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Biomedical subjects

Krista L Lanctôt

Publications and source records attributed to Krista L Lanctôt.

At least 19 recordsLinked to original sources
PubMed2006

A placebo-controlled trial of valproate for agitation and aggression in Alzheimer's disease.

BACKGROUND/AIMS: To assess the efficacy and tolerability of valproate for the treatment of agitation and aggression in moderate-to-severe Alzheimer's disease (AD). METHODS: This was a randomized, double-blind, placebo-controlled crossover trial of valproate in institutionalized AD patients. Patients were assessed with the Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory at baseline and after 6 weeks of treatment with valproate and placebo, with 2 weeks between phases to allow for placebo washout and tapering. RESULTS: Fourteen patients (8 male/6 female) aged 85.6 +/- 4.5 years with baseline Mini Mental State Examination scores of 4.5 +/- 4.6 and NPI agitation/aggression scores of 6.4 +/- 3.5 were randomized to treatment. NPI agitation/aggression treatment change scores significantly worsened during valproate treatment compared with placebo (Z = -2.03, p = 0.04). Tolerability of valproate was also poor, with patients experiencing a significantly greater mean number of adverse events during valproate therapy compared to placebo (Z = -2.82, p = 0.005). CONCLUSION: Valproate is not effective for the management of agitation in moderate-to-severe AD, and may be poorly tolerated in this population.

Aged↗
PubMed2006

Behavioral correlates of GABAergic disruption in Alzheimer's disease.

BACKGROUND: Losses of gamma-aminobutyric acid (GABA) have been variably demonstrated in Alzheimer's disease (AD) and may be related to the presence of behavioral and psychological symptoms of dementia (BPSD) in AD. Our objective was to assess the relationship between plasma GABA (pGABA) levels and specific BPSD in patients with severe AD. METHODS: pGABA levels and BPSD were measured in 14 institutionalized AD patients (8M/6F, mean age +/- S.D. = 85.6 +/- 4.5 years) with severe cognitive impairment (Mini-mental State Examination score = 4.5 +/- 4.6) and prominent behavioral disturbances (Neuropsychiatric Inventory (NPI) score = 33.4 +/- 23.6). RESULTS: pGABA was positively correlated with depression and apathy scores on the NPI and negatively correlated with age. Apathy and age were independent predictors of pGABA levels. CONCLUSIONS: The final stages of AD are associated with GABAergic changes, which may contribute to depression and apathy in AD.

Affect↗
PubMed2006

The contribution of neuropsychiatric symptoms to the cost of dementia care.

OBJECTIVE: To estimate the contribution of behavioral and psychological symptoms of dementia (BPSD) to the costs of care. METHOD: A one-year prospective study of resource utilization recorded monthly by 500 caregivers of community dwelling patients with dementia. The effect of behavior on total, direct and indirect costs of care was examined. RESULTS: The total cost of care was $1,298 per month and there was a significant independent relationship between costs and BPSD. The incremental cost of a one point increase in Neuropsychiatric Inventory score was $30 per month (95% CI: $19-$41). CONCLUSION: BPSD contribute significantly to the overall costs of dementia care. Interventions targeted at BPSD may help to reduce the staggering societal costs of this illness.

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PubMed2006

Atypical antipsychotics for neuropsychiatric symptoms of dementia: malignant or maligned?

