Influence of the FDA Talk Paper upon the use of atypical antipsychotics for psychotic symptoms in older patients with dementia in Japan

Background: Atypical antipsychotic medications have often been used in the treatment of behavioral and psychological symptoms of dementia (BPSD). Recently, the US Food and Drug Administration (FDA) issued new safety information concerning atypical antipsychotic drugs, indicating that their use may increase the risk of cardiovascular adverse events among elderly adults with BPSD. Based on this information, the Japanese Ministry of Health, Labor and Welfare issued a similar warning against the use of atypical antipsychotic drugs licensed in Japan. We then sought to determine whether or not the use of typical antipsychotics should be recommended to replace atypical antipsychotics. In this paper, we discuss the influence of these warnings on the withholding of use of risperidone exemplified in seven case histories. Methods: Seven inpatients who exhibited BPSD received risperidone monotherapy in our hospital. In response to the FDA notice, the atypical antipsychotics used to treat these patients were replaced with typical antipsychotic agents. Results: During the period of risperidone administration, all patients exhibited clinical improvement compared with their baseline results and showed no adverse events. Two of our seven patients developed psychotic exacerbation and exhibited extrapyramidal symptoms coinciding with the replacement of risperidone with conventional antipsychotics. Conclusion: To the best of our knowledge, this is the first clinical report on the influence of the FDA alert on the use of atypical antipsychotics for psychotic symptoms in older patients with dementia in Japan. In two of our seven BPSD cases, there was no benefit from taking conventional antipsychotics. Our results lead to the conclusion that the use of typical antipsychotics should not be recommended to replace atypical antipsychotics. Although close attention should be paid to the FDA alert, clinicians must take into consideration the balance of benefits and risks when evaluating the appropriate use of antipsychotics in older patients with dementia.     

Behavioural and psychological symptoms of dementia (BPSD): effects of EGb 761

Dementia patients often present with behavioural and psychological symptoms, with prevalence rates reaching 90%. It is therefore important to know whether an antidementia drug that improves cognitive function can also reduce the burden of behavioural and psychological symptoms of dementia, and whether it can improve cognitive function in patients suffering from such non-cognitive symptoms. Therefore, three types of study with Ginkgo special extract EGb 761 (definition see editorial) were reviewed: 1) studies on patients with impairment of cerebral function or dementia associated with behavioural and psychological symptoms (BPSD); 2) studies on patients suffering from impairment of cerebral function and depression; 3) dementia studies on patient samples with a high prevalence of BPSD. Compared to placebo, EGb 761 improved these symptoms significantly in all studies that used a scale to measure the presence and intensity of BPSD. Moreover, EGb 761 was found to be superior to placebo with respect to improvement in cognitive function, daily living activities and global assessment in dementia patients suffering from BPSD. It may be concluded that EGb 761 is of particular interest to patients with dementia and BPSD since it improves both the patient's cognitive ability and behavioural and psychological symptoms.     

Partial compliance with antipsychotics and its impact on patient outcomes

Partial compliance with antipsychotic medications is a common and complex phenomenon that is underestimated by physicians. The consequences of partial compliance include an increased risk of relapse, rehospitalization and suicide attempts. Stigma, negative attitudes towards medications, cognitive impairment and diminished insight negatively impact treatment adherence. Oral atypical antipsychotics may improve both insight and cognitive function, but compliance with these agents is not assured. Depot conventional antipsychotics ensure medication delivery but are associated with side-effects such as EPS and dysphoria that decrease compliance. Long-acting atypicals provide significant symptom improvement, foster adherence and may help achieve improvement in insight and cognition. Addressing issues of partial and non-compliance is a significant consideration in relapse prevention strategies for patients with schizophrenia, given the devastating consequences associated with psychotic relapses.     

Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration

BACKGROUND/AIMS: Vitamin B12 and folate deficiencies have been associated with cognitive impairment and various psychiatric symptoms but not specifically with behavioural and psychological symptoms of dementia (BPSD). A limitation of previous studies in dementia was lack of concurrent homocysteine measurement especially as it may provide a better indicator of tissue activities of these vitamins. This study was designed to clarify whether a relationship exists between plasma homocysteine concentration and BPSD. METHODS: Plasma homocysteine, serum vitamin B12 and folate were measured in 23 Alzheimer's disease (AD) patients with BPSD and 27 AD patients without BPSD as determined through the use of the Neuropsychiatric Inventory (NPI). Blood levels of measured substances were also correlated with individual NPI scores and with cumulative NPI scores for different cluster of symptoms. RESULTS: There was no significant difference (p = 0.956) in the mean plasma homocysteine levels between AD patients with BPSD (17.48 micromol/l) and AD patients without BPSD (17.34 micromol/l). Similarly, there was no significant difference between the two groups in the mean serum B12 (382.61 and 391.60 pg/ml, respectively) and folate (7.95 and 10.02 ng/ml, respectively). Mean levels for both vitamins were well within the laboratory reference range. Neither individual nor cluster NPI scores correlated significantly with plasma homocysteine. CONCLUSION: This study shows for the first time that BPSD are not associated with hyperhomocysteinaemia in Alzheimer dementia. Although previous studies have identified homocysteine as an independent risk factor in AD, the results reported here do not lend weight to an aetiological role for homocysteine specifically in BPSD.     

Impact of Antipsychotics on Geriatric Patients: Efficacy, Dosing, and Compliance

People today are living longer. Old age is the number one risk factor for dementia, which is often associated with behavioral disturbances and psychosis as well as cognitive and memory impairment. Elderly persons with dementia-particularly those who are agitated or aggressive-are often placed in nursing homes and consequently treated with antipsychotic medications. Most of the studies of antipsychotic efficacy and safety have been conducted in young schizophrenic patients, but there are differences in dosing schedules, efficacy, and compliance when these drugs are used in elderly patients with dementia and psychosis. A review of both nonpharmacologic and pharmacologic treatment is herewith presented for the treatment of elderly dementia patients, especially those living in long-term care facilities.     

Kampo therapy as an alternative to pharmacotherapy using antipsychotic medicines for behavioral and psychological symptoms of dementia (BPSD)

The behavioral and psychological symptoms of dementia (BPSD), including aggression, agitation, screaming, wandering, hallucinations, and delusions, occur in 50–90% of patients with dementia, and have a negative impact on the activity of daily living (ADL) of patients, as well as caregivers. Patients with severe BPSD often require management with antipsychotic medicines. However, an increased mortality rate has been reported in patients with dementia taking antipsychotic medicine and, thus, there is an urgent need to develop safer treatments for BPSD. Kampo medicines are an alternative to antipsychotic medicines and several Kampo medicines have been reported to be effective in the treatment of BPSD. Oren‐gedoku‐to has been reported to be effective for the treatment of irritability and sullenness in patients with vascular dementia, as well as improving excitement, depression, anxiety, and restlessness of patients with cerebrovascular lesions. Choto‐san has been reported to be effective in the treatment of delirium, insomnia, and hallucinations/delusions in patients with vascular dementia. Toki‐syakuyaku‐san has been reported to improve emotional lability, restlessness, and sleep disturbances in patients with dementia. Yokukan‐san has been reported to be effective for hallucinations, agitation/aggression, irritability/lability, and aberrant motor activity, as well as being effective in the treatment of visual hallucinations in patients with dementia with Lewy bodies (DLB). A multicenter randomized crossover study confirmed that Yokukan‐san is effective in the treatment of BPSD and is well‐tolerated. Kampo medicines do not induce extrapyramidal or anticholinergic symptoms and have no adverse effects on ADL or cognitive function. Thus, Kampo therapy is recommended for patients who cannot tolerate treatment with neuroleptics, patients who have extrapyramidal symptoms and gait disturbance, and patients with DLB. In future, to confirm the effectiveness of Kampo medicines in the treatment of BPSD, further studies, such as randomized control trials, are needed. In addition, basic studies are required to elucidate the processes by which Kampo medicines are metabolized, as well as any interactions between Western and Kampo medicines.     

