Nathan Herrmann

IntroductionCholinesterase inhibitors (ChEIs) are medications used to treat cognitive symptoms associated with Alzheimer’s disease. Previous studies examining the determinants of continued use or withdrawal of ChEIs during the transition into a nursing home have lacked detailed clinical information needed to understand the range of factors associated with pharmacotherapeutic decision-making. Objectives and ApproachPopulation-based clinical and administrative health databases were linked to examine patterns of ChEI use among 47,851 adults (aged 66+) with dementia newly admitted to nursing homes in Ontario between April 2011-March 2015. We examined whether resident frailty, among other factors, was associated with ChEI discontinuation in the following year. Frailty was calculated using a validated 72-item index derived from the Resident Assessment Instrument (RAI-MDS 2.0). Discontinuation was defined as a 30-day period when no dispensations occurred and no supply of ChEI was available. Subdistribution hazard models estimated the association between resident characteristics and discontinuation, accounting for competing risk of death. ResultsOver one-third (36.7%) of residents were receiving a ChEI at admission and this proportion was lower among those defined as frail (33.6%) vs. non-frail (40.7%) at admission. Among those on a ChEI at admission, 82.3% continued use and 17.7% discontinued during the following year. After accounting for resident characteristics, ChEI type and previous use, the incidence of discontinuation was 15% higher in frail residents vs. non-frail residents (hazard ratio (HR)= 1.15, 95\% confidence interval (CI) [1.01,1.30]). Residents with severe aggressive behaviours (HR=1.82, 95% CI [1.60, 2.07]), and higher levels of cognitive impairment (HR=1.29, 95% CI [1.10, 1.51]) were more likely to discontinue. Residents aged 85+ (HR=0.69, 95% CI [0.61, 0.77]) and those who were widowed (HR=0.84, 95% CI [0.77, 0.91]) were less likely to discontinue. Conclusion/ImplicationsMost residents who entered on a ChEI continued treatment during follow-up. The availability of linked clinical and administrative data allowed for a novel exploration of predictors of ChEI discontinuation. Frailty, severity of cognitive impairment and aggressive behaviours were associated with ChEI discontinuation; whereas selected sociodemographic factors predicted continued use.

Introduction: The prevalence of Alzheimer’s disease (AD) continues to rise, while treatment options for cognitive impairment are limited. Acetylcholinesterase inhibitors (AChEIs) aim to provide symptomatic benefit for cognitive decline, however these drugs are not without adverse events (AEs). The safety profile of each drug must be taken carefully into consideration before being prescribed, as new dosages and formulations have recently been approved. Areas covered: Donepezil, galantamine and rivastigmine are the three AChEIs approved for the treatment of varying stages of AD. Numerous clinical trials and post-marketing studies have evaluated the safety of these medications. This article will review the safety, efficacy and tolerability of these drugs in treating AD. Topics including pharmacovigilance databases, concomitant drug interactions, prescribing cascades, and treatment discontinuation are also covered. Expert opinion: AChEI use in those with mild, moderate or severe AD provide modest improvements in cognition, function and behavior. The pharmacological treatment of AD using AChEIs is associated with generally mild AEs. Differences in drug formulations should be taken into account when determining the most appropriate route of administration for each individual. Furthermore, discontinuation of AChEIs must be carefully monitored as it may be associated with worsening cognitive impairment.

Background: Depression occurs in approximately one‐third of patients following stroke based on studies that screen entire stroke populations. Less is known about the detection and treatment of post stroke depression (PSD) in routine clinical practice.Methods: This was a prospective cohort study of 7643 consecutive stroke patients >66 years of age, from 13 designated stroke centres in Ontario, Canada. PSD was defined as (a) presence of strong evidence of depression documented in the patient chart plus a prescribed antidepressant and a psychiatric consult, or (b) prescription of a new antidepressant following admission. The prevalence of PSD was determined and patients with and without PSD were compared on a variety of measures. Patients admitted to specialized stroke units were compared to patients admitted to standard units in order to determine if PSD detection and treatment rates differed.Results: PSD was diagnosed in 4.8%, and 6.7% were treated with a new antidepressant. Patients with PSD had more severe strokes, more functional handicap, longer hospital stays and were less likely to be discharged home (all p < 0.001). Patients admitted to specialized stroke units were more likely to be diagnosed with depression (5.2% vs 4.0%, p < 0.014) and were more likely to receive a new prescription for an antidepressant (7.8% vs 4.5%; p < 0.001).Conclusions: Rates of diagnosed and treated PSD in routine clinical practice are low and appear significantly lower than those from studies that utilize active screening of entire stroke populations. These results support the routine screening of all patients for PSD using validated instruments. Specialized stroke unit care may improve PSD detection and treatment rates. Copyright © 2011 John Wiley & Sons, Ltd.

Objective To determine if choice of drug and ease of administration affect persistence of therapy with Cholinesterase inhibitors (ChEIs) for treatment of dementia.

Background: The management of severe Alzheimer disease often presents difficult choices for clinicians and families. The disease is characterized by a need for full-time care and assistance with basic activities of daily living. We outline an evidence-based approach for these choices based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for the selection and quality assessment of articles, and a clear and transparent decision-making process. We selected articles published from January 1996 to December 2005 that dealt with the management of severe Alzheimer disease. Subsequent to the conference, we searched for additional articles published from January 2006 to March 2008 using the same search terms. We graded the strength of the evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: We identified 940 articles, of which 838 were selected for further study. Thirty-four articles were judged to be of at least good or fair quality and were used to generate 17 recommendations. Assessment of severe Alzheimer disease should include the measurement of cognitive function and the assessment of behaviour, function, medical status, nutrition, safety and caregiver status. Management could include treatment with a cholinesterase inhibitor or memantine, or both. Treatment of neuropsychiatric symptoms begins with nonpharmacologic approaches to addressing behavioural problems. Severe agitation, aggression and psychosis, which are potentially dangerous to the patient, the caregiver and others in the environment, can be treated with atypical antipsychotics, with consideration of their increased risk of cerebrovascular events and death. All pharmacologic approaches require careful monitoring and periodic reassessment to determine whether continued treatment is necessary. Caregiver support and use of community resources are essential. Interpretation: Severe Alzheimer disease requires frequent monitoring by health professionals. Simple nonpharmacologic approaches may address problems with mood and agitation. Antipsychotic drug therapy is occasionally necessary despite the inherent risks. Therapy with a cholinesterase inhibitor and memantine may be useful for selected patients.

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.