Five Alzheimer's disease cases with refractory behavioural psychological symptoms of dementia treated with blonanserin

Authors


Dr Atsushi Hamuro MD PhD, 1123 Ameku Naha Okinawa 900-0005, Japan. Email: ahamuro007@yahoo.co.jp

Abstract

The aim of the present study was to determine the efficacy, side-effects and tolerability of blonanserin for treating refractory behavioural psychological symptoms of dementia (BPSD). The present study was a 12-week, prospective, structured clinical trial of blonanserin for the treatment of BPSD. The degree of cognitive function, activities of daily living score, and the degree of BPSD were determined using the Mini-Mental State Examination (MMSE), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI) and the Rating Scale for Aggressive Behaviour in the Elderly (RAGE). The severity of extrapyramidal symptoms was assessed using the Drug-Induced Extrapyramidal Symptoms scale (DIEEPS). Five patients were enrolled. These patients met the NINCDS-ADRDA criteria. The patients were prescribed more than two kinds of existing antipsychotic drugs and were considered refractory cases; the drugs were discontinued because they were ineffectual and side-effects appeared. Each drug was prescribed independently for at least 2 weeks. The mean changes (at baseline and at the last week, respectively) in the MMSE (12.25, 9.25), in the DAD (6.5, 6.75), in the RAGE (5.5, 5.3) and in the DIEEPS (0.5, 1.5) were minimal. The mean changes in the NPI were two or fewer points. Some side-effects (one gait abnormality and one pneumonia) were observed. The results of this preliminary study show that blonanserin does not have adequate efficacy for the treatment of refractory BPSD.

BACKGROUND

Blonanserin, a 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocy cloocta [b]pyridine is a novel D2 and 5-HT2A receptor antagonist, was developed in the USA (Phase II) and is sold in Japan. Although its use in schizophrenia has already been studied,1 no study has examined its use in patients with behavioural psychological symptoms of dementia (BPSD). Medications for BPSD have been used carefully since the alert2 of the USA Food and Drug Administration Agency (FDA), but refractory cases remain, despite non-pharmacological and pharmacological treatments. The aim of the present study was to determine the efficacy, side-effects and tolerability of blonanserin for treating Alzheimer's disease patients with refractory BPSD.

METHODS

The present study was a 12-week, prospective, structured clinical trial of blonanserin for the treatment of BPSD.

The degree of cognitive function, activities of daily living score and the degree of BPSD were determined using the Mini-Mental State Examination (MMSE), Disability Assessment for Dementia (DAD),3 Neuropsychiatric Inventory (NPI) and the Rating Scale for Aggressive Behaviour in the Elderly (RAGE).4 The severity of extrapyramidal symptoms was assessed using the Drug-Induced Extrapyramidal Symptoms scale (DIEEPS).

Patients were evaluated at baseline, and during weeks 2, 4, 6, 8 and 12. The dose of blonanserin started at 4 mg and was increased by 2 mg every 2 weeks if needed.

Five patients were enrolled. These patients had ‘probable Alzheimer's disease’ based on the criteria of the National Institute for Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA).5

The patients had been prescribed more than two kinds of existing antipsychotic drugs and were considered refractory cases in whom the drugs were discontinued, because they were ineffectual and side-effects appeared. Each drug was prescribed independently for at least 2 weeks.

The patients' other characteristics (including complications, medication use) are presented in Table 1.

Table 1.  Characteristics of the five cases
 ComplicationsDrugs that were ineffective
  1. The drugs that were ineffective are listed by pharmaceutical name and maximum daily dose (mg).

Case 1NoneRisperidone 2 Olanzapine 1.2
Tiapride 25 Yi-Gan-San 10 g
Case 2NoneRisperidone 2 Quetiapine 25
Tiapride 25 Yi-Gan-San 5 g
Aripiprazole 6
Case 3CholecystitisRisperidone 1 Quetiapine 37.5
Case 4DiabetesRisperidone 0.8 Tiapride 50
Yi-Gan-San 10 g
Case 5Pulmonary dysfunctionOlanzapine 5 Tiapride 50
Levomepromazine 60

After a complete explanation of the study was given to the patients and caregivers, written, informed consent was obtained.

RESULTS

Three patients completed the clinical trial. Two were withdrawn from the study.

Case 4 developed a gait abnormality and Case 5 developed pneumonia.