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.     

阿尔茨海默病认知损害程度的相关影响因素分析

目的:探讨影响阿尔茨海默病(AD)认知损害程度的相关因素。方法:选择记忆障碍门诊就诊的不同严重程度的AD患者共229例,其中轻度101例,中重度128例,收集相关资料进行条件Logistic回归分析。结果:条件Logistic回归分析显示:病程长、低教育水平、低体重指数及伴发精神行为异常为AD病情严重的独立危险因素,OR值分别为1.729(5%CI:1.318～2.269)、0.854(95%CI:0.791～0.922)、0.853(95%CI:0.780～0.932)及2.865(95%CI:1.527～5.378)。结论:本研究提示病程、教育水平、体重指数及是否合并精神行为异常与AD病情的严重程度有明显相关性。     

Beneficial and adverse effects of pharmacotherapy with risperidone on behavioral and psychological symptoms of dementia (BPSD)

Background: Behavioral and psychological symptoms of dementia (BPSD) increase the burden of caregiving. In 2004, the US Food and Drug Administration issued a warning on an increase in the mortality rate in elderly patients using antipsychotics. Thereafter, although the need for antipsychotics for BPSD has increased, discussions regarding their indication have continued. Methods: The present study was performed in 18 patients with Alzheimer's disease (AD) and patients with vascular dementia (VaD) who were treated with risperidone because of BPSD. Changes in the dose of risperidone and the beneficial and adverse effects of risperidone were evaluated for 3 months after the start of antipsychotic therapy. Results: The mean starting dose of risperidone was 0.62 ± 0.30 mg (62 ± 30 mg chlorpromazine (CP) equivalents), which, after 3 months, increased to 0.99 ± 0.49 mg risperidone (99 ± 49 mg CP equivalents). The symptoms of BPSD at the beginning of treatment were delusions (48% of patients) and violence (22% of patients). In the 3‐month treatment period, an improvement in BSPD symptoms was recorded in 78% of patients. During the study period, adverse effects were observed in 65% of patients: 26% of patients reported falling and extrapyramidal symptoms were seen in 13%. There were no cardiovascular events or deaths. Conclusion: In the present study, low doses of risperidone were used for the treatment of BPSD and no serious side‐effects were observed. An atypical antipsychotic can be one of the treatment options if a thorough risk assessment of the cardiovascular system is made and informed consent is obtained.     

Adjunctive treatment with high frequency repetitive transcranial magnetic stimulation for the behavioral and psychological symptoms of patients with Alzheimer's disease: a randomized,double-blind,sham-controlled study

Background

Behavioral and psychological symptoms of dementia (BPSD) occur in 70-90% of patients at different stages of Alzheimer’s Disease (AD), but the available methods for managing these problems are of limited effectiveness.

Aim

Assess the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS), applied over the left dorsolateral prefrontal cortex (DLPFC), on BPSD and cognitive function in persons with AD.

Methods

Fifty-four patients with AD and accompanying BPSD were randomly divided into an intervention group (n=27) and a control group (n=27). In addition to standard antipsychotic treatment, the intervention group was treated with 20Hz rTMS five days a week for four weeks, while the control group was treated with sham rTMS.The Behavioral Pathology in Alzheimer''s Disease Rating Scale (BEHAVE-AD), the Alzheimer''s Disease Assessment Scale-Cognitive (ADAS-Cog), and the Treatment Emergent Symptom Scale (TESS) were administered by raters who were blind to the group assignment of patients before and after four weeks of treatment.