Recent concerns regarding the use of atypical antipsychotics when used for the treatment of neuropsychiatric symptoms in dementia have led to a flurry of studies attempting to re-evaluate their place in therapy. We critically review current evidence on the safety profiles of these agents in patients with behavioural and psychological symptoms of dementia (BPSD) and provide recommendations to guide the clinician. Potential risks with this class of medications include extrapyramidal symptoms (EPS), weight gain, diabetes mellitus, cardiac conduction abnormalities (e.g. corrected QT [QTc] interval prolongation), cerebrovascular adverse events and mortality. Compared with placebo, treatment of BPSD with atypical antipsychotics leads to little or no increase in EPS and no significant weight change. Compared with typical antipsychotics, treatment of BPSD with atypical antipsychotics leads to a reduced risk of EPS, lower incidences of tardive dyskinesias and no significant weight gain. Atypical antipsychotics have not been associated with glucose intolerance, diabetes or hyperlipidaemia in elderly dementia patients. Both typical and atypical antipsychotics have been associated with cardiac conduction abnormalities, with the magnitude of QTc prolongation being slightly smaller with atypical antipsychotics. Randomised controlled trials suggest that atypical antipsychotics are associated with an increased risk of cerebrovascular adverse events, such as stroke, and an increased mortality compared with placebo. However, it appears that typical antipsychotics have similar risks of cerebrovascular adverse events and death. An increased risk of anticholinergic adverse effects and falls must also be considered with both typical and atypical antipsychotics. In summary, atypical antipsychotics are associated with potentially serious adverse events. Before prescribing these medications in elderly dementia patients, baseline EPS, ECG abnormalities and concomitant medications should be assessed, and the presence of cardiovascular, cerebrovascular and metabolic risk factors should be taken into consideration when benefits and risks are being weighed.

Antipsychotic Agents↗
PubMed2005

Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits.

OBJECTIVES: To quantify and compare potential benefits (subjective reports of sleep variables) and risks (adverse events and morning-after psychomotor impairment) of short term treatment with sedative hypnotics in older people with insomnia. DATA SOURCES: Medline, Embase, the Cochrane clinical trials database, PubMed, and PsychLit, 1966 to 2003; bibliographies of published reviews and meta-analyses; manufacturers of newer sedative hypnotics (zaleplon, zolpidem, zopiclone) regarding unpublished studies. SELECTION CRITERIA: Randomised controlled trials of any pharmacological treatment for insomnia for at least five consecutive nights in people aged 60 or over with insomnia and otherwise free of psychiatric or psychological disorders. RESULTS: 24 studies (involving 2417 participants) with extractable data met inclusion and exclusion criteria. Sleep quality improved (effect size 0.14, P < 0.05), total sleep time increased (mean 25.2 minutes, P < 0.001), and the number of night time awakenings decreased (0.63, P < 0.001) with sedative use compared with placebo. Adverse events were more common with sedatives than with placebo: adverse cognitive events were 4.78 times more common (95% confidence interval 1.47 to 15.47, P < 0.01); adverse psychomotor events were 2.61 times more common (1.12 to 6.09, P > 0.05), and reports of daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001) in people using any sedative compared with placebo. CONCLUSIONS: Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small. The increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment. In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events.

Cognition Disorders↗
PubMed2005

Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis.

BACKGROUND: Due to the high prevalence of depression in women of childbearing age and coupled with the fact that approximately 50% of the pregnancies are unplanned, there is a high chance that these women have been exposed to antidepressants in early pregnancy. OBJECTIVE: To determine baseline rates of spontaneous abortions (SAs) and whether antidepressants increase those rates. METHODS: Rates of SAs in women taking antidepressants compared with non-depressed women were combined into a relative risk using a random effects model. MEDLINE, EMBASE, Healthstar, Toxline, Psychlit, Cochrane database, and Reprotox were searched for studies published in any language from 1966 to 2003. Key words used to identify articles included pregnancy outcome, abortion, miscarriage, spontaneous, antidepressant, depression, and the generic names of each antidepressant and class. Bibliographies, review articles, and reference lists from studies were also used to identify potential articles expected to provide evidence of safety of antidepressants in pregnancy. RESULTS: Of 15 potential articles, 6 cohort studies of 3567 women (1534 exposed, 2033 nonexposed) provided extractable data. All matched on important confounders. Tests found no heterogeneity (chi2 3.13; p = 0.98), and all quality scores were adequate (>50%). The baseline SA rate (95% CI) was 8.7% (7.5% to 9.9%; n = 2033). For antidepressants, the rate was 12.4% (10.8% to 14.1%; n = 1534), significantly increased by 3.9% (1.9% to 6.0%); RR was 1.45 (1.19 to 1.77; n = 3567). No differences were found among antidepressant classes. CONCLUSIONS: Maternal exposure to antidepressants may be associated with increased risk for SA; however, depression itself cannot be ruled out.

