Geriatric psychiatry: a subspecialty whose time has come.
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Biomedical subjects
Nathan Herrmann
Publications and source records attributed to Nathan Herrmann.
Canadian Outcomes Study in Dementia: study methods and patient characteristics.
OBJECTIVE: To describe the methods and patient characteristics of the Canadian Outcomes Study in Dementia (COSID). METHODS: COSID is a 3-year prospective study of dementia patients living in the community at the time of study registration. We assessed patients' cognition, behaviour, and functioning every 6 months, using the Modified Mini-Mental State Examination (3MS), the Neuropsychiatric Inventory (NPI), and the Functional Autonomy Measurement System (SMAF), respectively. We assessed caregivers, using the Zarit Burden Interview (ZBI). Additional information included the Global Deterioration Scale (GDS), patients' driving status, and clinical information including family history, dementia type, concomitant medications, and comorbid conditions. From the patient or caregiver, we collected details of inpatient and outpatient resources used by the patient and (or) caregiver. RESULTS: We enrolled 766 patients from 31 Canadian sites. Overall mean age was 76.8 years, and mean age of onset was 73.1 years. Of the total patients, 98% were white, 54% were women, and 84% were diagnosed with Alzheimer's disease. Mean baseline 3MS was 66.5, NPI was 9.5, and SMAF was 18.30. Of these patients, 48% reported a GDS score of 3 (that is, moderate), 16% reported a GDS score of 4 (that is, moderately severe), and the remaining 36% reported a GDS score of 1 or 2 (that is, mild or very mild). At baseline, 83% of patients received cholinesterase inhibitors, 46% received nonsteroidal antiinflammatory drugs, 39% received vitamin E, and 25% received antidepressants. Adult day care and home help were the largest cost factors in this population, with mean monthly costs of $65 and $64, respectively. We found interesting differences in the resources used among geographic regions and care settings. CONCLUSIONS: COSID is already generating valuable information about treatment patterns, outcomes, and resource use in Canadian patients with dementia. As the data mature, it will be possible to build robust models on treatment effectiveness and costs of care.
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GABAergic function in Alzheimer's disease: evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia.
Alzheimer's disease (AD) is characterized by disruptions in multiple major neurotransmitters. While many studies have attempted to establish whether GABA is disrupted in AD patients, findings have varied. We review evidence for disruptions in GABA among patients with AD and suggest that the variable findings reflect subtypes of the disease that are possibly manifested clinically by differing behavioural symptoms. GABA, the major inhibitory neurotransmitter, has long been a target for anxiolytics, hypnotic sedatives, and anticonvulsants. We review the clinical use of GABAergic agents in treating persons with AD symptoms. While newer generation GABAergic medications are now available, they have yet to be evaluated among patients with AD.
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The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer's disease.
The 'second-generation' cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer's disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug-drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.
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Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis.
BACKGROUND: Cholinesterase inhibitors (ChEIs) are the only drugs marketed for the treatment of Alzheimer's disease. Despite numerous randomized controlled trials, the efficacy and safety of this group of medications has not been quantified. Our objective was to quantitatively summarize data on the efficacy and safety of ChEIs in Alzheimer's disease in a format useful to clinicians. METHODS: We performed a meta-analysis of randomized, double-blind, placebo-controlled, parallel-group trials of currently marketed ChEIs (donepezil, rivastigmine and galantamine), used in therapeutic doses for at least 12 weeks, from which a cognitive outcome was reported. Studies were identified through 3 electronic databases searched to May 2002, pharmaceutical companies and journals. We extracted the proportions of subjects who responded, experienced adverse events, discontinued treatment for any reason or discontinued treatment because of adverse events. RESULTS: In the 16 identified trials that met the inclusion criteria, 5159 patients were treated with a ChEI and 2795 received a placebo. The pooled mean proportion of global responders to ChEI treatment in excess of that for placebo treatment was 9% (95% confidence interval [95% CI] 6%-12%). The rates of adverse events, dropout for any reason and dropout because of adverse events were also higher among the patients receiving ChEI treatment than among those receiving placebo, the excess proportions being 8% (95% CI 5%-11%), 8% (95% CI 5%-11%) and 7% (95% CI 3%-10%), respectively. The numbers needed to treat for 1 additional patient to benefit were 7 (95% CI 6-9) for stabilization or better, 12 (95% CI 9-16) for minimal improvement or better and 42 (95% CI 26-114) for marked improvement; the number needed to treat for 1 additional patient to experience an adverse event was 12 (95% CI 10-18). INTERPRETATION: Treatment with ChEIs results in a modest but significant therapeutic effect and modestly but significantly higher rates of adverse events and discontinuation of treatment. The numbers needed to treat to benefit 1 additional patient are small.
