After 1994, when the International Psychogeriatric Association (IPA) proposed the concept of behavioral and psychological symptoms of dementia (BPSD; http://www.ipa-online.org/ipaonlinev3/ipaprograms/taskforces/bpsd/Default.asp), BPSD began to be evaluated from a variety of standpoints. In the biological treatment of BPSD, the pathological conditions must be accurately understood by clarifying the mental symptoms of demented patients and evaluating their biological background.
SPECIFIC SYMPTOMS OF BPSD
Figure 1 shows the psychological symptoms of BPSD on the right and the behavioral symptoms on the left. One of the psychological symptoms of BPSD reported is often a depressive state,1 but the depressive state changes as major depression enters the regressive stage or organic depression progresses to dementia, and reduced volition gradually emerges. These organic factors may underlie the ineffectiveness of antidepressants in the treatment of geriatric depression (Fig. 2).
Hirono et al.2 compared BPSD in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) and reported that delusions and hallucinations were notable in DLB, that disinhibition was observed at a significantly higher frequency in FTD, that apathy was noted frequently in all three groups with no significant difference between them, and that agitation, dysphoria, anxiety, euphoria, irritability, and abberant motor function were also observed in all three groups at similar frequencies. Ikeda et al.3 compared BPSD between AD and vascular dementia (VaD) and observed a generally infrequent occurrence of symptoms of BPSD in VaD except for apathy, which was observed significantly more often in VaD than in AD. Furthermore, when the details of delusions were investigated in 53 patients with AD who experienced delusions, a delusion of theft was most frequent, occuring in 75.5% of cases, followed by delusions of ‘the presence of uninvited guests’ or phantom boarders in 30.2% of cases, and delusions of persecution in 27.1% of cases.4 Capgras syndrome was seen in only 1.9% of cases.4
PSYCHIATRIC SYMPTOMS OF DLB AND PROGRESSIVE SUPRANUCLEAR PALSY
A variety of hallucinations and delusions appear in DLB. For example, in a 73-year-old woman, nightmares involving fire and being killed and loud somniloquence were noted, but the distinction between the patient's dreams and reality was blurred, even while the patient was awake, and confusion and fear were observed. Visual hallucinations of ghosts and dwarfs were noted, and the patient made comments including ‘a spaceship is landing in my garden’; ‘dwarfs appear to be increasing and waging war; it seems we have lost’; and ‘I feel lightheaded, because dwarfs sprinkle drugs. I know it, because I can smell it.’ In this case, the patients Mini-Mental State Examination (MMSE) score was 23. Visual hallucinations of DLB are vivid, as for this patient, and patients can accurately describe them later. Some patients complain of optical illusions and metamorphopsia. Auditory hallucinations are rare and are often associated with visual hallucinations. Hallucinatory experiences of stereognotic perception, misidentification of people and places, duplicated memory errors, and Capgras syndrome are also common findings.
Psychiatric symptoms are also observed frequently in progressive supranuclear palsy (PSP) and include anxiety, euphoria, hallucinations, delusions, indifference, a periodic stupor-like condition,5 and subcortical dementia. Attention to free-floating psychiatric symptoms that are changeable is necessary even in neurodegenerative disorders.
BIOLOGICAL BACKGROUND OF BEHAVIORAL ABNORMALITIES
Behavioral abnormalities are diverse, as shown in Fig. 1, but their anatomical background should be considered more as they become more severe. The case below is a good illustration of this.
A woman who died at 74 years of age and had exhibited forgetfulness and paranoid speech and behavior since 69 years of age, was found to have general cerebral atrophy by head computed tomography (CT) at 71 years of age and was subsequently diagnosed with senile dementia.6 She frequently exhibited incoherent speech and behavior from about 72 years of age and, with marked memory defects, started to often shout, speak in a strange voice, and wander. At approximately 74 years of age, logoclonia appeared, and restlessness and hyperactivity persisted. The autopsy revealed relatively mild atrophy of the frontal lobe, but very severe degenerative atrophy of the temporal lobes, hippocampus, and amygdaloid nucleus. Although senile plaques and neurofibrillary tangles were observed diffusely in the cerebral cortex, neuronal loss was particularly notable in the amygdaloid nucleus, hippocampus, and parahippocampal gyrus. Lesions are often found on the medial sides of the temporal lobes, such as the amygdaloid nucleus, and in the frontal lobe and basal ganglia as factors underlying hyperactivity, shouting, and increased irritability in the advanced stage of dementia (Fig. 3).
