GM 43, March 2013
Dr Dwaipayan Sen
Approximately 8–10% of people aged over 65 years suffer from cognitive impairment in the western societies. The prevalence rises from 2% in people aged over 65 years to 35% in people aged over 85 years.1 According to current data about 700,000 people suffer from dementia in the UK. A significant proportion of these patients have behavioural disturbances and are managed with various modalities, use of antipsychotic medication being the most common. At present 180,000 patients with dementia are on antipsychotic medication resulting in a £80 million spending.2
The spectrum of different behavioural symptoms are covered under the term “behavioural and psychological symptoms of dementia (BPSD).” It ranges from mild symptoms of apathy, fidgeting and wandering to much more difficult to control verbal and physical aggression. These symptoms arise mainly out of unhappiness and boredom and often reversible factors like pain and depression play a part in it. Most of these symptoms resolve spontaneously or if reversible factors are sought and dealt with effectively. Therefore if they are not very severe, adopting a policy of watchful waiting might be entirely reasonable.3 If intervention is needed a variety of options are available, which can be broadly divided into non-pharmacological and pharmacological treatment. Pharmacological treatment again has several options including antipsychotic medication, cholinesterase inhibitors, antiepileptics, benzodiazepines and antidepressant medication. We will review the effectiveness, risks, side effects and evidence base behind each of these treatment modalities.
Behavioural symptoms often arise out of boredom, unhappiness and fear of being in an unfamiliar surrounding. A number of different non-pharmacological strategies have been described to manage such individuals. In general, people with dementia do well in a familiar, calm and quiet environments and within stable daily routines. Often symptoms worsen at night (sundowning).
Carers can be encouraged to keep a diary of such symptoms in an attempt to identify trigger factors. In future, avoidance of these trigger factors may reduce the incidence of such symptoms. Carers should also be encouraged not to leave such patients in unfamiliar surroundings alone. During periods of aggression the person should always be approached from the front and eye contact should be established. Questions and other techniques should be used to distract the person’s attention to something more pleasurable. Contradicting or confronting the person should be avoided as it leads to an escalation of the problem.3
Wandering habits generally do not respond to any medication. The aim should be to make the environment safe and aggressive patients should be allowed to wander in such safe environments. Labelling different rooms, installing mirrors on doors, and alarms and concealed or childproof locks on exit doors can singly or in combination be used to implement such a strategy.
Sundowning is another difficult symptom to control, which is poorly responsive to medication. Increased daytime activity, avoidance of caffeine, alcohol etc. and discouragement of daytime naps are some of the strategies described to tackle sundowning.3 Aromatherapy and other methods of sensory stimulation like soft background music have also been described to have a calming effect on patients.
The evidence base for these non-pharmacological methods shows some benefit overall. A study compared an intervention of activity programme, medication review and carer educational sessions to a control group over a period of six months in 81 people in a nursing home with BPSD. The intervention was carried out at a significantly increased cost due to additional staff usage. The results show a 23% reduction in behavioural symptoms and antipsychotic drug use in the intervention group as compared to 9% in the control group.4
Another study compared aromatherapy with placebo in patients with dementia and agitation over a four-week period. Seventy-two people residing in NHS care facilities with clinically significant BPSD were randomly assigned to aromatherapy with Melissa essential oil or placebo. Changes in clinically significant agitation (Cohen-Mansfield Agitation Inventory [CMAI]) and quality of life indices were compared between the two groups over a four-week period. Seventy-one patients completed the trial. No significant side effects were observed. 60% of the treatment group and 14% of the placebo-treated group experienced a 30% reduction of CMAI score, with an overall improvement in agitation. Quality of life indices also improved significantly in the treatment arm.5 Although such results look encouraging, it must be remembered that these were trials involving very small numbers and therefore even a small improvement in terms of actual numbers may translate into a huge benefit in terms of percentages. Results of such trials should therefore be interpreted with caution.
