Trazodone for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease: a retrospective study focused on the aggression and negativism in caregiving situations]

Behavioral and psychological symptoms of dementia (BPSD) includes anxiety, depression, hallucination, delusion, aggression, irritability, agitation and wandering. BPSD often causes a deterioration of activity of daily living (ADL) and worsens caregiver burden. Trazodone, an atypical antidepressant, is used for the treatment of BPSD, but the effectiveness is controversial. In this study, we retrospectively analyzed the medical records of the 13 AD patients who were rated as having the aggression and negativism in caregiving situation and were treated by trazodone. The BPSD of the per-treatment stage of the patients was assessed with Neoropsychiatric Inventory(NPI). Improvement of BPSD after trazodone was observed in 9 patients, and the aggression and negativism in caregiving situations were improved in 6 patient. Trazodone may be effect for the treatment of a certain type of BPSD such as aggression and negativism in caregiving situations. Prospective studies of this issue are recommended in AD patient.     

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.     

Atypical antipsychotic medication improves aggression, but not self-injurious behaviour, in adults with intellectual disabilities

Objective Atypical antipsychotic medications have largely supplanted their typical counterparts, both for psychosis and for the treatment of aggression and/or self‐injurious behaviour (SIB), in persons with intellectual disabilities (ID). However, with the exception of risperidone, little systematic research supports their use in such persons. Method A retrospective review of 31 adult residents of a state developmental centre, who were treated for aggression and/or SIB with atypical antipsychotics. Average monthly counts of aggression and SIB for 1 year of treatment with typical antipsychotics, were compared with monthly averages for the next 12 months of treatment with atypical antipsychotics. Results Twenty‐seven of 31 subjects (87%) completed a full year of atypical antipsychotic treatment. Subjects ranged in age from 24 to 54 years (mean = 39); 18/31 (58%) had profound ID. Twelve of 26 (46%) had typical antipsychotics discontinued within the year of atypical treatment; another 7/26 (27%) had their typical antipsychotic dose decreased. Twenty‐three of 31 trials involved risperidone; 7/31 olanzapine; 1/31 quetiapine. Subjects gained an average of 6.6 pounds during the year of atypical treatment, but no significant changes in glucose or cholesterol were found. Subjects with aggression alone (N = 14) had significant decreases in the number of aggressive acts per month during the year of atypical treatment (P = 0.03); those with both aggression and self‐injury (N = 12), or those with self‐injury alone (N = 5) had no significant improvement. Conclusion The findings suggest that atypical antipsychotics can be successfully substituted for typical agents in individuals with ID and decrease the frequency of aggression over one year of treatment. The weight gain seen in our sample reinforces the necessity of regular monitoring of weight and metabolic changes in persons with ID treated with atypical antipsychotics.     

Role of serotonin transporter polymorphisms in the behavioural and psychological symptoms in probable Alzheimer disease patients

BACKGROUND/AIMS: Alzheimer disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in AD has been demonstrated. This is an investigation of whether the linked polymorphic region and variable number tandem repeat variants of the serotonin transporter (SERT) are associated with BPSD. METHODS: The longitudinal measures of BPSD of our large cohort of 367 AD patients were assessed by the Neuropsychiatric Inventory. Measures with good evidence of serotonergic involvement (delusions, hallucinations, depression, anxiety, agitation/aggression and irritability) were related to genotype and allele frequencies of the linked polymorphic region and variable number tandem repeat variants. RESULTS: Analysis revealed significant relationships between the linked polymorphic region variant long allele with irritability and the variable number tandem repeat 10-repeat allele with psychosis, but no associations were found with depression, anxiety or agitation/aggression. CONCLUSION: Our data and review of previous studies suggest SERT could play a minor role in development of psychosis and aggressive/irritable tendencies; however, further investigations are required in large, well-characterized cohorts.     

Clinical research on antipsychotics in bipolar disorder

Antipsychotics are commonly used in bipolar disorder, both for acute mania and in maintenance treatment. The authors review available clinical research concerning the use of both conventional and atypical antipsychotics in bipolar disorder and present recommendations for a number of key clinical situations based on this review. They also consider a number of important related questions, including whether there is evidence for an increased risk of tardive dyskinesia (TD) in patients with bipolar disorder, the potential role for antipsychotics in the treatment of bipolar depression, the role of antipsychotics in maintenance treatment of bipolar disorder, the potential for antipsychotics to induce depression in bipolar illness, and whether antipsychotics can be considered mood stabilizers with a place as monotherapy for bipolar mania. They conclude that standard treatment for acute mania should begin with a mood stabilizer, with benzodiazepines used as an adjunct for mild agitation or insomnia and antipsychotics used as an adjunct for highly agitated, psychotic, or severely manic patients. They also conclude that atypical antipsychotics are preferable to conventional antispychotics because of their more favorable side effect profile and reduced risk of tardive dyskinesia. They review the evidence for using atypical antipsychotics as first-line monotherapy for mania and conclude that more evidence concerning the risk of TD and their efficacy as maintenance treatment in bipolar disorder is needed before a conclusion can be made. Should the eventual risk of TD associated with atypical antipsychotics be found to be minimal and their efficacy in maintenance treatment found to be high, they could eventually be considered first line monotherapy for bipolar disorder. They conclude that treatment with an antipsychotic during bipolar depression should be limited to those patients who have psychosis and that atypical antipsychotics are preferred over conventional antipsychotics in this situation, not only because of their reduced risk of side effects but also because theoretically they may have antidepressant efficacy due to their effects on the serotonin system. The clinical research findings summarized in the article are, for the most part, supported by a recently published guideline based on a consensus of clinical experts.     

Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients

OBJECTIVE: Until recently, conventional antipsychotics were the standard pharmacotherapy for psychosis and behavioral disturbances associated with dementia. This double-blind, placebo-controlled study compared the acute efficacy of the selective serotonin reuptake inhibitor citalopram and the neuroleptic perphenazine with placebo for the treatment of psychosis and behavioral disturbances in nondepressed patients with dementia. METHOD: Eighty-five hospitalized patients with at least one moderate to severe target symptom (aggression, agitation, hostility, suspiciousness, hallucinations, or delusions) were randomly assigned to receive either citalopram, perphenazine, or placebo under double-blind conditions for up to 17 days. RESULTS: Patients treated with citalopram or perphenazine showed statistically significant improvement on several Neurobehavioral Rating Scale factor scores. Compared to those receiving placebo, only patients treated with citalopram showed significantly greater improvement in their total Neurobehavioral Rating Scale score as well as in the scores for the agitation/aggression and lability/tension factors. Side effect scores were similar among the three treatment groups. CONCLUSIONS: Citalopram was found to be more efficacious than placebo in the short-term hospital treatment of psychotic symptoms and behavioral disturbances in nondepressed, demented patients.     

The many faces of psychosis in the elderly

PURPOSE OF REVIEW: As the population ages, the number of older patients with psychosis will greatly rise. This review focuses on the etiology, biologic and clinical findings, and treatments of common causes of psychosis in the elderly. RECENT FINDINGS: Recent studies on psychosis related to Alzheimer's disease indicate that antipsychotic drugs have equivocal efficacy in improving psychotic symptoms and may have side effects or risks that outweigh their benefits. Behavioral interventions for agitation in dementia are showing some promise. In older adults with schizophrenia, intramuscular ziprasidone was found to be effective, and evidence is emerging for the use of hormone replacement therapy. For depression with psychosis, a recent study found that the combination of an antidepressant with an antipsychotic is no more effective than an antidepressant alone. SUMMARY: There is support for the use of antipsychotic drugs for all types of psychosis in the elderly. While the atypical antipsychotics have a 'black box warning' on risk of death in elderly patients with dementia, the typical antipsychotics carry an even higher risk of death and adverse effects. Weighing the potential risks and benefits of treatment options is essential. Please refer to your country's regulations regarding the use of antipsychotic drugs.     

The role of norepinephrine in the behavioral and psychological symptoms of dementia

The behavioral and psychological symptoms of dementia (BPSD) are common serious problems that are a major contributor to caregiver burden. Despite their significance, the underlying neurobiology of these disturbances is still unclear. This review examines the role of norepinephrine (NE) on BPSD, including depression, aggression, agitation and psychosis. A number of lines of evidence suggest that NE dysfunction leading to BPSD may result from increased NE activity and/or hypersensitive adrenoreceptors compensating for loss of NE neurons with progression of Alzheimer's disease (AD). With greater appreciation of the underlying neurobiology of behavioral and psychological symptoms of dementia (BPSD) more effective, rational, targeted pharmacotherapy will hopefully emerge.     

Behavioral and psychological signs and symptoms of dementia: a practicing psychiatrist's viewpoint

Alzheimer's disease typically presents with two often overlapping syndromes, one cognitive, the other behavioral. The behavioral syndrome is characterized by psychosis, aggression, depression, anxiety, agitation, and other common if less well-defined symptoms subsumed under the umbrella entity "behavioral and psychological symptoms of dementia" (BPSD), itself divided into a number of subsyndromes: psychosis, circadian rhythm (sleepwake) disturbance, depression, anxiety, and agitation, it is BPSD with its impact on care providers that ultimately precipitates the chain of events resulting in long-term institutional care. The treatment challenge involves eliminating unmet medical needs (undiagnosed hip fracture and asymptomatic urinary tract infection or pneumonia). Pharmacologic intervention relies on risperidone and, increasingly cholinesterase inhibitors for the control of psychosis (but with response rates of only 65% at tolerable doses), olanzapine and risperidone for anxiety, and carbamazepine and valproic acid for agitation. However, evidence increasingly favors nonpharmacologic interventions, to the extent that these should now be considered as the foundation of BPSD treatment. Problem behaviors are viewed as meaningful responses to unmet needs in the therapeutic milieu. Because the progression and impact of BPSD varies between patients, interventions must be explored, designed, implemented, and assessed on an individual basis. They include: family support and education, psychotherapy reality orientation, validation therapy, reminiscence and life review, behavioral interventions, therapeutic activities and creative arts therapies, environmental considerations (including restraint-free facilities), behavioral intensive care units, and workplace design and practices that aid the ongoing management of professional caregiver stress.     

