not responded and were not gaining any benefit from treatment but were still aumulating osts. In linial pratie these patients treatment would be disontinued and the ost urtailed. Patients, arers, liniians, and interested organisations have been onfused by the hange of stane by NICE in their new draft guidelines, as the evidene for the effetiveness of ChEIs has improved sine their original guidelines, whih reommended the treatments. At the time of writing, NICE have postponed their final assessment and are onsidering further information. DONEPEZIL, GALANTAMINE, AND RIVASTIGMINE There are urrently three ChEIs regularly used in the UK that are liensed for the treatment of mild to moderate AD: donepezil, galantamine, and rivastigmine. They have eah been shown to produe the benefits of ChEI treatment mentioned earlier and in pratie there is very little to hoose between them in terms of ore effiay. Donepezil (Ariept) omes in two doses (5 and 10 mg) and until reently had the unique advantage of one a day presribing. The dose for rivastigmine (Exelon) ranges from mg a day and has a buturylholinesterase ation in addition to aetylholinesterase. Galantamine (Reminyl) has a niotini reeptor allosteri ation and has just beome available in an extended release daily apsule. INITIATING TREATMENT WITH CHOLINESTERASE INHIBITORS One a diagnosis of AD has been made it is important to disuss in detail with the patient and their relative/arer what treatment will entail. For most the diagnosis of a dementia an be devastating and understandably they may have high expetations, sometimes unrealisti, of any treatments offered. It is therefore important to be lear from the outset on several key points: Table 1 disease NICE guidane for the treatment of Alzheimer s Alzheimer s disease must be diagnosed in a speialist lini where assessments should inlude ognitive and behavioural funtioning, ativities of daily living, and likelihood of ompliane with treatment Treatment should be initiated by speialists but may be ontinued by general pratitioners The arer s views should be sought before and during treatment Treatment should only be ommened in patients with mild or moderate Alzheimer s disease whose MMSE sore is above 12 points The patient should be assessed 2 4 months after a maintenane dose is established. Treatment should only ontinue if the MMSE has improved or not hanged and if behavioural or funtional assessment shows improvement The patient should be assessed every 6 months. Treatment should usually only ontinue if MMSE sore remains above 12 and it is onsidered that treatment is having a worthwhile effet on funtioning and behaviour MMSE, mini mental state examination. The mediations are not a ure. The mediations do not work for everyone. The rule of thirds in mediine applies approximately: one third get better, one third do not deteriorate further, and in one third it makes no differene and the patient deteriorates at the rate as if untreated. The mediation will be disontinued if the patient does not respond to it. The NICE guidane 8 (table 1) published in 2001 provided a struture whih inludes systemati monitoring whih, although under review, provides a sensible template for the presription of the drugs. It has been suggested that the primary aim of the guidelines is to ontain presribing and ontrol drug osts. 11 The guidane ertainly laks some pratial elements. It is, for example, important for patients to have an eletroardiogram (ECG) before starting a holinesterase inhibitor, as bundle branh blok is a relative ontraindiation to their presription. A set of pratial guidelines for initiating treatment with holinesterase inhibitors is set out in table 2. WHICH CHOLINESTERASE INHIBITOR SHOULD BE STARTED AND BY WHOM? There is no real differene in the effetiveness of the three holinesterase inhibitors. The few omparative studies published are small and have been onduted over a relatively short period. The results are inonsistent and offer no basis to make a linial hoie. Rivastigmine has the reputation of more ommonly ausing side effets, partiularly nausea and vomiting. This may be due to the initial dosing regimen being too quik (table 3); slowing the titration period to four instead of two weeks will help redue the side effets. To redue nausea rivastigmine should be taken with food. As both galantamine and rivastigmine have additional modes of ation, apart from aetylholinesterase (AChE) inhibition, many liniians believe they are more effetive in later stages of AD when AChE onentrations are low. The urrent NICE guidelines stipulate that presribing should be initiated by speialists but may be ontinued by general pratitioners under a shared-ared protool. This J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. Proteted by opyright.