Ballard C et al reviewed eight RCTs involving use of different non-pharmacological methods in the management of behavioural symptoms in Alzheimer’s disease and concluded that there was some overall benefit observed along with a reduction in use of antipsychotic medication used. As expected these interventions were well tolerated and no adverse effects were noticed.6
Over the years antipsychotic medication use has emerged as the most common measure against behavioural problems. Over the past decade there have been concerns that use of such medication have led to increased risk of developing cerebrovascular events and sudden cardiovascular death. According to a Department of Health document, in 2009 approximately 180,000 people with dementia were on antipsychotic medication in the UK, but only 20% experienced benefit. They were also implicated in 1800 additional deaths a year and 1620 additional cerebrovascular events a year.2
Both typical and atypical antipsychotics have been studied in a number of RCTs for their effectiveness on behavioural symptoms. Risperidone and haloperidol were compared to placebo over a 13-week period in 344 patients with BPSD living within institutional facilities.7 The patients were randomly assigned to receive placebo or flexible doses of risperidone or haloperidol. Behavioural symptoms were assessed by the Behavioural Pathology in Alzheimer’s Disease Rating scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression (CGI) scale. Although non significant, a higher percentage of patients receiving risperidone than those receiving placebo showed clinical improvement (>30% reduction from baseline to endpoint in BEHAVE-AD total score) at endpoint and week 12. A post hoc analysis showed significantly greater reductions in the BEHAVE-AD aggressiveness score with risperidone than haloperidol at week 12. Summarising the results, there was no significant difference in the behavioural scores between the three groups, but a subgroup analysis concluded that both risperidone and haloperidol were better in control of aggression, the most dominant symptom, in comparison to placebo.
There was high rate of discontinuation in all groups due to either adverse effects (50%) or lack of efficacy (44%). Extra pyramidal symptoms occurred in 22% in the haloperidol group compared to 15% in the risperidone group and 11% in the placebo group. Somnolence was more prevalent in both treatment groups as compared to placebo.
Another trial included 345 elderly patients with a DSM-IV diagnosis of Alzheimer’s dementia, vascular dementia or mixed dementia and significant BPSD, and randomised them to receive, for a period of 12 weeks, a flexible dose of either placebo or risperidone.8 Outcome measures were the CMAI, BEHAVE-AD rating scale and the Clinical Global Impression of Severity (CGI-S) and of Change (CGI-C) scales. The trial was completed by 67% of patients in the placebo group and 73% of patients in the risperidone group. The primary endpoint of the study, the difference from baseline to endpoint in CMAI total aggression score, showed a significant reduction in aggressive behaviour for risperidone versus placebo. A similar improvement was also seen for the CMAI total non-aggression subscale and for the BEHAVE-AD total and psychotic symptoms subscale. At endpoint, the CGI-S and the CGI-C scores indicated a significantly greater improvement with risperidone compared with placebo.
However adverse effects occurred more frequently in the treatment arm. These included somnolence (37% versus 25%), urinary tract infections and cerebrovascular events (9% versus 2%). There was no significant difference in the number of patients who reported extrapyramidal symptoms between the risperidone (23%) and placebo (16%) groups. The study concluded that treatment with low-dose risperidone resulted in significant improvement in aggression, agitation, and psychosis associated with dementia.
A similar trial involving 625 patients with BPSD compared risperidone to placebo over a 12-week period and found similar results of reduction in aggression and psychosis in the risperidone arm.9
Cochrane Database of Systematic reviews have reviewed the use of haloperidol in dementia and concluded that there was evidence for its use in the control of aggression but not for any other form of behavioural symptom.10 Variations in degree of dementia, dosage and length of haloperidol treatment, and in ways of assessing response to treatment suggested caution in the interpretation of reported effects of haloperidol in the management of agitation in dementia. The review recommended that haloperidol should not be used routinely to treat patients with agitated dementia.