SLEEP DISORDERS THAT OFTEN ACCOMPANY DEMENTIA
Sleep disorders associated with dementia include circadian rhythm disorders, delirium and sunset syndrome, sleep apnea syndrome, sleep myoclonus syndrome, and REM sleep behavioral disorders (RBD). Sleep myoclonus syndrome is insomnia due to the periodic repetition of stereopathic limb movements, whereas RBD appears as a diverse series of abnormal behaviors that occur repeatedly during periods of REM sleep. The abnormal behaviors range from laughing, talking, and shouting to getting up and running, as well as even more violent actions such as punching and kicking. Clonazepam, melatonin, donepezil, and levodopa are effective for the treatment of these disorders.
MEDICAL TREATMENT FOR BPSD
Presently, medical treatment is the primary biological treatment for BPSD.
Preparation of guidelines for the treatment of psychiatric symptoms and behavioral disorders
The Study Group for the Guideline for the Diagnosis, Treatment, and Care of Alzheimer's Disease of the Ministry of Health, Labor and Welfare (Chief: Akira Honma) searched for references concerning ‘medical treatment for the symptoms of’: (i) agitation and psychiatric symptoms; (ii) symptoms of depression; (iii) delirium; and (iv) sleep disorders.7
Methods and contents
The literature from 1990 to 2006 was screened. Relevant publications were collected primarily from PubMed (http://www.ncbi.nlm.nih.gov/PubMed/) and the Japana Centra Revuo Medicina (http://www.jamas.gr.jp/), but also from other appropriate sources and selected using the evidence-based medicine (EBM) procedure. In addition, an abstract table was prepared, and the publications were sorted taking into consideration factors such as clinical efficacy and clinical applicability.
The evidence level was classified as follows: I, systematic reviews/meta-analyses; II, one or more randomized comparative studies; III, non-randomized comparative studies; IV, analytical epidemiological studies, such as cohort research and case-control studies; V, descriptive studies, such as case reports and case series; and VI, opinions of special committees or individual experts not based on patient data. The recommendations were graded as follows: A, strongly recommended; B, recommended; C, no grounds for strong recommendation; and D, not recommended.
Draft examples of guideline for the treatment of psychiatric symptoms and behavioral disorders
The procedures for drafting the guidelines and the compilation of guideline contents are described in the following example. Medical treatments for agitation and psychiatric symptoms were selected according to their order of frequency in the literature, and evidence levels supporting their use and recommendation grades were examined. In this way, the atypical antipsychotic risperidone was selected first. Part of the procedure investigating risperidone is described below.
1. Katz et al.8 (evidence level II): Effects on agitation, aggression, and psychiatric symptoms associated with dementia at doses of 0.5, 1, and 2 mg/day risperidone were compared with those of a placebo group. Aggression was alleviated at doses of 0.5 mg risperidone or greater, and psychiatric symptoms were reduced at doses of 1 mg risperidone or greater. Because extrapyramidal symptoms and somnolence are often observed at doses of 2 mg risperidone or above, a dose of 1 mg/day risperidone was recommended. No significant difference was observed in efficacy between doses of 1 and 2 mg/day risperidone.
2. De Deyn et al.9 (evidence level II): A randomized comparative study of haloperidol and risperidone. No significant differences were noted in the efficacy against agitation or psychiatric symptoms between the two treatment groups. Significant improvements were noted compared with a placebo group. Risperidone was more efficacious against aggression and less frequently induced extrapyramidal symptoms. No significant differences were observed among the three groups concerning cognitive ability or the ability of patients to conduct activities of daily living.