3 Table 2 Initiating treatment with holinesterase inhibitors Establish diagnosis of Alzheimer s disease using standardised riteria (for example, ICD-10) through interviewing the patient, taking a ollateral history, and undertaking a ognitive assessment. The patient should have a full dementia blood sreen and neuroimaging, when appropriate, to identify o-morbidities and reversible auses of ognitive impairment Explain and disuss diagnosis, prognosis, and treatment options with patient and arer Agree a treatment plan with involvement from a multidisiplinary team. Suggest and enourage the patient and arer to ontat the loal branh of the Alzheimer s Soiety Establish baseline sores for ognitive funtion, global funtioning, neuropsyhiatri symptoms, and ativities of daily living using standardised rating sales Commene holinesterase inhibitor Make sure an ECG has been onduted reently to exlude problems with ardia ondution Monitor the patient s progress regularly using linial skills and standardised rating sales ECG, eletroardiogram; ICD-10, International lassifiation of diseases, 10th revision. means that after an initial phase the patient reeives their ChEI from the same soure as their other mediation whih redues onfusion and improves the likelihood of ompliane. SIDE EFFECTS OF CHOLINESTERASE INHIBITORS The three ChEIs have broadly similar side effet whih are summarised in table 4. The most ommon side effets are gastrointestinal and are usually transient, lasting a few weeks. Most patients are able to ontinue on the mediations while side effets pass. Gastrointestinal effets an be limited by slow titration and taking the mediation with food. If nausea and vomiting are problemati, treatment with an anti-emeti should be onsidered. Rivastigmine may be partiularly prone to ausing gastrointestinal side effets as it is the ChEI whih inhibits butyrylholinesterase (BuChE) whih is found in the gastrointestinal trat. The inhibition of AChE may inrease parasympatheti tone, therefore ChEIs should be used with great aution in Table 3 Dosing requirements for holinesterase inhibitors Donepezil start on 5 mg one a day if tolerated, inrease to 10 mg one a day maximum dose: 10 mg a day Galantamine start on 4 mg twie a day and after 4 weeks inrease to 8 mg twie a day aording to response and tolerane, inrease to 12 mg twie a day maximum dose: 12 mg twie a day Rivastigmine start on 1.5 mg twie a day and after 2 weeks, inrease to 3 mg twie a day after at least another 2 weeks onsider inreasing dose to 4.5 mg twie a day aording to response and tolerane the dose an be inreased to 6 mg twie a day maximum dose: 6 mg twie a day patients with bradyardia, sik sinus syndrome, or ardia ondution disturbanes. SWITCHING CHOLINESTERASE INHIBITORS There have been few published studies on swithing ChEIs, although it has been reported that over 50% of patients will gain benefit from the new ChEI. 12 Current opinion is that mediations an be hanged overnight. STOPPING CHOLINESTERASE INHIBITORS When a patient who has only reently started treatment does not appear to be responding to a ChEI there are three options: inrease the dose Table 4 Main side effets of holinesterase inhibitors Nausea Vomiting Diarrhoea Anorexia Abdominal pain Headahe Dizziness Tremor Weight loss Fatigue swith to another ChEI withdraw the drug and onsider memantine. A more diffiult deision is when to stop a ChEI in a patient who has responded but there is a suspiion, based on either a global impression or deterioration on a rating sale, that the treatment effet is wearing off. The NICE guidelines 8 reommend disontinuation one the mini mental state examination (MMSE) sore is below 12, but as ChEIs an provide other benefits it is perhaps wise to onsider the possibility of effetiveness in all areas, not just ognition, before disontinuing treatment. The risks and benefits of stopping must be disussed fully with the patient and arer. If there is doubt about whether a drug is doing more harm than good a trial of withdrawal is appropriate. Cliniians often find that stopping a ChEI in a patient leads to an unexpeted deterioration of behaviour (for example, inreased agitation) or ognition, proving the drug was having more of an effet than realised. When attempting withdrawal it is important to monitor losely for any deterioration in order that the mediation an be reinstated quikly so the same level of symptomati effet an be regained. USEOFCHOLINESTERASEINHIBITORSINOTHER DEMENTIAS Cholinergi defiits are also found in patients with VaD and DLB. There is growing support for the use and effetiveness of ChEIs in these dementias and so far no indiation that their use should be managed differently from ChEI treatment for AD. Dementia with Lewy bodies ChEIs are being inreasingly used as the first line pharmaologial treatment for DLB. They have been shown to provide symptomati improvement of apathy, delusions, and halluinations. 13 The holinergi defiit in DLB is thought to v55 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. Proteted by opyright.