Results

Twenty-six subjects from each group completed the study. After four weeks of antipsychotic treatment with adjunctive real or sham rTMS treatment, the mean (sd) total BEHAVE-AD scores and mean total ADAS-Cog scores of both groups significantly decreased from baseline. After adjusting for baseline values, the intervention group had significantly lower scores (i.e., greater improvement) than the control group on the BEHAVE-AD total score, on five of the seven BEHAVE-AD factor scores (activity disturbances, diurnal rhythm, aggressiveness, affective disturbances, anxieties and phobias), on the ADAS-Cog total score, and on all four ADAS-Cog factor scores (memory, language, constructional praxis, and attention). The proportion of individuals whose behavioral symptoms met a predetermined level of improvement (i.e., a drop in BEHAVE-AD total score of > 30% from baseline) in the intervention group was greater than that in the control group (73.1% vs.42.3%, X²=5.04, p=0.025).

Conclusion

Compared to treatment of AD with low-dose antipsychotic medications alone, the combination of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD.     

The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis.

Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.     

Treating the cognitive deficits of schizophrenia

Schizophrenia is characterized by significant cognitive impairments that predict impairment in multiple domains of community outcome. Pharmacologic and psychosocial treatments are available that address these cognitive deficits. There is growing evidence that patients taking second-generation antipsychotic medications perform better on tests of cognitive function than those taking conventional neuroleptics. In addition, there have been a number of medications from other classes being investigated as cognitive enhancers for schizophrenia. Cognitive rehabilitation approaches focus on bypassing, compensating for, or remediating observed impairments in cognitive function. Outcomes for patients have been improved by cognitive remediation, errorless learning, and the use of supportive environments. Combining the newest pharmacologic interventions for cognitive dysfunction with state of the art psychosocial treatments aimed at ameliorating or bypassing deficits is likely to produce the most favorable outcomes for individuals with schizophrenia.     

Behavioral and psychological symptoms of dementia (BPSD) in dementia with Lewy bodies

Behavioral and psychological symptoms of dementia (BPSD) bother patients with dementia with Lewy bodies (DLB) and their families so frequently that early diagnosis of DLB before the appearance of prominent cognitive impairment is important. Because BPSD in DLB can be reduced or improved by early intervention, medical intervention is important. Of BPSD in DLB, vivid visual hallucinations and delusions are most important. Other visual cognitive impairments and sleep disturbances, including disorders in rapid eye movement (REM) sleep, are also frequently seen. Cholinesterase inhibitors, including donepezil chloride, are the first choice for the therapy of BPSD; Yokukansan (a type of Kanpo (traditional Chinese herbal) medicine) is the second choice. When neither treatment is effective, atypical antipsychotics, such as quetiapine, risperidone, and aripiprazol, may be used.     

Challenges in the treatment of depression with psychotic features.

Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is a most difficult form of depression to treat. Patients with MDpsy exhibit more frequent relapses and recurrences and have increased use of services, greater disability, and a poorer clinical course when compared with nonpsychotically depressed patients. Patients with MDpsy demonstrate distinct biological abnormalities in studies of the hypothalamic-pituitary-adrenal (HPA) axis, dopaminergic activity, enzyme studies, brain imaging, electroencephalogram sleep profiles, and measures of serotonergic function when compared with nonpsychotic depression. The social and occupational impairment in MDpsy has been hypothesized to be secondary to subtle cognitive deficits caused by the higher cortisol levels frequently observed in MDpsy patients. Several studies support a relationship between bipolar disorder and MDpsy, particularly in young-onset MDpsy. The most efficacious treatments for MDpsy include the combination of an antidepressant and an antipsychotic, amoxapine, or electroconvulsive therapy. Atypical antipsychotic medications may have particular relevance for the treatment of MDpsy because of the potential for reduced risk of extrapyramidal side effects and tardive dyskinesia, as well as antipsychotic and possibly antidepressant qualities. Based on the observations that MDpsy patients exhibit marked dysregulation of the HPA axis and elevated cortisol levels, several antiglucocorticoid strategies have been employed to treat MDpsy patients. Many questions regarding the acute and long-term treatment of MDpsy remain for future studies to address.     

论坛：抗精神病药在痴呆中的应用抗精神病药治疗老年期痴呆精神行为症状的争议

老年期痴呆的临床表现除认知缺损和社会生活功能减退外,几乎所有病人在病程中都表现有精神行为症状,一般称为痴呆的精神行为症状（behavioralandpsychologicalsymptomsofdementia,BPSD）。     

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.     