Table 1 lists the recommendations made on the basis of the results of the literature search and evaulation of the published data.
|Treatments for agitation and hallucinations/delusions associated with AD|
|Recommendation Grade A|
|1. Risperidone started at 0.5 mg/day (may be increased to 2 mg/day)|
|2. Olanzapine started at 2.5 mg/day (may be increased to 10 mg/day)|
|3. Quetiapine started at 25 mg/day (may be increased to 100 mg/day)|
|4. Aripiprazole started at 2 mg/day (may be increased to 15 mg/day)|
|Recommendation Grade B|
|1. Tiapride started at 50–100 mg/day (may be increased to 300 mg/day)|
|2. Haloperidol started at 0.75 mg/day (may be increased to 2–3 mg/day)|
|If the above medications are ineffective:|
|3. Carbamazepine started at 100–300 mg/day (may be increased to 600 mg/day)|
|Recommendation Grade C|
|1. Sodium valproate, trazodone, SSRIs etc.|
|Depending on a patient's condition, initial administration of lower doses of the drugs listed above may be necessary. Increases in dose must be made with sufficient caution concerning adverse effects. Olanzapine and quetiapine are contraindicated in diabetic patients. In Japan, none of these drugs is covered by medical insurance. Aggressive behavior, excitation, wandering, and delirium as sequelae of cerebral infarction are indications for the use of tiapride.|
|Treatments for depression|
|Recommendation Grade B|
|No evidence concerning the relative recommendation (in May 2006) or the dose of fluvoxamine and paroxetine, which are marketed in Japan, has been obtained. Taking into consideration the older age of patients, it is generally desirable to use relatively low starting doses (e.g. fluvoxamine 10–25 mg/day; paroxetine 10–20 mg/day).|
|Treatments for delirium|
|Recommendation Grade C (but close to Grade B)|
|1. Risperidone started at 0.5–1.0 mg/day|
|2. Quetiapine started at 25–50 mg/day|
|3. Olanzapine started at 2.5–5 mg/day|
|4. Tiapride started at 25–50 mg/day|
|The underlying causative diseases of delirium must be determined in each patient before antipsychotic medication is started. In addition, improvements to a patient's environment are necessary. Dose increases must be made with sufficient caution concerning adverse effects. Olanzapine and quetiapine are contraindicated in diabetes. None of the drugs is covered by medical insurance in Japan. Aggressive behavior, excitation, wandering, and delirium as sequelea of cerebral infarction are indications for the use of tiapride.|
|Treatments for sleep disorders|
|Recommendation Grade B|
|1. Zolpidem 5–10 mg/day|
|Recommendation Grade C (but close to Grade B)|
|1. Benzodiazepine sleep inducers (short-acting, intermediate-acting)|
|2. Trazodone and antipsychotics|
|Improvement of the environment is also important. Unsupervised long-term administration should be avoided.|
In the future biological treatment of BPSD, electroconvulsive therapy will be used for the treatment of psychiatric symptoms, whereas vaccinations will be effective in both the prevention and treatment of dementing diseases, as well as for the control of BPSD. At present, drug therapy is the primary treatment. Considerable caution is necessary when administering drug therapy to demented patients, who are mostly elderly. The US Food and Drug Administartion analyzed 5106 cases in 17 placebo-controlled comparative trials of the atypical antipsychotics olanzapine, aripiprazole, risperidone, and quetiapine in the treatment of behavioral disorders in elderly demented patients and concluded that the mortality rate was 1.6–1.7-fold higher in treated patients than in the placebo-treated controls (http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm053171.htm). It requested that pharmaceutical companies mention in package inserts that the drugs may increase mortality and that treatment of BPSD is an off-label indication. Presently, the situation is also the same in Japan. It is essential to inform patients and their families of the status of this drug therapy and obtain their consent to proceed, to use the drugs at as low a dose as possible and for a short period of time, and to always pay attention to any adverse physical effects.10