4 v56 be greater than in AD and it has been hypothesised that patients with DLB have a better response to ChEI than those with AD. As patients with DLB often tolerate antipsyhoti mediations poorly, ChEIs provide the most pratial option for treating the neuropsyhiatri symptoms found in DLB. ChEIs are not liensed for use in DLB but are being inreasingly used Vasular dementia There is a treatment effet of ChEIs in patients with AD and erebrovasular disease and there is growing evidene of similar benefits in VaD only. Cholinergi strutures are vulnerable to ishaemi hanges whih an lead to signifiant loss of holinergi neural pathways although rarely to the magnitude seen in AD. Donepezil and galantamine have been shown to have a signifiant effet on ognition and global funtion, and estimated effet sizes are similar to those seen in the first trials for AD. 14 ChEIs, however, are still not liensed, and therefore rarely used, for the treatment of VaD. With reent doubts over the future of ChEI use in AD, this is unlikely to hange in the near future. Parkinson s disease with dementia Rivastigmine has been shown in one trial to produe signifiant improvements in ognition, global ratings of dementia, and behavioural symptoms whih were of the same magnitude observed in ChEI trials for AD. 15 ChEIs are frequently, despite not being liensed, presribed for the treatment of neuropsyhiatri symptoms of Parkinson s disease with dementia. ChEIs have not been found to worsen the motor symptoms of Parkinson s disease. MEMANTINE Memantine, a partial glutamate reeptor antagonist, is the only drug liensed in the UK for the treatment of moderate to severe AD. It has, however, been used in Germany for over 20 years for various neurologial symptoms and ognitive impairment. It was not inluded in NICE s 2001 guidelines 8 and therefore does not require the same monitoring as ChEIs, although many dementia treatment linis inlude patients treated with memantine in their ChEI treatment protools. The new NICE draft guidelines 9 did, however, inlude memantine and, as for ChEIs, its use was not reommended beause of lak of ost effetiveness. Use of memantine in dementia Despite only being liensed for use in moderate to severe dementia in AD, memantine has been shown to have benefiial effets in slowing deterioration in ognition in patients with mild to moderate AD and VaD too. 16 The initial dose is 5 mg one a day whih should be inreased in 5 mg inrements at intervals of at least one week until a maximum dose of 10 mg twie a day is reahed. Memantine is generally better tolerated than the ChEIs. The most ommon adverse events of memantine inlude dizziness, headahes, fatigue, diarrhoea, and gastri pain. In linial experiene the side effets whih are most likely to lead to disontinuation are restlessness and hyperexitation. Memantine urrently is predominantly used in the treatment of moderate to severe AD when it is felt that ChEIs are no longer effetive. They also have a role as an alternative to ChEIs in the treatment of patients with mild to moderate AD who are either unable to tolerate ChEIs or when ChEIs are ontraindiated for example, problems with ardia ondution. COMBINATION THERAPY A donepezil memantine ombination performed signifiantly better than donepezil plaebo on ognition, ativities of daily living, and behavioural neuropsyhiatri sales in a randomised ontrolled trial. The ombination was well tolerated. 17 OTHER DRUG TREATMENTS FOR DEMENTIA ChEIs and memantine are the mainstay of treatment, but other agents have been tried whih have generally been unsuessful. Ginkgo biloba There have been mixed results in the trials, but meta-analysis shows a small but statistially signifiant benefit on ognition relative to plaebo. 18 The effet is smaller than the effet found with ChEIs. Non-steroidal anti-inflammatory drugs (NSAIDs) Observational studies have found an assoiation between anti-inflammatory drugs and lower risk of AD, but the result of linial trials are negative. 19 Oestrogens Trials have not been suessful and several safety problems have arisen, inluding inreasing risk of venous thrombosis. Selegiline A systemati review of selegiline onluded that although there is some evidene of improvement in ognition and ativities of daily living in dementia in the short term, the magnitude was not linially important. 20 Vitamin E Vitamin E may maintain the funtional status of people with AD. 21 There is no evidene to suggest it an help prevent dementia or improve ognitive funtion. MANAGEMENT OF VASCULAR DEMENTIA The main fous here is primary and seondary prevention, by ontrolling risk fators to redue vasular events. Early identifiation and treatment of hypertension, whih is also a risk fator for AD, with agents suh as the angiotensin onverting enzyme inhibitor perindopril has been shown to redue the risk of dementia among patients who have experiened stroke. 