HM Medical Clinic

Barry W. Rovner, M.D.
Teresa Rummans, M.D.
Lon S. Schneider, M.D.
Pierre N. Tariot, M.D.
During development and approval of this guideline watch, from July 2012 to September 2014, Dr. Rabins reports providing legaltestimony for Janssen Pharmaceutica, Dr. Rovner reports serving as a consultant to GE Healthcare, and Dr. Rummans reports thatshe has nothing to disclose. From 3 years before development was initiated in July 2012 through September 2014, Dr. Schneider andthe University of Southern California received research or other grants from Abbott Laboratories, AstraZeneca, Baxter, Forest Phar-maceuticals, Inc., Forum, Genentech, Johnson & Johnson, Eli Lilly and Company, Lundbeck, Merck, Myriad, Novartis, Pfizer,Roche, and TauRx, Ltd. and from NIH (USC ADRC, ADCS, ADNI, Banner Alzheimer's Initiative, CitAD, phytoSERMs, Alzheim-er's disease trial simulations, allopregnanolone, P50 AG05142, R01 AG033288, R01 AG037561, UF1 AG046148), and the state ofCalifornia (California Alzheimer's Disease Program, California Institute for Regenerative Medicine). During that same time period,Dr. Schneider served as a consultant or on advisory panels for Abbott Laboratories, Abbvie, AC Immune, Accera, Allon, AstraZeneca,Avraham Pharmaceuticals, Ltd., Biogen Idec, Cerespir, Forest Pharmaceuticals, Inc., Forum, GSK, Johnson & Johnson, Eli Lilly andCompany, Lundbeck, Merck, Novartis, Orion, Roche, Servier, Stemedica, Ltd., Takeda, Targacept, TauRx, Toyama/FujiFilm, andZinfandel. In addition, Dr. Schneider serves on the editorial boards of Alzheimer's and Dementia: Translational Research and ClinicalIntervention (editor-in-chief), The Lancet Neurology (editorial board), Cochrane Collaboration (editor base), BMC Psychiatry (section ed-itor), Alzheimer's & Dementia (senior associate editor), Current Alzheimer Research (associate editor), Clinical Neuropharmacology (edi-torial board) and on the guidelines committee for the World Federation of Societies of Biological Psychiatry; served as an expert wit-ness or consultant on federal and state cases for plaintiffs against Lilly, Johnson & Johnson, and Pfizer and for defendants AstraZenecaand Pfizer; and has consulted with the state of California Department of Justice. During development and approval of this guidelinewatch, Dr. Tariot reports receiving consulting fees from Abbott Laboratories, AbbVie, AC Immune, Adamas, Avanir, Avid, Boehringer-Ingelheim, Bristol Myers Squibb, California Pacific Medical Center, Chase Pharmaceuticals, Chiesi, CME, Inc., Cognoptix, Elan,Eli Lilly, GlaxoSmithKline, Janssen, Medavante, Medivation, Merck and Company, Merz, Otsuka, Roche, and Sanofi-Aventis. Dr.
Tariot reports receiving research support from AstraZeneca, Avanir, Avid, Baxter Healthcare Corp., Bristol Myers Squibb, Cognop-tix, Eli Lilly, Functional Neuromodulation (f(nm)), GE, Genentech, GlaxoSmithKline, Janssen, Medivation, Merck and Company,Pfizer, Roche, Targacept, and Toyama as well as the National Institute on Aging and the Arizona Department of Health Services. Dr.
Tariot also reports stock options in Adamas and that he is listed as a contributor to a patent owned by the University of Rochester,"Biomarkers of Alzheimer's Disease." The American Psychiatric Association's (APA's) practice guidelines are developed by expert work groups using an explicit method- ology that includes rigorous review of available evidence, broad peer review of iterative drafts, and formal approval by the APA As-sembly and Board of Trustees. APA practice guidelines are intended to assist psychiatrists in clinical decision making. They are notintended to be a standard of care. The ultimate judgment regarding a particular clinical procedure or treatment plan must be madeby the psychiatrist in light of the clinical data presented by the patient and the diagnostic and treatment options available.