Abortion, Spontaneous↗
PubMed2005

Do atypical antipsychotics cause stroke?

Post hoc analyses of pooled results from 11 randomised controlled trials of risperidone and olanzapine in elderly dementia subjects revealed an increased incidence of cerebrovascular adverse events compared with placebo. Reanalysis of the risperidone trials suggests that some of the increased incidence may be accounted for by nonspecific events that were not strokes. Large observational administrative health database studies appear to confirm that risperidone and olanzapine are not associated with an increased risk of stroke in elderly patients compared with typical antipsychotics or untreated dementia patients. A larger number of subjects with vascular and mixed dementias were included in the risperidone studies compared with the olanzapine studies, which likely accounts for the increased incidence of cerebrovascular adverse events in the risperidone trials compared with the olanzapine studies. Potential mechanisms proposed to explain an association between atypical antipsychotics and cerebrovascular adverse events include thromboembolic effects, cardiovascular effects (e.g. orthostatic hypotension, arrhythmias), excessive sedation resulting in dehydration and haemoconcentration, and hyperprolactinaemia. However, there is little evidence to support these hypothesised mechanisms at present. The association between atypical antipsychotics and cerebrovascular adverse events requires further clarification. At the present time, this association is another factor that clinicians should consider when weighing the risks and benefits of treating behavioural and psychological disturbances in elderly dementia patients.

Antipsychotic Agents↗
PubMed2004

Medial temporal hypoperfusion and aggression in Alzheimer disease.

BACKGROUND: It is not understood why some patients with Alzheimer disease (AD) display aggression and others do not. OBJECTIVE: To examine the relation between regional brain perfusion and aggression in AD. DESIGN: Single-photon emission computed tomographic scans were coregistered to a standardized template in Talairach space, generating mean ratios of uptake referenced to the cerebellum. PARTICIPANTS: Forty-nine outpatients (25 men and 24 women; mean +/- SD age, 74 +/- 11 years) with probable AD (Mini-Mental State Examination score, 17.7 +/- 5.0; 30 aggressive and 19 nonaggressive), comparable in age, sex, and severity of cognitive impairment. MAIN OUTCOME MEASURES: Regional perfusion ratios were determined for 5 bilateral regions of interest: orbitofrontal, middle medial temporal, inferior medial temporal, hypothalamus/thalamus, and anterior cingulate. RESULTS: Compared with nonaggressive patients, aggressive ones displayed hypoperfusion in the right and left middle medial temporal regions of interest (P = .02 for both), but not the others (all (t tests, unpaired, 2-tailed). On regression analyses, right middle temporal hypoperfusion (P = .001), younger age (P = .002), greater activity disturbances (P = .004), and higher Mini-Mental State Examination scores (P = .04) independently predicted aggression, accounting for 44% of the total variance (F = 8.7; P<.001). Statistical parametric mapping analyses supported right middle medial temporal hypoperfusion in the aggressive group (P = .008). CONCLUSION: In this sample of patients with AD, the right middle medial temporal region emerged as an important neural correlate of aggression.

Aged↗
PubMed2004

Growth hormone response to clonidine predicts aggression in Alzheimer's disease.