14 Lipid lowering mediations are also important in seondary prevention of stroke and may protet against dementia. Other fators whih are ruial in reduing the risk of vasular dementia are stopping smoking, weight redution, ontrol of atrial fibrillation with antioagulation, and nutritional eduation. Table 5 Types of behavioural and psyhologial symptoms of dementia (BPSD) Aggression Agitation Apathy Biting Delusion Depression Halluinations Kiking Restlessness Sreaming Shaking Poor sleep Wandering J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. 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5 Table 6 Non-pharmaologial approahes for the treatment of BPSD Verbal therapies Behavioural therapy Cognitive behavioural therapy Interpersonal therapy Reality orientation Reminisene therapy Validation therapy Non-verbal therapies Aromatherapy Bright light therapy Exerise and ativities Multisensory therapy Musi therapy TREATMENT OF BEHAVIOURAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA Behavioural and psyhologial symptoms of dementia (BPSD) refer to a group of symptoms and behaviours summarised in table 5. BPSD are ommon in all types of dementia, and 80% of patients will experiene them during the ourse of their illness. They are more ommon in patients with severe dementia and ertain types of dementia for example, DLB, where psyhoti symptoms our in more than 80% of patients. BPSD ause distress for both the patient and arer and are assoiated with inreased arer burden and institutionalisation. The first line treatment for BPSD has been psyhotropi mediation, partiularly antipsyhoti drugs. There has, Table 7 Management of behavioural and psyhologial symptoms 1. What are the symptoms? What behaviours are being exhibited? Is the patient depressed or halluinating? Is there evidene of apathy or sleep disturbane? however, been growing onern 22 over the use of the mediations as they are assoiated with: inreased ognitive deline inreased rate of stroke parkinsonism risk of ardia arrhythmias inreased risk of falls inreased mortality. An inreasing number of non-pharmaologial therapies (table 6) are now available and should be onsidered before pharmaologial treatment. Table 7 outlines strategies and questions a liniian should ontemplate when faed with a patient with BPSD. An assessment needs to be made of what the urrent symptoms are. It is imperative that the liniian exludes an underlying medial ause. Agitation, for example, an often our when a patient has a urinary trat infetion or is onstipated. The patient may also be in pain and it is reasonable if suspiion is high and the patient, beause of their ognitive impairment, is unable to onfirm that they are in pain to give a trial of an analgesi to see if the BPSD improves. A brief outline of approahes to both pharmaologial and non-pharmaologial treatment will be desribed for the broad groups of BPSD. For a more in-depth disussion see Overshott et al. 23 AGITATION Non-pharmaologial interventions Overshott et al Agitation and aggression are probably the BPSD whih auses the most distress among patients and their arers. Before a treatment plan an be organised there needs to be some understanding of the behaviours and symptoms. Behavioural management tehniques systematially doument behaviours, 2. What is the diagnosis? Does the patient have an established diagnosis of dementia? Whih type? Is there an underlying medial ondition ausing a delirium on top of the dementia? Arrange appropriate physial investigations for example, infetion sreen. Is the patient in pain? 3. Examine the behaviours ABC (anteedents, behaviours and onsequenes) analysis of behaviours Is there a pattern? Eduation for arers (for example, how to approah the patient, sleep hygiene) 4. Consider non-pharmaologial therapies Is there a role for other therapies? For example, aromatherapy, musi therapy for agitation, bright light therapy for sleep disturbane 5. Consider pharmaologial therapies Review response to interventions so far. If symptoms are still distressing or unmanageable onsider starting pharmaologial treatment Is the use of a holinesterase inhibitor indiated? If starting an antipsyhoti or benzodiazepine, initiate treatment autiously with a low dose For example, daily dose, in divided doses: promazine mg lorazepam mg lomethiazole 1 3 aps/5 15 ml syrup trazodone mg v57 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. Proteted by opyright.

