Alzheimer Disease: Herrmann N

Herrmann N. · No affiliation provided · Can J Psychiatry. · Pubmed #18020109 No free full text.

Abstract: The practice of EBM has evolved since it was first defined. Even the most ardent EBM proponents have recognized the need to modify the EBM approach and now include elements such as the patient's clinical state and circumstances, the patient's preferences and actions, and the physician's clinical expertise, as well as the research evidence. Part of the clinical expertise required in this model is the ability to interpret and apply the research evidence. This editorial has highlighted some of the challenges faced by clinicians who would treat AD with an EBM approach. It suggests that, without a sophisticated understanding of the primary research studies, it might be hazardous to rely on a single RCT, or even on a systematic review, for treatment recommendations. If expert assistance is required, one solution might be to rely on clinical practice guidelines developed through a consensus approach. Although clinical practice guidelines have also been criticized, they appear to provide the best blend of EBM and expert opinion. The results of the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia will be published shortly. Hopefully, this will provide helpful guidance for Canadian clinicians and their AD patients.

Herrmann N, Knopman D. · No affiliation provided · Neurology. · Pubmed #15277606 No free full text.

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Herrmann N, Black SE. · No affiliation provided · Neurology. · Pubmed #11087763 No free full text.

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Herrmann N, Gauthier S. · Department of Psychiatry, Sunnybrook Health Sciences Centre and University of Toronto, Ont., Canada. · CMAJ. · Pubmed #19047609 links to  free full text

Abstract: 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.

Herrmann N, Lanctôt KL. · Department of Psychiatry, University of Toronto, Ontario. · Can J Psychiatry. · Pubmed #18020111 No free full text.

Abstract: 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.

Herrmann N. · Department of Psychiatry, Division of Geriatric Psychiatry, Faculty of Medicine, University of Toronto, Sunnybrook & Women's College Health Sciences Centre, Toronto, ON, Canada. · Can J Neurol Sci. · Pubmed #17469692 No free full text.

Abstract: Moderate to severe Alzheimer's disease (AD) is characterized by increasing cognitive, functional, and behavioural dysfunction that results in increased caregiver burden and, eventually, complete dependence. Despite its significance as a societal health problem, there are few treatment trials of cognitive enhancers or disease modifying agents for this stage of illness. Studies suggest the cholinesterase inhibitors, especially donepezil, may provide benefit. Several studies provide support for the use of the NMDA receptor antagonist memantine as monotherapy or added to a cholinesterase inhibitor for moderate to severe AD. While there are no published guidelines for the treatment of moderate to severe AD, these studies do provide guidance for recommendations for study design and outcome measures. Such studies are urgently needed.

Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. · Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Ontario. · Can J Psychiatry. · Pubmed #15362248 No free full text.

Abstract: 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.

Thompson S, Lanctôt KL, Herrmann N. · Sunnybrook and Women's College Health Sciences Centre, Department of Psychiatry, Rm FG-05, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada. · Expert Opin Drug Saf. · Pubmed #15335298 No free full text.

Abstract: 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.

Lanctôt KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, Einarson TR. · Neuropharmacology Research Program, Department of Psychiatry, Sunnybrook & Women's College Health Sciences Centre, Toronto, ON. · CMAJ. · Pubmed #12975222 links to  free full text

Abstract: 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.

Lanctôt KL, Herrmann N, LouLou MM. · Neuropsychopharmacology Research Program and HOPE Research Centre, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ont. · J Psychiatry Neurosci. · Pubmed #12587847 links to  free full text

Abstract: 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.

Herrmann N. · Department of Psychiatry, Division of Geriatric Psychiatry, Faculty of Medicine, University of Toronto Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5. · Can J Psychiatry. · Pubmed #12420649 No free full text.

Abstract: 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.