OBJECTIVE: The neurobiology of aggression in Alzheimer's Disease (AD) remains unknown. The objective of this study was to determine if altered central noradrenergic (NE) responsiveness is related to aggression in AD. METHODS: Fifteen institutionalized, non-depressed elderly (11 males, four females, mean age 81.5 +/- 5.5) with probable AD, severe cognitive impairment (MMSE mean 3.3 +/- 4.6) and significant behavioral disturbances (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. Growth Hormone (GH) response to clonidine challenge (5 microg/kg) was used as an index of central alpha(2)-adrenergic function. RESULTS: When patients were divided into those with preserved GH response (GH maximum change from baseline > 0, n = 6) and those with blunted GH response (GH maximum change from baseline < or = 0, n = 9) there were significant differences in levels of aggression as measured by the Cohen-Mansfield Agitation Inventory (CAMI) physical aggression subscale (p = .026). Patients with blunted GH response also had significantly higher levels of aggression against others on the retrospective Overt Aggression Scale (p = 0.027). CONCLUSIONS: Certain types of physically aggressive behaviors are associated with a blunted GH response to clonidine challenge. This finding is consistent with compensatory down-regulation of post-synaptic alpha(2)-adrenergic receptors in response to enhanced NE outflow in aggressive AD patients.

Adrenergic alpha-Agonists↗
PubMed2004

Atypical antipsychotics and risk of cerebrovascular accidents.

OBJECTIVE: Randomized controlled trials have suggested that at least one atypical antipsychotic may be associated with an increased risk of stroke in older people with dementia. This study examined the association between atypical antipsychotic use and stroke in the elderly. METHOD: The authors conducted a retrospective population-based cohort study of patients over the age of 66 by linking administrative health care databases. Three cohorts-users of typical antipsychotics, risperidone, and olanzapine-were identified and compared. RESULTS: Subjects treated with typical antipsychotics (N=1,015) were compared with those given risperidone (N=6,964) and olanzapine (N=3,421). Model-based estimates adjusted for covariates hypothesized to be associated with stroke risk revealed relative risk estimates of 1.1 (95% CI=0.5-2.3) for olanzapine and 1.4 (95% CI=0.7-2.8) for risperidone. CONCLUSIONS: Olanzapine and risperidone use were not associated with a statistically significant increased risk of stroke compared with typical antipsychotic use.

Aged↗
PubMed2004

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.

Animals↗
PubMed2004

Noradrenergic activity is associated with response to pindolol in aggressive Alzheimer's disease patients.

Loss of noradrenergic (NE) neurones in the locus ceruleus and compensatory changes in NE activity have been described in Alzheimer's disease (AD), but have never been linked to treatment. The hypothesis of this study was that central NE responsivity would predict aggression response to treatment with a NE medication, pindolol. Fifteen institutionalized AD subjects [Mini-Mental State Examination (MMSE), mean 3.3 +/- 4.6] with significant behavioural disturbances (Neuropsychiatric Inventory Score, mean 30.6 +/- 14.6) were studied. Growth hormone (GH) response to clonidine challenge (5 microg/kg) was used as a measure of central NE responsivity. Subjects were then randomized to 7 weeks of treatment with pindolol, maximum dose 20 mg b.i.d., or an identical placebo capsule in a cross-over design. The primary outcome measure was change on the retrospective Overt Aggression Scale (r-OAS). Five of 11 completers (45%) had decreased total r-OAS scores. There was significant improvement noted on the r-OAS verbal aggression subscale (paired t = -2.5, p = 0.03) compared to placebo, but not r-OAS total. Higher baseline aggression, higher MMSE and lower GH response predicted improvement in aggression, accounting for 82% of the variance (r = 0.91, F = 10.5, p = 0.006). Changes in NE responsivity, as reflected by a blunted GH response to clonidine challenge and more severe aggression, were associated with better response to the NE agent pindolol. Individual patient characteristics, including underlying neurotransmitter changes, may be useful for predicting response to therapy.

Administration, Oral↗
PubMed2004

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.

Aged↗
PubMed2004

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.

Aged↗
PubMed2003

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↗
PubMed2003

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.

Adult↗
PubMed2003

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.

Aged↗