6 v58 using a diary or hart, and reord the triggers, behaviours, and reinforements. This approah is also known as ABC: anteedents, behaviours, and onsequenes. For example, it may be found that the patient is only agitated when sat in a partiular hair beause they feel a draft or only beomes restless when a ertain visitor leaves. The analysis also provides an opportunity to understand the behaviours from the patient s perspetive: what are they trying to tell us? Reality orientation (RO), reminisene therapy (RT), and validation therapy (VT) have all been shown to have a positive effet, to some extent, on behaviour, soial interation, and well being, although not ognition. All three therapies an be provided on an individual basis or in groups. The strongest evidene is for the effiay of RO whih is widely used and involves reminding patients with dementia, through disussion and presentation of materials, fats about themselves, urrent affairs, and their environment. RT uses similar tehniques to RO exept it fouses on past events and helps the patient relive pleasant earlier experienes, espeially signifiant events suh as weddings. VT attempts to ommuniate with the patients by empathising with the feelings and meanings hidden behind their onfused speeh and behaviour. In VT there is validation of the patient s urrent experiene. RO and RT are easier therapies to implement on a formal or informal basis and in linial experiene less likely to ause distress than VT. Several therapies entring on sensory stimulation have been shown to be effetive in reduing agitation and behavioural problems. The two main essential oils used in aromatherapy for dementia are lavender and Melissa, whih are relaxants and thought to modulate neurotransmitter ations. Aromatherapy an be administered, to suit the patient, via several routes inluding inhalation, bathing, massage, and topial appliation. There have so far been few side effets reported. Musi therapy delivered via various methods (for example. live/taped musi, patient s hoie/ relaxation musi, and listening/playing) has also been reported as an effetive treatment, 23 while the findings for bright light therapy (BLT) have so far been mixed. Multisensory therapy of Snoezelen, whih stimulates the primary senses of sight, hearing, touh, taste, and smell through the use of lighting effets, tatile surfaes, meditative musi, and aromatherapy, may also be useful. Pharmaologial interventions The evidene for ChEIs, although not unequivoal, is promising with regards to treating agitation. Few studies have rarely had neuropsyhiatri symptoms as their primary outome but, as already disussed, they may be the safest and most effetive pharmaologial treatment, espeially in DLB. Antipsyhoti mediations have, without doubt, been overused in the past. Ironially there is no overwhelming evidene to support their use. Of all atypial antipsyhotis, risperidone has the largest database of double blind ontrolled trials to support its effiay and safety in the treatment of agitation, aggression, and psyhosis assoiated with dementia. 24 Its superiority over plaebo for agitation appears to be independent of dementia type, dementia severity, presene of psyhosis, or drug indued somnolene. Risperidone, however, along with olanzapine, in the UK is felt to be unsuitable for patients with dementia beause of the onerns about inreased risk of stroke and mortality. 25 As atypial antipsyhotis have a more favourable side effet profile than typial antipsyhotis, there is no ompelling reason to reommend the use of more traditional antipsyhotis. In fat it has been reported that risperidone and olanzapine are not assoiated with a statistially signifiant risk of stroke ompared with typial antipsyhotis. 