Ballard C et al performed a comprehensive review of the use of antipsychotics in the management of BPSD. The review included 18 trials comparing atypical antipsychotics to placebo. 15 trials were over a period of 6–12 weeks and three trials over a period 6–12 months. The review concluded that there was significant improvement with the atypical agents when used for a short period up to 12 weeks.6
Both typical and atypical antipsychotics act by interfering with different groups of neurotransmitter receptors. Their main effect is by blocking the dopaminergic receptors D1–D4, with the maximal effect on the D2 receptors. They also interact with cholinergic, alpha adrenergic, serotonergic and histaminergic receptors. It therefore does not surprise us that such interactions result in some physiological effects on the cardiovascular homeostasis of the body. Such effects include:
• Negative inotropic effect
• Reduced cardiac output
• Postural hypotension
• Prolongation of QTc interval.
The development of arrhythmias like Torsades de pointes secondary to QTc prolongation and acute hypotensive episodes have been implicated as possible mechanisms of sudden cardiac death that have been associated with the use of these drugs.
Atypical antipsychotics have been associated with development of cardiovascular risk factors such as obesity, hyperlipidaemia, and hyperglycaemia, either singularly or in combination as a metabolic syndrome. The risk is said to be highest with atypical agents like olanzapine and clozapine, but other atypical and typical agents also increase the risk to a lower extent. The atypical agent clozapine has been associated with development of myocarditis in patients, a proportion of whom go on to develop late cardiomyopathy.
The typical antipsychotic agents have been in use from the 1950s. The atypical antipsychotics came into use since the late 1980s and gradually replaced the typical agents due to their advantage of fewer incidences of extrapyramidal symptoms. However the extent of cardiovascular risk of these agents was unknown at that time. Over the next few years there was increasing concern that these drugs were associated with increased risk of cardiovascular and cerebrovascular events. A meta-analysis of 15 trials involving comparison of 16 different atypical antipsychotic medications to placebo for a period of 10 to 12 weeks was published in 2005.11 The review found an increased risk of sudden death with these agents as compared to non users. Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis. Based on such facts the FDA in the US issued a warning regarding use of atypical antipsychotic medication. However, the advisory did not apply to conventional antipsychotic medications resulting in renewed interest in this group.
A retrospective cohort study of mortality was published involving 22,890 patients 65 years of age or older who had drug insurance benefits in Pennsylvania and who began receiving a conventional or atypical antipsychotic medication between 1994 and 2003.12 Results confirmed that conventional antipsychotic medications were associated with a significantly higher adjusted risk of death than were atypical antipsychotic medications at all intervals studied and in all subgroups defined according to the presence or absence of dementia or nursing home residency. The greatest increases in risk occurred soon after therapy was initiated and with higher dosages of conventional antipsychotic medications.
These results suggested that conventional antipsychotic medications are at least as likely as atypical agents to increase the risk of death among elderly persons and that conventional agents should not be used to replace atypical agents discontinued in response to the FDA warning. Another similar retrospective analysis compared both typical and atypical antipsychotic medication users to non-users.13 The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched non-users of antipsychotic drugs. Results showed that current users of typical and atypical antipsychotic drugs had higher rates of sudden cardiac death than did non-users of antipsychotic drugs. There was no difference in the risk of sudden cardiac death between typical and atypical groups. For both classes of drugs, the risk for current users increased significantly with an increasing dose. The study concluded that current users of typical and atypical antipsychotic medication had a similar dose related increased risk of sudden cardiac death.
Most of the studies which looked at the use of cholinesterase inhibitors in Alzheimer’s dementia were not designed to primarily look at non cognitive and behavioural symptoms. Therefore the effect of these drugs on behavioural disturbances of dementia remains understudied.
A study included 134 patients with Alzheimer’s dementia with neuropsychiatric symptoms pretreated for 12 weeks with donepezil, and randomised them to either continued donepezil therapy or drug replacement with placebo.14 The patients were monitored for 12 weeks and a modest improvement was noticed in the donepezil group. However only 60% of patients completed the study, most withdrawals being due to adverse effects or inefficacy of the medication.