Lanctôt KL, Herrmann N, Mazzotta P. · No affiliation provided · J Neuropsychiatry Clin Neurosci. · Pubmed #11207325 links to  free full text

Abstract: The behavioral and psychological symptoms of dementia (BPSD) can have serious debilitating effects on the patient and increase caregiver burden. Investigations into the underlying neuropathology indicate that the serotonergic system may contribute to BPSD. In addition, serotonergic pathways are known to interact extensively with the cholinergic, noradrenergic, GABAergic, and dopaminergic systems. Hence, serotonergic therapies may be used to manipulate other neurotransmitters systems to alleviate BPSD or in combination with agents specific for the other neurotransmitter receptor sites. Neurotransmitter-modulated behaviors and evidence provided by pharmacological interventions are reviewed, focusing primarily on the serotonergic system.

Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. · Division of Neurology, University of British Columbia Hospital, Vancouver, Canada. · Lancet Neurol. · Pubmed #17509485 No free full text.

Abstract: OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Herrmann N, Lanctôt KL, Eryavec G, Khan LR. · Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre and University of Toronto, Toronto, Ontario, Canada. · J Psychopharmacol. · Pubmed #15260910 No free full text.

Abstract: 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.

Herrmann N, Lanctôt KL, Eryavec G, Van Reekum R, Khan LR. · Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre, Room FG05, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. · Psychoneuroendocrinology. · Pubmed #15219643 No free full text.

Abstract: 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.

Lanctôt KL, Herrmann N, van Reekum R, Eryavec G, Naranjo CA. · Psychopharmacology Research Program and Geriatric Psychiatry, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, 207s Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. · Int J Geriatr Psychiatry. · Pubmed #12112177 No free full text.

Abstract: 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.

Ismail Z, Herrmann N, Francis PL, Rothenburg LS, Lobaugh NJ, Leibovitch FS, Black SE, Lanctôt KL. · Centre for Addiction and Mental Health, Toronto, Ont., Canada. · Dement Geriatr Cogn Disord. · Pubmed #19246910 No free full text.

Abstract: BACKGROUND/AIMS: This study aimed to investigate the possible association of regional cerebral perfusion and sleep loss in Alzheimer's disease (AD). METHODS: 55 AD patients were characterized as having (SL) or not having (NSL) nocturnal sleep loss based on standard AD scales assessing sleep over the previous 4 weeks. (99m)Tc-ethylcysteinate dimer SPECT scans were performed in a relaxed, wakeful state. Whole-brain analysis using Statistical Parametrical Mapping (SPM5) was performed to compare perfusion across groups. In addition, the AD groups were compared to normal control (NC) subjects of comparable age and gender to provide a context for interpretation of findings. RESULTS: SPM analysis showed increased perfusion in the right middle frontal gyrus (R-MFG, Brodman area 9, p = 0.016, familywise-error-corrected) in SL versus NSL patients. Comparison with NC subjects confirmed that perfusion in the R-MFG among SL patients did not exceed that found in NCs (relative rather than absolute hyperperfusion). CONCLUSIONS: In this sample of mild-to-moderate AD patients, relative hyperperfusion in the R-MFG is associated with reports of SL. This region may play a role in regulating sleep.

Lanctôt KL, Herrmann N, Black SE, Ryan M, Rothenburg LS, Liu BA, Busto UE. · Department of Psychiatry, University of Toronto, Toronto, Canada. · Am J Geriatr Psychiatry. · Pubmed #18591575 No free full text.