Alzheimer Disease↗
Contribution of informant and patient ratings to the accuracy of the mini-mental state examination in predicting probable Alzheimer's disease.
OBJECTIVES: To determine whether the accuracy of the Mini-Mental State Examination (MMSE) in predicting future Alzheimer's disease (AD) could be improved by the addition of patient and informant ratings of cognitive difficulties. DESIGN: An inception cohort of nondemented patients followed longitudinally for 2 years. SETTING: Patients referred to a university teaching hospital research investigation by their family physicians because of concerns about memory impairment. PARTICIPANTS: One hundred sixty-five community-residing patients were included who did not have dementia or any identifiable cause for memory impairment. After 2 years, 29 met criteria for AD, and 95 were not demented. MEASUREMENTS: Baseline assessments included MMSE, an Informant Rating Scale, and a Patient Rating Scale of cognitive difficulties. After 2 years, patients were diagnosed following the reference standard for probable AD. Diagnosticians were blind to baseline scores. RESULTS: Age and education were included in all analyses as covariates. The best logistic regression model included the Informant Rating Scale and the MMSE (sensitivity = 83%, specificity = 79%). An empirically reduced six-item model that included two items each from the MMSE, the Patient Rating Scale, and the Informant Rating Scale produced a significantly better model than the one with the full test scores (sensitivity = 90%, specificity = 94%). CONCLUSION: Results indicate that inclusion of informant ratings with the MMSE significantly improved its accuracy in the prediction of probable AD. Replication in a new prospective cohort of nondemented patients is necessary to confirm these findings.
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Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects.
Elderly insomniacs are often treated pharmacologically with benzodiazepines, antihistamines, or natural products. A double-blind, randomized, crossover, placebo-controlled study was performed to assess the comparative pharmacodynamics of single doses of temazepam (15 and 30 mg), diphenhydramine (50 and 75 mg), and valerian (400 and 800 mg) in 14 healthy elderly volunteers (mean age, 71.6 years; range, 65-89). Assessments were made at 0, 0.5, 1, 2, 3, 4, 6, and 8 hours postdosing with use of validated measures of subjective sedation and mood (visual analogue scales, Tufts University Benzodiazepine scale) and psychomotor performance (manual tracking and digit symbol substitution tests). Temazepam had dose-dependent effects on sedation and psychomotor ability with a distinct time course. Temazepam 30 mg had the most detrimental effect on psychomotor ability (p < 0.001 compared with all other treatments). Temazepam 30 mg and both doses of diphenhydramine elicited significantly greater sedation than placebo (p < 0.05, all), and temazepam had the greatest effect. There was no difference in sedation scores between 50 and 75 mg diphenhydramine. Sedative effects were slightly lesser with 15 mg temazepam and were not significant in comparison with placebo. Psychomotor impairment was evident after administration of 75 mg diphenhydramine in comparison with placebo on the manual tracking test (p < 0.05); this was less than the impairment with 30 mg temazepam (p < 0.001) but similar to that with 15 mg temazepam (NS). No psychomotor impairment was detected with 50 mg diphenhydramine. Valerian was not different from placebo on any measure of psychomotor performance or sedation.