Post‐marketing survey of donepezil hydrochloride in Japanese patients with Alzheimer's disease with behavioral and psychological symptoms of dementia (BPSD)

Background: To investigate the efficacy and safety of donepezil hydrochloride (Aricept^®; Eisai Co., Ltd, Tokyo, Japan), we conducted a post‐marketing survey in Japanese patients with Alzheimer's disease (AD) who also had behavioral and psychological symptoms of dementia (BPSD), such as hallucinations/delusions, wandering, and aggression, which cause the greatest burden on caregivers. Methods: A prospective, centrally registered investigation was conducted through regular clinical settings with patients diagnosed as mild to moderate AD presenting with hallucinations/delusions, wandering, and/or aggression. The treatment period was 12 weeks and no restrictions were placed on concomitant medications. Results: The BPSD improvement rates at last‐observation‐carried‐forward (LOCF) were 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For all symptoms, improvement rates increased with the duration of the treatment period. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Assessment of cognitive function with both the revised Hasegawa Dementia Scale (HDS‐R) and Mini‐Mental State Examination (MMSE) indicated significant improvements after treatment. There were significant differences in the changes in HDS‐R scores between patients whose hallucinations/delusions or wandering were improved and patients whose symptoms were not improved. Moreover, the data suggested a possible correlation between changes in hallucinations/delusions and HDS‐R scores, changes in hallucinations/delusions and MMSE scores, and changes in wandering and MMSE scores. Patients in whom BPSD improved also demonstrated a greater improvement in cognitive function compared with patients in whom no improvement in BPSD was noted. Nursing burden on caregivers at LOCF showed 3.6% for ‘No burden’, 54.1% for ‘Burden decreased’, and 4.5% for ‘Burden increased.’ There was an increase in the combined ratio of ‘No burden’ and ‘Burden decreased’ in proportion with prolonged treatment period. Patients with improved BPSD had a significantly greater ratio (88.5–94.4%) of ‘No burden’ plus ‘Burden decreased’ than those patients in whom no improvement in BPSD was noted. Conclusions: These results suggest that donepezil not only improves the cognitive dysfunction of AD patients, but may also relieve BPSD in these patients. Treatment with donepezil was also found to alleviate the burden of caregivers for approximately 60% of patients. Moreover, the results indicate that donepezil is unlikely to trigger potential risks of excessive deterioration of BPSD, which would result in a heavier burden of nursing care.     

The profile of behavioral and psychological symptoms in vascular cognitive impairment with and without dementia

Objective:

The objective of this study was to compare the occurrence and severity of behavioral and psychological symptoms of dementia (BPSD) between vascular dementia (VaD) and vascular cognitive impairment-no dementia (VCI-ND).

Materials and Methods:

Consecutive patients presenting with cognitive impairment at least 3 months after an ischemic stroke and with a Hachinski Ischemic Score ≥4 were included. VaD was diagnosed as per National Institute of Neurological Disorders and Stroke – Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria for probable VaD and VCI-ND on the lines of the Canadian study of health and aging. The severity of cognitive impairment and the behavioral/psychological symptoms were studied by means of the clinical dementia rating scale and the neuropsychiatric inventory (NPI) respectively.

Results:

All patients with VaD and 89% of those with VCI-ND had at least one BPSD. The mean no. of symptoms per patient and the total NPI scores were higher in VaD than in VCI-ND. Apathy and night-time behavior disturbances were significantly more common and severe in VaD.

Conclusions:

BPSD are very common both in VCI-ND and in VaD. The profile of BPSD is similar in both groups, albeit more severe in VaD. The net burden of BPSD is higher in VaD as compared to VCI-ND.Key Words: Behavioral and psychological symptoms, neuropsychiatric inventory, vascular cognitive impairment, vascular cognitive impairment-no dementia, vascular dementia