Abstract: OBJECTIVE: To assess the role of the dopaminergic brain reward system (BRS) in apathy associated with Alzheimer disease (AD). DESIGN: BRS function was probed in 20 AD patients using dextroamphetamine (d-amph) challenge. After baseline behavioral testing, patients were given a single 10 mg dose of d-amph. The time course of the subjective response to d-amph was assessed at hourly intervals for 4 hours. SETTING: Three outpatient dementia clinics associated with a university-affiliated hospital. PARTICIPANTS: Twenty AD patients aged 77 +/- 8 years with Neuropsychiatric Inventory (NPI) apathy scores of 3.4 +/- 3.5 and Mini-Mental State Examination scores of 20.4 +/- 5.1. MEASUREMENTS: Patients were classified as apathetic based on an NPI apathy subscore of > or =4. Apathy severity was assessed using the Apathy Evaluation Scale (AES). The subjective and behavioral responses to d-amph were assessed using computerized versions of the Addiction Research Centre Inventory (ARCI), Profile of Mood States and Connor's Continuous Performance Task. RESULTS: Repeated measures ANOVA revealed a significant interaction between the presence of apathy and the peak subjective response to d-amph on the ARCI, such that while nonapathetic AD patients were responsive to the rewarding effects of d-amph, apathetic patients were not (F(1,17) = 4.93, p = 0.04). Continuous AES scores were predicted by peak ARCI positive effects scores and baseline overall behavioral disturbances (NPI total) in a backward linear regression analysis using the entire study sample (F(2,17) = 10.00, p = 0.01, R(2) = 0.49). CONCLUSIONS: Apathy in AD is associated with a blunted subjective response to d-amph, which may be indicative of dysfunction in the BRS.

Ismail Z, Herrmann N, Rothenburg LS, Cotter A, Leibovitch FS, Rafi-Tari S, Black SE, Lanctôt KL. · Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · J Neurol Sci. · Pubmed #18495162 No free full text.

Abstract: BACKGROUND: Alzheimer's Disease (AD) is frequently associated with changes in appetite. This study investigated the relationship between regional cerebral perfusion and appetite loss in AD. METHODS: 64 patients with possible or probable AD were characterized as being with (n=22) or without (n=44) appetite loss based on the Neuropsychiatric Inventory (NPI) Appetite subscale. 99mTc-ECD SPECT scans were coregistered to a standardized template in Talairach space generating mean ratios of uptake referenced to the cerebellum. Regions of interest (ROIs) included anterior cingulate cortex (ACC), middle mesial temporal cortex (MTC-m), inferior mesial temporal cortex (MTC-i), insula (INS), orbitofrontal cortex (OFC) and thalamus-hypothalamus (THAL). RESULTS: Backward stepwise logistic regression analysis of these ROIs showed hypoperfusion in the L-ACC (p=0.015) and L-OFC (p=0.015), relative sparing of perfusion in the R-ACC (p=0.010), R-OFC (p=0.010) and L-MTC-m (p=0.006), and greater anxiety (p=0.005) independently predicted loss of appetite (chi(2)=22.24, p=0.001, Nagelkerke R(2)=0.41). CONCLUSIONS: Hypoperfusion in the left anterior cingulate and left orbitofrontal cortices, and relative sparing of perfusion in the right anterior cingulate, right orbitofrontal and left middle mesial temporal cortices emerged as predictors of appetite loss in this sample of patients. These findings are consistent with impairments in the extrinsic motivational pathways of eating and impaired reward value of food as components of appetite loss in AD.

Herrmann N, Rothenburg LS, Black SE, Ryan M, Liu BA, Busto UE, Lanctôt KL. · Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. · J Clin Psychopharmacol. · Pubmed #18480686 No free full text.

Abstract: Apathy is a common behavioral symptom of Alzheimer's disease (AD), being present in up to 70% of patients. Apathy in AD and non-AD populations has been associated with dysfunction in the dopaminergic brain reward system, suggesting that pharmacotherapeutic targeting of this system may be an effective treatment for apathy in AD. We therefore performed a randomized, double-blind, placebo-controlled crossover trial of methylphenidate in a sample of 13 apathetic AD patients (6 men, 7 women; age mean 77.9 years [SD, 7.8 years]; Mini Mental Status Examination score, 19.9 [SD, 4.7]). Patients were treated with methylphenidate (10 mg PO twice a day) or an identical placebo in two 2-week phases separated by a 1-week placebo washout. All patients participated in a dextroamphetamine challenge test (one 10-mg oral dose) before treatment with methylphenidate to gauge the functional integrity of the dopamine brain reward system. Overall, patients demonstrated greater improvement with methylphenidate compared with placebo according to Apathy Evaluation Scale total change scores (end of treatment - baseline: Wilcoxon Z = -2.00; P = 0.047). However, a significantly greater proportion of patients experienced at least 1 adverse event with methylphenidate compared with placebo (3 vs 1; chi = 4.33, P = 0.038). Two patients experienced serious adverse events with methylphenidate, consisting of delusions, agitation, anger, irritability, and insomnia, which resolved upon discontinuation of the medication. Response to methylphenidate was associated with increases in inattention on a continuous performance task after dextroamphetamine challenge. Psychostimulants may be effective in treating features of apathy in AD, and dopaminergic changes may predict response.