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Pharmacokinetic and pharmacodynamic evaluation of the inhibition of alprazolam by citalopram and fluoxetine.
The selective serotonin reuptake inhibitor antidepressant fluoxetine inhibits alprazolam metabolism in vivo by inhibition of the cytochrome P450 3A4 enzyme. Citalopram is a selective serotonin reuptake inhibitor antidepressant that has not yet been fully evaluated with respect to its potential for cytochrome P450 3A4-mediated drug interactions in vivo. Building on the existing in vitro and in vivo evidence that suggest a minimal effect of citalopram on cytochrome P450 3A4, we hypothesized that therapeutic doses of citalopram (20 mg/d), as compared with fluoxetine (20 mg/d), would cause less impairment in the metabolism of the probe drug alprazolam (1 mg) through inhibition of the cytochrome P450 3A4 isozyme as measured by pharmacokinetic and pharmacodynamic parameters in vivo. We found that fluoxetine prolonged the half-life of alprazolam by 16% and increased the area under the curve 0-infinity of alprazolam by 32%, while citalopram did not affect these parameters, although the time of maximum concentration of alprazolam was prolonged by 30 minutes after citalopram administration. Neither selective serotonin reuptake inhibitor significantly affected the pharmacodynamic profile of alprazolam. This experiment suggests differential effects by citalopram and fluoxetine on alprazolam kinetics.
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Old and homeless: a review and survey of older adults who use shelters in an urban setting.
OBJECTIVES: Research on the mental health and service needs of homeless seniors has been scant. This paper reviews the available literature and presents findings of a Toronto survey in an effort to describe the demographics of homeless seniors, their level of impairment, and their mental and physical health needs. METHODS: We searched the Medline, AgeLine, and PsycINFO databases, using the following key words: elderly homeless, elderly hostel users, and urban geriatrics. To better describe the service needs of the elderly homeless, we obtained demographic data from the Community and Neighbourhood Services Department and distributed a survey questionnaire to 11 Toronto hostel directors. The questionnaire elicited data relating to reasons for shelter use, problem behaviours, and mental health needs of those over age 65 years. RESULTS: Although seniors represent a small percentage of the homeless population, their numbers are growing. The available literature suggests a high prevalence of psychiatric disorders and cognitive impairment in this population, with a greater proportion of older women than men having severe mental illness. Further, our survey suggests that the service needs of elderly hostel users in Toronto differ from those of their younger counterparts. CONCLUSION: The homeless elderly are the most vulnerable of this impoverished population. Although more research is needed to define their mental and physical health needs and ways of meeting them, their characteristics appear to be unique. Geriatric psychiatrists could play a significant role in evaluating and treating this population more comprehensively.
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The cost-benefit of cholinesterase inhibitors in mild to moderate dementia: a willingness-to-pay approach.