A placebo-controlled, double-blind, multicentre study was done in 120 patients with lewy body dementia from the UK, Spain, and Italy.15 Individuals were given up to 12mg rivastigmine daily or placebo for 20 weeks, followed by three weeks’ rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis. Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine than on placebo showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks requiring substantial attention. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. The study concluded rivastigmine 6–12mg daily produces statistically and clinically significant behavioural effects in patients with lewy body dementia, and seems safe and well tolerated if titrated individually. Worsening of Parkinsonian features was not observed with rivastigmine in this study.
Carbamazepine and valproate have been tried in the management of behavioural disturbances in dementia. A study compared carbamazepine to placebo in 51 patients with dementia and agitation over a six-week period. There was a significant improvement in behavioural scores in the treatment group, but unfortunately side effects were also significantly common in the carbamazepine group (59% versus 29%). However subsequent studies failed to show such benefits with carbamazepine.16 Cochrane performed an updated review on use of valproate preparation in the management of agitation in dementia. This corroborated the earlier findings that valproate preparations are ineffective in treating agitation among demented patients and is associated with an unacceptable rate of adverse effects. On the basis of current evidence, valproate therapy cannot be recommended for management of agitation in dementia.17
Benzodiazepines have been tried in control of behavioural symptoms in dementia but they have been shown to be largely ineffective and resulted in significant incidence of side effects like somnolence, falls and confusion.
Different antidepressants have been tried in the management of behavioural symptoms in dementia. Trazodone has been suggested in the management of depressive symptoms and agitation in patients with dementia by the SIGN guidelines on dementia. However a Cochrane review suggested that there is currently insufficient evidence to recommend use of trazodone for management of agitation in dementia.18 The review suggested that in order to assess effectiveness and safety of trazodone, longer-term RCTs are needed, involving larger samples of participants with a wider variety of types and severities of dementia.
Memantine is a NMDA receptor antagonist which is a subgroup of glutamate receptors. More recently its use has been postulated in management of BPSD and results from initial studies have been encouraging. Ballard C et al reviewed six RCTs involving use of memantine over a period of 12–24 weeks and reported benefits in agitation and aggression.6 An added advantage was that the drug has been generally well tolerated.
In summary we have seen that management of BPSD is one of the most difficult aspects of dementia care. There is no consensus wisdom in what should be the best practice. Atypical antipsychotic medications have remained the mainstay of management over the years. Current evidence suggests that they are only effective if used for a limited short duration up to 10–12 weeks. Longer term use carries an increased risk of mortality and development of cerebrovascular events, and there is no evidence that they are effective beyond 10–12 weeks. Typical antipsychotic agents were associated with only a modest improvement of symptoms but a significantly increased incidence of extrapyramidal side effects. They too carry at least a similar increased risk of sudden cardiac death. Given this evidence there is no wisdom in recommending routine use of antipsychotics in the management of BPSD. The evidence for other pharmacological agents are not extensive, although it suggests that cholinesterase inhibitors might be effective and initial data involving memantine looks promising. However, more research and data gathering is needed before these effects can be conclusively proved or refuted. The non-pharmacological methods do have some evidence to back them and their use is strengthened by the fact that they have no adverse effects.
Symptoms can be a result of boredom or unhappiness due to reversible factors like pain or depression and often they settle on their own. Therefore, if they are not distressing, taking a watchful waiting policy while searching for reversible causes and altering the environment to suit the person better are entirely reasonable first steps. If intervention is needed non-pharmacological methods should be first choice because of their lack of side effects. If pharmacological treatment becomes necessary then each prescription should be tailored to suit the individual needs of the patient. If antipsychotic medication is prescribed the patient should be regularly monitored for the development of side effects.
Conflict of interest: none. Acknowledgments: This work was done as part of MSc in Geriatric Medicine under Salford University.
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