Correspondence : Byoung Hoon Oh, MD, PhD, Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Severance Mental Health Hospital, 696-6 Tanbeol-dong, Gwangju 464-100, Korea
Tel : +82-31-765-0443, Fax : +82-31-761-7582, E-mail : drobh@yumc.yonsei.ac.kr

Introduction

Dementia is a typical neuropsychiatric disorder, and the number of dementia patients is rapidly increasing due to the increase in the elderly population.¹ The main symptom of dementia is progressive cognitive impairment, but there are also various BPSD, e.g. anxiety, depression, delusions and hallucinations. BPSD produce significant problems for both patients and caregivers. Aggravated BPSD accelerate the impairment of cognitive function and lead to early nursing home replacement, increased cost and decreased quality of life. Effective treatment is needed for the management of BPSD. When the BPSD are mild, non-pharmacological treatment can be considered and additional pharmacological intervention is unnecessary. However, in patients with moderate to severe BPSD, pharmacological intervention is essential.²

Behavioral and Psychological Symptoms in Dementia

In 1996, the International Psychogeriatric Association convened a Consensus Conference on BPSD to review the knowledge of these symptoms and to reach a consensus of opinion with regard to the nosology, etiology, clinical symptoms and research directions of dementia. The Consensus Group defined BPSD as symptoms of disturbed perception, thought content, mood or behavior that frequently occur in patients with dementia.³
Psychotic symptoms are a common feature associated with dementia, occurring in 25-50% of Alzheimer's disease patients.⁴ Tariot reported that about 44%, 34% and 28% of dementia patients experience agitation, delusion and hallucination, respectively.⁵ The most common delusions have persecutory contents and most often involve both visual and auditory hallucinations. Cummings reported that the behavioral manifestations of Alzheimer's disease were, in order of decreasing prevalence, apathy 72%, agitation 60%, anxiety 45%, irritability 42%, depression 38%, motor behavior 38%, disinhibition 36%, appetite change 31%, night behavior 24%, delusion 22% and hallucination 10%.⁶ Finkel also reported that the prevalences of BPSD were delusion 20-72%, misperceptions 23-50%, hallucination 10-20%, depression up to 80%, mania 3-15%, personality change up to 90%, behavioral problems 50% and aggression/hostility 20%.⁷
Oh studied the characteristics of the behavioral and psychological symptoms as a function of the dementia stage using the Korean Version of the Neuropsychiatric Inventory. The most common behavioral disturbances were apathy/indifference, depression/dysphoria, and aberrant motor behavior. The mean composite score of aberrant motor behavior increased with increasing stage of dementia severity with statistical significance.⁸

Management of BPSD

In the treatment of dementia, in addition to the cognitive symptoms, the management of a wide variety of psychotic and behavioral symptoms is also very important.⁹ These symptoms affect both the patients and the caregivers, and sometimes require early institutionalization.¹⁰ In the management of BPSD, non pharmacological intervention is recommended in the early or mild stage, but in the moderate or severe stages, appropriate pharmacological treatment is essential. A wide variety of drugs have been used for the control of BPSD.¹¹ Neuroleptics have been the main treatment for psychotic symptoms, but benzothiazepines, antidepressants, other anticonvulsants, beta-blockers, buspirone and lithium have also been used for a variety of BPSD.^12,13 The conventional neuroleptics exert their effect principally by the blockade of the dopamine receptors. Although conventional neuroleptics have been widely used in the management of BPSD, side effects have been reported such as cognitive deterioration, sedation and tardive dyskinesia.¹⁴ High potency neuroleptics in particular can causes extrapyramidal side-effects, and low potency neuroleptics can also be associated with adverse effects such as blurred vision, delirium and confusion.
Recently, the new generation of antipsychotics such as risperidone, olanzapine and quetiapine have been reported to be more effective than conventional neuroleptics in the treatment of BPSD. Their toxicity is lower than that observed with conventional neuroleptics, especially in terms of extrapyramidal symptoms, which are uncommon at appropriately low doses for elderly dementia patients. More adverse events have been reported for patients receiving 2 mg/day than for those receiving 1 mg/day of risperidone, for patients receiving over 5 mg/day than for those receiving 3 mg/day of olanzapine and for patients receiving 100 mg/day than for those receiving 50 mg/day of quetiapine.^15,16
Usually, low doses of risperidone (0.5-1 mg/day), olanzapine (3-5 mg/day) and quetiapine (25-50 mg/day) were effective and well tolerated in elderly dementia patients, being associated with a low incidence of extrapyramidal and anticholinergic symptoms (Table 1).^17,18

Issues Regarding the Pharmacotherapy of Dementia

The current treatment guidelines depend on the patient's symptoms, whether or not the underlying cause is known. Unfortunately, these guidelines are not really supported by the current evidence, so the main problem is to demonstrate their efficacy and safety.
In fact, randomized controlled trials of the newer neuroleptics have been carefully conducted. The treatment guidelines for the newer neuroleptics with regard to their efficacy and safety are as follows (Source: Data from IXth Congress of the Int. Psychogeriatric Assoc, Vancouver 1999).³

Olanzapine
Safe and effective in reducing psychosis and behavioral disturbances in Alzheimer's disease compared with a placebo. Somnolence and abnormal gait reported significantly more frequently in olanzapine-treated patients than in the placebo-treated group. A dose of 5 mg/day is appropriate for most elderly patients with dementia.

Risperidone
Significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Efficacy was most evident for aggressive symptoms. Severity and incidence of extrapyramidal symptoms with risperidone were nor different from a placebo, but significantly less than with haloperidol. A dose of 1 mg/day is appropriate for most elderly patients with dementia.
Another problem is that the specific drug-responsive behaviors for each medication are not clarified as yet. Moreover, the neurobiology of most psychotic behaviors in dementia is not well understood. Therefore, the rational treatment guidelines based on behaviors are not evidence-based and may not be useful to the clinician. However, recently, approaches based on neurotransmitters and novel ligands for neuroimaging offered evidence-based information, and this information may be more closely linked with the treatment options for the newer neuroleptics.¹⁹ Also, these approaches may eventually lead to the identification of the subtypes of psychotic symptoms and thus to better treatment outcomes.

Conclusion

Typical psychotic symptoms such as delusions and hallucinations should be treated when they cause distress to the patients. Most clinicians use neuroleptics to treat psychosis or behavioral dyscontrol in dementia.
The priority in the treatment of psychotic symptoms is the optimization of comorbid illnesses, especially delirium, and the removal of the offending substance or medications. Also, chemical restraints due to polypharmacy should be avoided and careful monitoring for side effects, especially extrapyramidal symptoms, must be done. In general, antipsychotic agents can cause dry mouth and lethargy in the short term, whereas their long-term use can lead to tardive dyskinesia. Therefore, developing safe and effective treatments is a clinical priority. The majority of the studies conducted so far have used newer neuroleptic agents such as risperidone, olanzapine and quetiapine. Overall, these drugs are significantly more effective than a placebo. These atypical agents are better tolerated than traditional neuroleptics.
In summary, the results indicate that newer neuroleptics such as risperidone, olanzapine and quetiapine have beneficial effects on a variety of BPSD, especially aggression, agitation and psychotic symptoms. Since elderly dementia patients have decreased drug metabolism, risperidone, olanzapine and quetiapine should be used carefully using a "start low and go slow" approach, generally with optimum doses of 1 mg/day, 5 mg/day and 50 mg/day, respectively. Further double-blinded, placebocontrolled for atypical neuroleptics studies involving larger numbers of subjects are needed, in order to establish guidelines for the treatment of the psychotic symptoms of dementia.

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