OBJECTIVE: This study aimed to measure the economic value of cholinesterase inhibitors when used to treat Alzheimer's disease using the willingness-to-pay (WTP) approach and the framework of cost-benefit analysis. METHODS AND STUDY DESIGN: A cost-benefit analysis using the WTP approach was employed. The study sample consisted of 28 nonprofessional caregivers of outpatients with mild to moderate dementia from Toronto, ON, Canada. The caregivers were presented with four scenarios. In the first scenario, scenario A, a hypothetical patient with mild dementia was stabilised with a cholinesterase inhibitor. In the second scenario, scenario A with adverse effects, the above patient (A) experienced adverse effects caused by the drug. In the third scenario, scenario B, the patient exhibited behavioural symptoms in addition to mild dementia, and both were stabilised with the drug. In the fourth scenario, scenario B with adverse effects, the above patient (B) experienced adverse effects caused by the drug. The caregivers were then asked what amount they would pay, in Canadian dollars, each year to buy the medication, assuming that they were the caregivers of the patient described. A multivariate regression analysis was performed to assess the relationship between the demographic data (including the caregiver's yearly income) and the WTP. The average WTP was also predicted for the general population and the elderly population of Canada using data from Statistics Canada, and these values were compared with the cost of the medication. STUDY PERSPECTIVE: Nonprofessional caregiver perspective. All monetary values are 1999 values unless otherwise specified. RESULTS: The mean yearly WTP was $Can4540 (95% CI 2334-6746) for scenario A, $Can3686 (95% CI 1530-5842) for scenario A with adverse effects, $Can5003 (95% CI 2661-7345) for scenario B and $Can4486 (95% CI 2222-6750) for scenario B with adverse effects. The WTP decreased when drug adverse effects were present (significantly in scenario A; p = 0.04), but did not significantly increase when behavioural symptoms were present and stabilised. In all scenarios, caregiver yearly income was the only significant predictor of WTP, in the direction expected. For all scenarios, the calculated WTPs from the regression analysis using our sample mean, the average Canadian population data and the elderly population data were all higher than the yearly cost of the cholinesterase inhibitors, with the net benefit ranging from $Can1723 to $Can4508. CONCLUSIONS: The results of the study, from a small sample of nonprofessional caregivers, revealed that the caregivers are willing to pay more for cholinesterase inhibitors than the drugs cost, even when the adverse effects of the drugs are taken into consideration. This indicates a net benefit for cholinesterase inhibitors in the treatment of mild to moderate dementia from a consumer's point of view.
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Correlates of response to acetylcholinesterase inhibitor therapy in Alzheimer's disease.
Cholinesterase inhibitors improve cognition and behaviour in some patients with Alzheimer's disease (AD). Studies that have focused on methods to predict response to anticholinesterase therapy and markers for response are reviewed. Among the possible predictors of improvement in cognitive outcomes are apolipoprotein genotype, pretreatment postural blood pressure drop, quantitative electroencephalography (qEEG) and disease progression rate. Of these, qEEG profile after a single dose of an acetylcholinesterase inhibitor was consistently found to be a good predictor of cognitive response. Studies have assessed baseline behavioural profiles and baseline single-photon emission computed tomographic profiles as possible predictors of improvement of behavioural symptoms of AD, but these require further study. Possible markers of response during drug treatment include red blood cell cholinesterase inhibition, cerebrospinal fluid monoamine measurement, pupillary response and platelet amyloid precursor protein analyses. Although they, too, require further study, the analysis of platelet amyloid precursor protein may have value as a correlate of the putative disease-modifying effects of long-term treatment. Studying correlates of response may help to elucidate the mechanism of action of acetylcholinesterase inhibitors.
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Probing brain reward system function in major depressive disorder: altered response to dextroamphetamine.
BACKGROUND: The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms. METHODS: In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure. RESULTS: Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R(2) = 0.63; interaction P =.04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P =.02). Patients with severe symptoms reported rewarding effects 3.4-fold greater than controls. CONCLUSIONS: The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies.
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Gender, aggression and serotonergic function are associated with response to sertraline for behavioral disturbances in Alzheimer's disease.
BACKGROUND: Indications for serotonergic medications in the treatment of behavioral disorders associated with Alzheimer's disease (AD) remain to be established. METHOD: Sertraline (100 mg OD) was evaluated in a double-blind, randomized, placebo-controlled cross-over study in 22 nondepressed patients with severe probable AD and significant behavioral disturbance. Each subject was given a fenfluramine challenge to evaluate central serotonergic tone. RESULTS: Eight of 21 (38%) completers responded to sertraline. Drug responsive behaviors included aggression/agitation, irritability and aberrant motor behavior. Low aggression, female gender and large prolactin increase were associated with a better response. There was a trend for decreased aggression during sertraline versus placebo (p = 0.08). CONCLUSION: Aggression, gender and serotonergic function were associated with sertraline response. Larger randomized controlled trials are needed to clarify the profile of responders.
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How much are atypical antipsychotic agents being used, and do they reach the populations who need them? A Canadian experience.