The efficacy of atypical antipsychotics in the treatment of depressive symptoms, hostility, and suicidality in patients with schizophrenia

Depressive symptoms and syndromal depression commonly occur in patients with schizophrenia. Schizophrenia is also associated with aggression directed at self and others. For this article, the available literature regarding the efficacy of clozapine, risperidone, olanzapine, quetiapine, and ziprasidone in the treatment of depression, hostility, and suicidality in patients with schizophrenia was reviewed. These studies suggest that atypical antipsychotics may exert therapeutic effects on depression and hostility as well as psychosis and that clozapine and olanzapine may reduce suicidality in patients with schizophrenia. These therapeutic actions appear to represent additional advantages of atypical antipsychotics compared with standard agents.     

Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease.

OBJECTIVE: To systematically review published clinical trials of the pharmacotherapy of neuropsychiatric symptoms of Alzheimer disease (AD). METHOD: We searched MEDLINE and EMBASE for published English-language medical literature. Our review focused on randomized controlled trials (RCTs) and corresponding metaanalyses. RESULTS: The pharmacotherapy of neuropsychiatric symptoms of AD has been studied with numerous RCTs. The largest number of studies has focused on antipsychotics. Data are of reasonably high quality and indicate that risperidone and olanzapine are more effective than placebo for institutionalized patients with severe agitation, aggression, and psychosis. The efficacy of antipsychotics is counterbalanced by safety concerns that include cerebrovascular adverse events and mortality. Cholinesterase inhibitors and memantine appear to have modest benefits for patients with mildly to moderately severe symptoms. Antidepressants are effective for treating depression in AD, but more data are required to determine the efficacy of trazodone and citalopram for agitation and aggression. Carbamazepine appears to be efficacious, although side effects and concerns about drug-drug interactions limit its use. The data do not support the use of valproate. Benzodiazepines should only be used for short-term, as-needed use. There are insufficient data on other pharmacologic interventions, such as beta blockers, buspirone, and estrogen preparations. CONCLUSIONS: Although there have been numerous well-designed studies of the pharmacotherapy of neuropsychiatric symptoms in AD, safer and more effective treatments are urgently needed.     

Orally versus intramuscularly administered antipsychotic drugs in psychiatric emergencies

High utilization of emergency services by patients at increased risk for agitation and aggression makes the determination of effective therapy a major concern of psychiatric care. Agitated and aggressive behavior needs to be treated rapidly and effectively to minimize the risk to both patients and staff. Traditionally, short-acting intramuscular (IM) formulations of conventional antipsychotic drugs have been preferred in the emergency setting due to their rapid onset of action and the ability to administer them to uncooperative patients. IM injections, however, may not always be the preferred option. Recently, orally administered second generation (atypical) antipsychotics have been shown to be at least as effective in managing acute agitation as conventional antipsychotic drugs, with a superior tolerability profile. The current review evaluates pharmacokinetic parameters, formulation options, and clinical efficacy data for the treatment of acute agitation or aggressive behavior with antipsychotic medications. A synthesis of data from individual clinical trials, meta-analyses, review articles, and expert consensus recommendations is used to develop a working clinical algorithm for the acute management of aggression and agitation.     

Atypical antipsychotics in the elderly

INTRODUCTION: Although their primary purpose is to treat psychosis, antipsychotics are commonly prescribed for the elderly to treat the behavioural disturbances and agitation associated with dementia. Such use is controversial. Atypical antipsychotics cause fewer extrapyramidal sideeffects than the older drugs in younger adults, but the evidence base for their efficacy and tolerability in the elderly is poor. The aims of this study were to determine the prevalence of atypical antipsychotic prescribing for the elderly, the indications for use and documented side-effects. METHOD: The medication cards of all patients from 19 Trusts, occupying a psychiatric bed for the over 65s, were screened during one week in March 2000. Data were collected by pharmacists from the clinical notes. RESULTS: Half of those prescribed an antipsychotic received an atypical, and risperidone was the one most commonly prescribed. Half the sample had a diagnosis of dementia. Documented side-effects from the atypical were uncommon. CONCLUSION: Atypicals are frequently prescribed as first-line antipsychotics for behavioural problems associated with dementia, despite the poor evidence base for their efficacy and safety in this population. Undermonitoring of side-effects may remain a problem.     