The mean blonanserin dose at the end-point was 3.8 mg/day. The mean changes (at baseline and at the last week, respectively, not including Case 5) in the MMSE (12.25, 9.25), in the DAD (6.5, 6.75), in the RAGE (5.5, 5.3) and in the DIEEPS (0.5, 1.5) were minimal. The mean changes in the NPI are presented in Table 2.

Table 2.  Neuropsychiatric Inventory scores between baseline and last week
 Baseline
Fr × Se/Cb
Last week
Fr × Se/Cb
  1. The points for euphoria were zero. Cb, caregiver burden; Fr × Se, frequency × severity.

Delusions1.5/1.01.5/1.0
Hallucinations0/00.25/0.25
Aggression3.5/2.53.5/2.25
Depression2.0/0.751.0/0.5
Anxiety2.75/1.51.75/1.25
Apathy0/02.75/0.5
Disinhibition0.25/0.50.75/1.0
Irritability2.0/1.251.25/1.5
Aberrant motor activity3.0/1.251.5/0.5

Case 1

An 89-year-old woman at the time of onset had shown cognitive dysfunction, as well as delusions of robbery and agitation at the age of 90 years. Due to worsening of these BPSD, she was hospitalized at the age of 92 years. The MMSE score at the first medical examination on admission was 4. The computed tomography (CT) scan findings were a moderate enlargement of sulcus, and frontoparietal and hippocampal atrophy. She had never taken Aricept. She continued to be delusional and agitated throughout the study period.

Case 2

A 77-year-old man at the time of onset had a cognitive disorder, as well as insomnia and wandering at the age of 78 years. Due to worsening of these symptoms, screaming and violent behaviour, he was hospitalized at the age of 79 years. The MMSE score at the first medical examination on admission was 18. The CT scan findings were a mild enlargement of ventriculus, mild hippocampal and moderate parietal atrophy. He had been prescribed a dose of Aricept 5 mg at the age of 78 years, but the treatment with Aricept had been discontinued for 1 month because of irritability. He showed physical aggression toward other patients, and screamed continuously day and night during the study period.

Case 3

A 72-year-old man at the time of onset had memory impairment, as well as sundowning and wandering at the age of 74 years. Due to worsening of these symptoms and violent behaviour, he was hospitalized at the age of 74 years. The MMSE score at the first medical examination on admission was 11. The CT scan findings were mild enlargement of sulcus and moderate diffuse atrophy. He had never taken Aricept. He continued to display wandering and violent behaviour during the study period.

Case 4

A 77-year-old man at the time of onset had cognitive dysfunction, as well as hallucinations and wandering at the age of 80 years. Due to worsening of wandering, adverse sleep and violent behaviour, he was hospitalized at the age of 80 years. The MMSE score at the first medical examination on admission was 16. The CT scan findings were mild enlargement of ventriculus and moderate hippocampal atrophy. He had been prescribed a dose of Aricept 5 mg at the age of 79 years for 1 year, but it was discontinued because hallucinations and wandering appeared. After 2 weeks of taking blonanserin, he developed gait abnormality and wandering remained. Blonanserin was discontinued.

Case 5

A 71-year-old man at the time of onset had cognitive dysfunction, as well as delusions of robbery and violent behaviour at the age of 73 years. Due to worsening of these symptoms, he was hospitalized at the age of 74 years. The MMSE score at the first medical examination on admission was 10. The CT scan findings were moderate enlargement of ventriculus and moderate diffuse atrophy. He had never taken Aricept. After 13 days of taking blonanserin, he developed pneumonia. Blonanserin was discontinued.

CONCLUSION

The results of the present preliminary study show that blonanserin does not have adequate efficacy for the treatment of refractory BPSD.

Studies of treatments for BPSD have shown that atypical antipsychotics (including risperidone,6 olanzapine7 and quetiapine8) are partially effective. However, the FDA alert2 caused some confusion in some hospitals and nursing homes.

In the present study, blonanserin was selected because it was expected that it, as a novel agent for the treatment of BPSD, would have a lower prevalence of extrapyramidal symptoms as a result of having equivalent affinity to 5-HT2A receptor antagonists as existing atypical antipsychotics and decreased psychomotor excitement as a strong D2 receptor antagonist.

As Case 4, who failed medical therapy, was very drug-sensitive, he developed a gait abnormality. As Case 5 had poor pulmonary function with blonanserin, which is a strong D2 receptor antagonist and might affect the relation between dopamine and substance P, he developed pneumonia. The limitations of the present study were the small number of participants, the inability to analyze the results statistically, and the appropriate dosage of blonanserin was unclear. Therefore, further research is needed to clarify any potential associations.

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