BACKGROUND: The introduction of new antipsychotic agents in the past decade has helped alter the treatments available to 2 vulnerable populations-those with schizophrenia and related psychotic conditions and elderly individuals with dementia. OBJECTIVE: After examining overall trends in antipsychotic use, this analysis reviews patterns of atypical antipsychotic use in the elderly and financially disadvantaged populations of Ontario. It identifies affected subpopulations and offers several interpretations of how observed patterns of use reflect outpatient prescribing practices. METHODS: This study used drug claims data from the Ontario Drug Benefit (ODB) program for the years 1992 to 1998. The use of antipsychotic agents was followed for 2 years in a subpopulation of ODB participants identified as consistent users of these agents (ie, those with evidence of > 1-time use). RESULTS: During the study period, the total number of ODB claimants grew by 1%, the number of claimants using antipsychotic agents increased by approximately 25%, and the expenditure per claimant in this group increased by nearly 250%. Much of this growth in expenditures was associated with use of the newer atypical antipsychotic agents olanzapine, risperidone, and quetiapine. Compared with patients aged > or = 65 years, those aged < 65 years were more likely to receive an initial prescription for an atypical antipsychotic or be switched to an atypical antipsychotic. However, the proportion of patients aged > 85 years consistently using antipsychotic agents was greater than predicted based on the proportion of the ODB population they represent. These patients were more likely to use conventional antipsychotic agents exclusively. CONCLUSIONS: The introduction of the atypical antipsychotic agents was paralleled by a striking increase in ODB expenditures for antipsychotic drugs, although use of these agents was not consistent across age groups. There was more switching to atypical antipsychotics, as well as greater use in general, among younger compared with older patients, despite evidence that the atypical antipsychotics may be safer in the elderly than conventional antipsychotics. Guideline dissemination may be an important way of familiarizing clinicians with the atypical agents. Health care systems should be aware of the potential for a substantial increase in health care costs with more widespread adoption of these medications.
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Central serotonergic activity is related to the aggressive behaviors of Alzheimer's disease.
The clinical correlates of reduced serotonin (5-HT) in Alzheimer's disease (AD) remain unknown. The hypothesis of this study was that altered central serotonergic activity is related to aggression in AD. Twenty-two institutionalized, nondepressed elderly (12 M/10 F, mean age +/- SD: 82.2 +/- 6.4) with probable AD, severe cognitive impairment (MMSE = 4.1 +/- 4.7) and significant behavioral disturbance (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. The prolactin (PRL) response to d,l-fenfluramine (60 mg p.o.) was used as an index of central serotonergic function. The NPI aggression score, NPI irritability score, and Behavioral Pathology in AD aggression score were positively correlated to prolactin concentrations following fenfluramine challenge (r(S) =.61, p =.003; r(S) =.53, p =.012; and r(S) =.47, p =.029 respectively). In addition, aggressive patients showed a greater mean PRL increase (% baseline) (215 +/- 60, n = 11) than nonaggressive subjects (123 +/- 54, n = 11) (p =.01, 2-tailed t-test). The change in PRL concentration depended on level of cognitive impairment (p =.0004) and the gender x aggression interaction (p =.015) with the overall regression model accounting for 74% of the variance (r = 0.86, F = 11.9, p =.0001). Female aggressive subjects with less cognitive impairment had the largest response to fenfluramine challenge. These results suggest a complex link between aggression in AD and central serotonergic dysfunction having interactions with gender and cognitive impairment.
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A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia.