Forensic psychology: A guide to practice

Metabolic side-effects of atypical antipsychotics have led to concern about their relative safety compared with low doses of conventional neuroleptics. Akathisia is an often misdiagnosed side-effect, which leads to non-compliance and sometimes even exacerbation of psychosis or suicidal behaviour. In fact, little is known about the differences between antipsychotic drugs in clinical practice, since only as few as 20% of patients may be eligible for studies comparing antipsychotic medications with each other. The aim of this study was to find out if the use of conventional antipsychotics is associated with an increased risk of akathisia (compared with atypical antipsychotics) even when low doses of conventional antipsychotics are used. The Barnes Akathisia Rating Scale was used to evaluate akathisia in 100 outpatients on antipsychotic medication. Conventional antipsychotics were associated with an increased risk of akathisia compared with atypical antipsychotics, although the chlorpromazine equivalent doses of conventional antipsychotics were lower than those of the atypicals. An additional akathisia-provoking effect of SSRIs could not be ruled out. The results suggest favouring atypical antipsychotic medication in patients who may easily develop akathisia.     

New therapeutic strategies for behavioral and psychological symptoms of dementia]

Interventional studies, with the aim of reducing the burden of care through drug or non-drug therapies of behavioral and psychological symptoms of dementia (BPSD), have been scarce. However, we are now able to do pharmacological management for BPSD with new drugs such as atypical neuroleptics, SSRIs, and cholinesterase inhibitors. Delusions of theft are one of the most frequently observed BPSD in patients with AD. In addition, the delusions and ensuing aggression and anxiety are major factors that increase the burden of caregivers. Delusions of theft in patients with AD were eliminated or reduced with low-dose atypical neuroleptics (risperidone). This significantly reduced the burden of care overall for caregivers. New therapeutic strategies such as cholinesterase inhibitors for visual hallucinations in DLB and SSRIs for overeating and stereotyped behavior in FTLD might also remarkably reduce the burden of care for these patients. For many dementia patients, there are still no drugs that offer a principal cure. It is, therefore, important to evaluate their BPSD correctly at the earliest possible time, so that the burden of caring can be reduced through appropriate drug treatment. This reduction is critical for the continuation of satisfactory at-home care and might contribute to the health economics.     

On the relationship of atypical and low-dose conventional antipsychotics with akathisia in a clinical patient population

Metabolic side-effects of atypical antipsychotics have led to concern about their relative safety compared with low doses of conventional neuroleptics. Akathisia is an often misdiagnosed side-effect, which leads to non-compliance and sometimes even exacerbation of psychosis or suicidal behaviour. In fact, little is known about the differences between antipsychotic drugs in clinical practice, since only as few as 20% of patients may be eligible for studies comparing antipsychotic medications with each other. The aim of this study was to find out if the use of conventional antipsychotics is associated with an increased risk of akathisia (compared with atypical antipsychotics) even when low doses of conventional antipsychotics are used. The Barnes Akathisia Rating Scale was used to evaluate akathisia in 100 outpatients on antipsychotic medication. Conventional antipsychotics were associated with an increased risk of akathisia compared with atypical antipsychotics, although the chlorpromazine equivalent doses of conventional antipsychotics were lower than those of the atypicals. An additional akathisia-provoking effect of SSRIs could not be ruled out. The results suggest favouring atypical antipsychotic medication in patients who may easily develop akathisia.     

Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community

BACKGROUND: Despite many studies about the association between caregiver burden and behavioral and psychological symptoms of dementia (BPSD), there have been no population-based studies to evaluate caregiver burden associated with each BPSD. OBJECTIVE: To evaluate caregiver burden associated with the individual BPSD in elderly people living in the community. METHODS: The subjects were 67 participants with dementia living with their caregivers (diagnosed in the third Nakayama study): 51 Alzheimer's disease, 5 vascular dementia and 11 other. The Neuropsychiatric Inventory (NPI) and NPI Caregiver Distress Scale (NPI-D) were used to assess subjects' BPSD and related caregiver distress, respectively. RESULTS: In the subjects exhibiting BPSD, aberrant motor behavior had the highest mean NPI score, and depression/dysphoria had the lowest. Agitation/aggression had the highest mean NPI-D score, and euphoria/elation had the lowest. Delusion, agitation/aggression, apathy/indifference, irritability/lability and aberrant motor behavior showed a correlation between the NPI and NPI-D scores. CONCLUSION: The burden associated with BPSD is different for each symptom and does not always depend on frequency and severity of BPSD. These findings suggest that some symptoms, such as agitation/aggression and irritability/lability, may affect the caregivers significantly, although their frequency and severity are low.     

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.