Herrmann N, Gill SS, Bell CM, Anderson GM, Bronskill SE, Shulman KI, Fischer HD, Sykora K, Shi HS, Rochon PA. · Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · J Am Geriatr Soc. · Pubmed #17697100 No free full text.

Abstract: OBJECTIVES: To examine current utilization patterns of cholinesterase inhibitor (ChEI) therapy for dementia to determine treatment duration, use in long-term care, how often patients receive these drugs until death, and frequency of switching between the available ChEIs. DESIGN: A population-based healthcare administrative database study. SETTING: Patients aged 66 and older from the Canadian province of Ontario who received a new prescription for a ChEI between June 1, 2000, and December 31, 2002. Patients were followed until discontinuation of ChEI therapy, death, or end of the observation period (March 31, 2005). PARTICIPANTS: Twenty-eight thousand nine hundred and sixty-one patients, including 4,601 residing in long-term care, mean age 80, 63% female. MEASUREMENTS: Information on diagnosis, medical comorbidity, physician visits, and concomitant medication use was obtained. Estimates of duration of continuous use were determined. The percentage of patients who remained on the initial dose prescribed, the proportion who switched to a second ChEI, and the percentage who remained on ChEIs until death were calculated. RESULTS: Patients had on average more than 26 physician visits in the year before ChEI therapy, but only 28% had seen a dementia specialist. Concomitant use of potentially inappropriate medications (strongly anticholinergic medications and benzodiazepines) was noted in 37% of patients. The average length of treatment for all patients was 866 days. Many patients (43%) remained on the initial dose prescribed, 6% switched to another ChEI, and 19% died while on ChEI therapy. CONCLUSION: Elderly patients with dementia are treated for lengthy periods of time with ChEIs in the community and in long-term care facilities. Further research is required to determine whether these utilization patterns are appropriate. It is also unclear whether these results are generalizable to other populations without universal health coverage or drug formulary benefits.

Lanctôt KL, Hussey DF, Herrmann N, Black SE, Rusjan PM, Wilson AA, Houle S, Kozloff N, Verhoeff NP, Kapur S. · Neuropharmacology Research Program and Geriatric Psychiatry, Toronto, Ontario, Canada. · Am J Geriatr Psychiatry. · Pubmed #17567932 No free full text.

Abstract: OBJECTIVE: The important role of serotonin-1A (5-hydroxytryptamine-1A [5-HT(1A)]) receptors in cognition, behavior, and drug response is increasingly being recognized. Postmortem studies suggest decreased 5-HT(1A) receptors in patients with Alzheimer disease (AD), but this has not been confirmed in vivo. Our primary objective was to assess the extent of 5-HT(1A) receptor losses in mild to moderate AD. METHODS: The authors examined 5-HT(1A) receptors in 10 patients with mild to moderate AD and 10 healthy volunteers with the same sex and similar age using positron emission tomography imaging with the selective 5-HT(1A) receptor radioligand, [(11)C]WAY-100635. Regions of interest (ROIs) were manually drawn on coregistered magnetic resonance images for the frontal, lateral temporal, medial temporal (MTC), parietal, and cerebellar cortices. Using the simplified reference tissue model, 5-HT(1A) binding potentials (BPs) were calculated relative to the cerebellum. RESULTS: After adjusting for partial volume effects, ROI analysis showed a significant group effect (AD versus comparison group) on BP. Analysis of between-subjects factors showed significantly decreased 5-HT(1A) BP in the right MTC, but not in the other ROIs. CONCLUSION: Given the strategic role of these receptors, loss of right medial temporal 5-HT(1A) receptors might play an important role in AD symptomatology.

