Pharmacological Treatment of Neuropsychiatric Symptoms of Dementia: A Review of the Evidence
ABSTRACT Neuropsychiatric symptoms of dementia are common and associated with poor outcomes for patients and caregivers. Although nonpharmacological interventions should be the first line of treatment, a wide variety of pharmacological agents are used in the management of neuropsychiatric symptoms; therefore, concise, current, evidence-based recommendations are needed.
To evaluate the efficacy of pharmacological agents used in the treatment of neuropsychiatric symptoms of dementia.
A systematic review of English-language articles published from 1966 to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and a manual search of bibliographies was conducted. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs) or meta-analyses of any drug therapy for patients with dementia that included neuropsychiatric outcomes. Trials reporting only depression outcomes were excluded. Data on the inclusion criteria, patients, methods, results, and quality of each study were independently abstracted. Twenty-nine articles met inclusion criteria.
For typical antipsychotics, 2 meta-analyses and 2 RCTs were included. Generally, no difference among specific agents was found, efficacy was small at best, and adverse effects were common. Six RCTs with atypical antipsychotics were included; results showed modest, statistically significant efficacy of olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical antipsychotics are associated with an increased risk of stroke. There have been no RCTs designed to directly compare the efficacy of typical and atypical antipsychotics. Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs investigating valproate showed no efficacy. Two small RCTs of carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors generally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatric symptoms.
Pharmacological therapies are not particularly effective for management of neuropsychiatric symptoms of dementia. Of the agents reviewed, the atypical antipsychotics risperidone and olanzapine currently have the best evidence for efficacy. However, the effects are modest and further complicated by an increased risk of stroke. Additional trials of cholinesterase inhibitors enrolling patients with high levels of neuropsychiatric symptoms may be warranted.
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ABSTRACT: Many dementia patients exhibit behavioral and psychological symptoms (BPSD), including psychosis and depression. Although antipsychotics are frequently prescribed off-label, they can have marked side effects. In addition, comparative preclinical studies of their effects are surprisingly scarce, and strategies for discovery of novel pharmacotherapeutics are lacking. We therefore compared eight antipsychotics in rat behavioral tests of psychosis, antidepressant-like activity, and cognitive impairment as a basis for preclinical evaluation of new drug candidates. The methods used in this study include inhibition of MK-801-induced hyperactivity, forced swim test (FST), passive avoidance (PA), spontaneous locomotor activity, and catalepsy. The drugs exhibited antipsychotic-like activity in the MK-801 test but with diverse profiles in the other models. Risperidone impaired PA performance, but with some dose separation versus its actions in the MK-801 test. In contrast, clozapine, olanzapine, lurasidone, and asenapine showed little or no dose separation in these tests. Aripiprazole did not impair PA performance but was poorly active in the MK-801 test. Diverse effects were also observed in the FST: chlorpromazine was inactive and most other drugs reduced immobility over narrow dose ranges, whereas clozapine reduced immobility over a wider dose range, overlapping with antipsychotic activity. Although the propensity of second-generation antipsychotics to produce catalepsy was lower, they all elicited pronounced sedation. Consistent with clinical data, most currently available second-generation antipsychotics induced cognitive and motor side effects with little separation from therapeutic-like doses. This study provides a uniform in vivo comparative basis on which to evaluate future early-stage drug candidates intended for potential pharmacotherapy of BPSD.Archiv für Experimentelle Pathologie und Pharmakologie 03/2014; 387(6). DOI:10.1007/s00210-014-0966-4 · 2.36 Impact Factor
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ABSTRACT: Scientists have worked for over a century to uncover the basis of Alzheimer's disease (AD) with the ultimate goal of discovering a treatment. However, none of the approaches utilized have defined the exact cause of the disease or an ultimate treatment for AD. In this review, we aim to define the role of vitamin D in AD from a novel and fundamental perspective and attempt to answer the following question: Why should we seriously consider "simple" vitamin D as a "fundamental factor" in AD? To answer this question, we explain the protective effects of vitamin D in the central nervous system and how the action of vitamin D and AD-type pathology overlap. Furthermore, we suggest that the role of vitamin D in AD includes not only vitamin D deficiency and vitamin D-related genes but also the disruption of vitamin D metabolism and action. This suggestion is supported by evidence that the disruption of vitamin D pathways mimic amyloid pathology. We define the term "inefficient utilization of vitamin D" as any alteration in vitamin D-related genes, including receptors, the enzymes related to vitamin D metabolism or the transporters of vitamin D, and we discuss the potential correlation of vitamin D status with the vulnerability of neurons to aging and neurodegeneration. Finally, in addition to the current knowledge that defines AD, we suggest that AD could be the result of a long-term hormonal imbalance in which the critical hormone is vitamin D, a secosteroid that has long been misnamed.Journal of Alzheimer's disease: JAD 01/2014; 40(2). DOI:10.3233/JAD-131970 · 3.61 Impact Factor
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ABSTRACT: ABSTRACT Neuropsychiatric symptoms (NPS) of dementia include aggression, agitation, depression, anxiety, delusions, hallucinations, apathy, and disinhibition. NPS affect dementia patients nearly universally across dementia stages and etiologies. They are associated with poor patient and caregiver outcomes, including increased health care utilization, excess morbidity and mortality, and earlier nursing home placement, as well as caregiver stress, depression and reduced employment. There are no FDA-approved medications for NPS, but it is a common clinical practice to use psychotropic medications such as antipsychotics, to control symptoms; however, antipsychotics show only modest efficacy in improving NPS and have significant risks for patients, including side effects and mortality. Nonpharmacologic treatments are considered first-line by multiple medical bodies and expert consensus, as they show evidence for efficacy and have limited potential for adverse effects. Ideally, nonpharmacological management of NPS in clinical settings occurs in multidisciplinary teams, where occupational therapists play an important collaborative role in the care of the person with dementia. Our group has articulated an evidence-informed structured approach to the management of NPS that can be integrated into diverse practice settings and used by providers of various disciplines. The "DICE" (Describe, Investigate, Create, and Evaluate) approach is inherently patient- and caregiver-centered, as patient and caregiver concerns are integral to each step of the process. DICE offers a clinical reasoning approach through which providers can more efficiently and effectively choose optimal treatment plans. The purpose of this paper is to describe the role of the occupational therapy in using the DICE approach for NPS management.Occupational Therapy in Health Care 01/2014; 28(1):4-20. DOI:10.3109/07380577.2013.867468