The objectives of this randomized clinical trial were to investigate the impact of the discontinuation of long-term antipsychotics in residents with dementia in chronic care institutions and to identify clinical predictors of safe discontinuation. Subjects included 34 residents with dementia who were on antipsychotics for more than 6 months and whose behavior was currently stable. Subjects were randomized to either continue receiving their regular dosage of antipsychotics or to receive placebo for 6 months. Early withdrawal from the study was not statistically different between the groups (relative risk [RR] = 1.57, 95% confidence interval [CI] 0.76-3.26), and though not significantly different, subjects in the placebo group were more likely to be withdrawn from the study because of worsening behavior (RR = 1.25, 95% Cl 0.33-4.76). Three subjects in the placebo group were withdrawn from the study due to worsening of extrapyramidal symptoms. The active treatment group had more behavioral problems (e.g., physical aggression towards others, p < .05) compared to the placebo group. The placebo group developed more apathy, but balancing this outcome was a relative improvement in cognitive functioning. Baseline antipsychotic dose was predictive of behavioral worsening upon discontinuation of long-term antipsychotic drugs. The primary limitation of the study was the small sample size. In conclusion, a trial of discontinuation of antipsychotics should be considered in this population.
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Brain reward system activity in major depression and comorbid nicotine dependence.
Major depressive disorder (MDD) and nicotine dependence are highly comorbid. MDD patients may use nicotine to ameliorate depressive symptoms. The pathophysiology of the comorbidity of these two disorders is unknown. We hypothesized that a dysfunctional dopaminergic brain reward system (BRS) might be a neurobiological link between MDD and nicotine dependence and that smoking modulates the activity of the BRS by enhancing dopaminergic activity and relieving some depressive symptoms. Eighteen nicotine-dependent, nonmedicated subjects with Diagnostic and Statistical Manual of Mental Disorders (4th edition) diagnosis of MDD and 16 nicotine-dependent, control subjects participated in a double-blind, placebo-controlled, randomized parallel study. A single 30-mg oral dose of d-amphetamine (d-amph) was used to release dopamine and probe the activity of the BRS. The d-amph-mediated physiological and rewarding effects were assessed at baseline and post-treatment using standardized and validated questionnaires. Our results show that d-amph significantly increased blood pressure (p < 0.001). Subjective rewarding d-amph effects increased in both groups. Negative subjective effects were reported while on placebo during nonsmoking sessions. A significant correlation between depression severity (Hamilton depression scale) and d-amph rewarding effects was found in MDD smoker subjects (Addiction Research Center Inventory composite: r = 0.89, p < 0.000; profile of mood states composite: r = 0.71, p < 0.003; and visual analog scales composite: r = 0.78, p < 0.005). These data show that smoking did not modify the response to d-amph in MDD or control subjects, but decreased overall negative mood state during placebo sessions. Severity of depression was significantly correlated with increased rewarding effects of d-amph. Thus, although the BRS may be dysfunctional in MDD subjects, chronic nicotine use does not modify response to d-amph.
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Cognitive pharmacotherapy of Alzheimer's disease and other dementias.
OBJECTIVE: The objective of this paper is to review the randomized controlled trials (RCTs) on the pharmacotherapy of Alzheimer's disease and other dementias and to provide evidence-based recommendations for treatment of the cognitive impairment associated with these disorders. METHOD: A Medline search was conducted for RCTs, using the following key words: Alzheimer's disease, dementia, therapy, cholinesterase inhibitor, donepezil, rivastigmine, and galantamine. Studies were critically appraised, followed by a review of published major clinical practice guidelines. Recommendations for treatment were made based on best available evidence. RESULTS: The pharmacotherapy of Alzheimer's disease should include the meticulous management of vascular risk factors (for example, hypertension, diabetes, cholesterol, and stroke prophylaxis) and consideration for supplementation with folate, vitamin B complex, and vitamin E. Patients should be offered at least 1 trial of a cholinesterase inhibitor, with the possibility of another trial if the first is poorly tolerated or ineffective. Patients with vascular dementia and dementia with Lewy bodies should also be offered treatment with cholinesterase inhibitors. At this time, we lack sufficient data to recommend the use of hormone replacement or antiinflammatory therapy for treatment of dementia as the primary indication. CONCLUSION: Reasonable evidence exists to provide recommendations for the pharmacotherapy of dementia. Treatment will likely result in modest but important benefits to patients, caregivers, and society.
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