Lanctôt KL, Moosa S, Herrmann N, Leibovitch FS, Rothenburg L, Cotter A, Black SE. · Department of Psychiatry, University of Toronto, Toronto, Ont., Canada. · Dement Geriatr Cogn Disord. · Pubmed #17565215 No free full text.

Abstract: BACKGROUND/AIMS: To assess the association between regional cerebral blood flow (rCBF) and apathy in Alzheimer's Disease (AD). METHODS: SPECT and MRI scans were obtained from 51 nondepressed outpatients meeting criteria for probable AD (age 77.6 +/- 6.6 years; MMSE 22.3 +/- 5.1; 23 apathetic, 28 nonapathetic) and 23 healthy elderly (75.6 +/- 3.8 years) controls. The following regions of interest (ROIs) were compared between apathetic and nonapathetic AD patients and then referenced against aged controls: anterior cingulate, orbitofrontal cortex, middle medial temporal cortex, hippocampus, medial superior temporal cortex, thalamus/hypothalamus and pons. RESULTS: Apathetic and nonapathetic patients had significant differences in rCBF. Relative to nonapathetic AD patients, apathetic AD patients had lower perfusion in 2 ROIs (right orbitofrontal cortex and left anterior cingulate) and higher perfusion in 5 ROIs (right and left hippocampi, left medial superior temporal gyrus, and right and left middle medial temporal cortex). Comparison of rCBF in these 7 ROIs to healthy elderly controls confirmed hypoperfusion in the left anterior cingulate and right orbitofrontal cortex and suggested a relative sparing of perfusion among apathetic AD patients in the remaining 5 ROIs. CONCLUSIONS: In this group of nondepressed patients with AD, apathetic subjects displayed significant perfusion differences compared to nonapathetic subjects.

Thompson S, Herrmann N, Rapoport MJ, Lanctôt KL. · Department of Psychiatry, Atlantic Health Sciences Corporation, Saint John, New Brunswick. · Can J Psychiatry. · Pubmed #17500306 No free full text.

Abstract: OBJECTIVE: Depression in patients with Alzheimer's disease (AD) is common (15% to 63%) and is associated with significant morbidity and increased mortality. Our objective was to quantitatively summarize the data on the efficacy and safety of antidepressant treatment for depression complicating AD. METHOD: We performed a metaanalysis of randomized, double-blind, placebo-controlled trials of antidepressants with a database search of the English literature (up to 2006) and a manual search of references in the retrieved articles. We extracted the proportion of subjects who responded and remitted, experienced adverse events (AEs), discontinued treatment due to AEs, or discontinued treatment for any reason. Cognition scores were also extracted. RESULTS: We included 5 studies, which involved 82 subjects treated with antidepressants and 83 subjects who received placebo treatment. Antidepressants were superior to placebo for both treatment response (odds ratio [OR] 2.32; 95% confidence interval [CI], 1.04 to 5.16) and remission of depression (OR 2.75; 95% CI, 1.13 to 6.65). There were no significant differences between the 2 groups for change in cognition (weighted mean difference -0.71, 95% CI, -3.20 to 1.79), overall dropouts (OR 0.70; 95% CI, 0.29 to 1.66) or dropout due to AEs (OR 1.41; 95% CI 0.36 to 5.54). The numbers needed to treat for one additional AD patient to respond to antidepressant treatment were 5 (95% CI, 3 to 59) and 5 (95% CI, 2 to 24) for remission of depression. CONCLUSIONS: Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population.

Herrmann N, Lanctôt KL, Rothenburg LS, Eryavec G. · Neuropharmacology Research Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Dement Geriatr Cogn Disord. · Pubmed #17148938 No free full text.

Abstract: 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.