26 As with starting any mediation, the possible risks and benefits of antipsyhoti mediation must be onsidered. With the onerns about atypial antipsyhotis, older mediations suh as promazine and benzodiazepines, whih have their own onsiderable side effets, have ome bak in vogue. Other alternatives, whih have limited evidene available, are arbamazepine, valproate, and trazodone. APATHY Apathy is often ignored and underdiagnosed. It is ommonly defined as a lak of interest, emotion, and motivation. Non-pharmaologial interventions Caregivers often beome frustrated with apatheti patients as they misinterpret their loss of motivation as being disinterested and lazy. Eduating aregivers an redue distress and blame direted towards the patient. Interventions, inluding behavioural tehniques, whih optimise funtioning, initiate goal direted behaviours, and inrease involvement in pleasant ativities are also useful. Pharmaologial interventions There have been very few studies of any mediations, but all three ChEIs have been shown to be effetive in the treatment of apathy. DEPRESSION Depression is ommon in AD, with a prevalene of approximately 20% and even higher in VaD and DLB. It an be very diffiult to diagnose depression aurately in dementia. The patient may not be able to report their symptoms reliably due to impaired memory and insight. Observations and ollateral history an therefore be important in making the diagnosis. Depression symptoms are often present in patients with dementia in the absene of oexistent depression. Non-pharmaologial interventions Cognitive behavioural therapy and interpersonal therapy may have signifiant benefits in the treatment of depression in dementia, but are likely to be limited in patients with severe dementia. Many other non-pharmaologial therapies have been shown to result in improvements, inluding RO, RT, VT, musi therapy, exerise, and rereational ativities. Most of these therapies are simple to implement and should probably be the first hoie in treating mild-moderate depressive symptoms. Pharmaologial interventions Most linial trials of antidepressants for depression in dementia have been inonlusive. Pharmaologial treatments should probably be reserved for patients with severe depression symptoms. The preferred hoie of antidepressant is seletive serotonin reuptake inhibitors (SSRIs), as triyli antidepressants an give holinergi side effets whih inreased ognitive and funtional impairments in people with dementia. PSYCHOSIS Non-pharmaologial There are few non-pharmaologial interventions whih are useful in treating true psyhosis. Correting visual and J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 November Downloaded from on 17 August 2018 by guest. Proteted by opyright.

7 hearing impairment and improving lighting an redue the risk of misinterpretations. Modifying sensory stimulations that may trigger psyhosis, suh as refletions in a mirror or window, an also be effetive. 29 Pharmaologial interventions ChEIs, as already disussed, are a safe and effetive treatment for psyhosis in dementia, partiularly DLB. The use of antipsyhotis raises the same issues as their role in treating agitation. If a patient is distressed by psyhoti symptoms and they have not responded to a ChEI, or a ChEI is not indiated, then the benefits of antipsyhoti treatment probably outweigh the risks. SUMMARY Dementia is distressing for patients, their families, and their arers. While a ure for any type of dementia is unlikely in the near future, urrent symptomati treatments offer genuine hope for improving the quality of life of patients and arers. All patients should have aess to proven safe and effetive treatments. Early, aurate diagnosis is essential so ChEIs an be ommened at the earliest opportunity. Management of BPSD should be patient and arer entred, utilising the full range of non-pharmaologial treatments available. Presribing drugs for BPSD should no longer be automati and instead should be onsidered arefully.... Authors affiliations R Overshott, A Burns, Department of Old Age Psyhiatry, Wythenshawe Hospital, Manhester, UK Competing interests: Dr Overshott has worked on linial trials sponsored by pharmaeutial ompanies, inluding a trial for memantine in Parkinson s disease with dementia. Professor Burns has been involved in linial trials on holinesterase inhibitors for Alzheimer s disease whih have been sponsored by their manufaturers. He has also reeived honoraria and hospitality from pharmaeutial ompanies. REFERENCES 1 Rosen WG, Mohs RC, Davies KL. A new rating sale for Alzheimer s disease. Am J Psyhiatry 1984;141: Stern RG, Mohns RC, Davidson M, et al. 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