Guideline watches summarize significant developments in practice that have occurred since publication of an APA practice guide- line. Watches may be authored and reviewed by experts associated with the original guideline development effort and are approvedfor publication by APA's Executive Committee on Practice Guidelines. Thus, watches represent the opinion of the authors and ap-proval of the Executive Committee but not APA policy.
APA Guideline Watch • ADCS-ADL Alzheimer's Disease Cooperative
APA American Psychiatric Association
Study–Activities of Daily Living • CI Confidence interval
ADAS-Cog Alzheimer's Disease Assessment Scale–
CGI Clinical Global Impression
Cognitive Subscale • CMAI Cohen-Mansfield Agitation Inventory
BADLS Bristol Activities of Daily Living Scale
DLB Dementia with Lewy bodies
CADASIL Cerebral autosomal dominant arteriopa-
FDA Food and Drug Administration
thy with subcortical infarcts and leucoencephalopathy • FTD Frontotemporal dementia
CATIE-AD Clinical Antipsychotic Trials of Inter-
MMSE Mini-Mental State Examination
vention Effectiveness–Alzheimer's Disease • NPI Neuropsychiatric Inventory
CIBIC+ Clinician Interview-Based Impression of
NSAIDs Nonsteroidal anti-inflammatory drugs
PDD Parkinson's disease dementia
CitAD Citalopram for Agitation in Alzheimer Dis-
RSG XR Extended-release rosiglitazone
SD Standard deviation
DART-AD Dementia Antipsychotic Withdrawal
sMMSE Standardized Mini-Mental State Examination
DOMINO trial Donepezil and Memantine in
Moderate to Severe Alzheimer's Disease trial This guideline watch summarizes new evidence and de- able but has not been studied in comparison with the velopments since the 2007 publication of APA's "Practice immediate-release formulation of the drug.
Guideline for the Treatment of Patients With Alzheimer's • New randomized controlled trials show effects that Disease and Other Dementias" (American Psychiatric As- are, at best, slight or of unclear clinical significance sociation, 2007). The authors of this watch participated in when memantine is added to cholinesterase inhibitors.
the work group that developed the 2007 guideline. Data Evidence for the sustained benefit of either cholines- from new studies have changed the strength of evidence terase inhibitors or memantine is unclear. supporting some of the recommendations in the 2007 • Additional evidence has clarified the adverse effects of guideline; however, in our opinion the recommendations re- cholinesterase inhibitors when these agents are used on main substantially correct and current. New information a long-term basis. Such effects include anorexia, weight highlighted in this watch includes the following.
loss, falls, hip fractures, syncope, bradycardia, and in-creased use of cardiac pacemakers.
• No new evidence supports the use of other pharmaco- logical agents to prevent or treat cognitive symptoms. • Available evidence remains modest for the efficacy of the cholinesterase inhibitors for mild to severe Al- • New evidence indicates that antipsychotics provide zheimer's disease and of memantine for moderate to weak benefits for the treatment of psychosis and agi- severe Alzheimer's disease. tation in patients with dementia. Adverse effects of an- • A higher-dose oral formulation of donepezil and a patch tipsychotics reported in new studies include sedation, formulation of rivastigmine are now available. Evidence metabolic effects, and cognitive impairment.
does not show clinically meaningful advantages to ad- • New evidence from a single trial suggests benefits for ministering higher doses of donepezil; higher doses of citalopram in the treatment of agitation in patients the rivastigmine patch may be associated with greater with Alzheimer's disease, but treatment may be con- strained by cognitive and cardiac side effects. • Three new trials of memantine for mild to moderate • New evidence indicates that for many patients with Alzheimer's disease showed no benefit. In addition, a Alzheimer's disease, antipsychotics can be tapered and sustained-release formulation of memantine is avail- discontinued without significant signs of withdrawalor return of behavioral symptoms.
Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
• New studies indicate that cholinesterase inhibitors demonstrate whether any specific psychosocial inter- and memantine have no clinically significant effects on vention is more effective than another.
• Support programs for caregivers and patients with de- mentia significantly decreased the odds of institution- alization and improved caregiver well-being. • There continues to be mixed evidence for the efficacy ALTERNATIVE TREATMENTS
of antidepressants to treat depression in patients withdementia.
• There is not enough definitive new evidence to warrant a change to the 2007 guideline statement that alterna- tive agents are not generally recommended because ofuncertain efficacy and safety.
• New evidence shows inconsistent effects of psycho- stimulants in treating severe apathy in patients with With the publication of the fifth edition of APA's Diag- nostic and Statistical Manual of Mental Disorders (AmericanPsychiatric Association 2013), there has been a shift in no- menclature to "major neurocognitive disorder" and "mildneurocognitive disorder" instead of the terms "dementia" • Available research does not conclusively show which and "mild cognitive impairment," respectively. For the pur- psychosocial intervention works best for which service pose of this guideline watch, we have continued to use the setting, specific behavior, disease stage, or caregiver and terms "dementia" and "minimal cognitive impairment" be- patient profile.
cause DSM-IV diagnoses were used in the studies described • Additional evidence suggests the value of psychosocial herein. Aspects of diagnosis, such as diagnostic criteria and interventions to improve or maintain cognition, func- use of imaging or laboratory studies for diagnostic pur- tion, adaptive behavior, and quality of life but does not poses, are outside the scope of this guideline watch. The systematic literature review for the 2007 guideline disorders," "cognitive impairment," or "cognitive impair- ended in 2004, although some publications from 2005, ments." Titles, abstracts, and keywords in the Cochrane 2006, and 2007 were included. For this guideline watch, database were searched for the words "dementia," "demen- we searched the Cochrane database and MEDLINE, us- tias," and "cognitive." After duplicate citations were elim- ing PubMed, for meta-analyses, systematic reviews, ran- inated, these search strategies yielded 5,956 articles, which domized trials, and other controlled trials on humans and were screened by two separate raters for relevance to the adults published in English from 2002 through January treatment of patients with dementia: 5,228 articles were 2012. In PubMed, we searched using the MeSH terms excluded as not relevant to treatment (e.g., the study pop- "Alzheimer Disease," "Creutzfeldt-Jakob Syndrome," ulation was not human; the study population did not in- "Dementia," "Dementia, Multi-Infarct," "Dementia, Vas- clude individuals with dementia; the study did not include cular," "Lewy Body Disease," "Pick Disease of the Brain," an intervention intended to treat dementia or dementia and "Cognition Disorders" as well as the following title symptoms), and 728 articles were retained and reviewed by and abstract words or phrases: "Alzheimer," "Alzheimer's," the authors. A separate search of "memantine," "donepe- "CADASIL," "cortical dementia," "cortical dementias," zil," "galantamine," or "rivastigmine," using the same term "dementia with lewy bodies," "dementia," "dementias," limits described above, was conducted for the year 2012.
"frontotemporal dementia," "lewy body dementia," "mild This search yielded an additional 984 articles, of which 22 cognitive impairment," "Parkinson's dementia," "subcorti- were retained and reviewed by the authors. Other articles cal dementia," "subcortical dementias," "vascular demen- were identified and included during draft development and tia," "vascular dementias," "cognitive disorder," "cognitive APA Guideline Watch PHARMACOLOGICAL TREATMENTS FOR COGNITIVE SYMPTOMS CHOLINESTERASE INHIBITORS AND MEMANTINE
ability to undertake normal daily activities. Efficacy of Since 2007, new randomized controlled trials of the cholin- galantamine was also not found for patients with mild esterase inhibitors and memantine have been conducted cognitive impairment without dementia in two 24-month to treat cognitive symptoms of dementia. The following randomized double-blind studies (Winblad et al. 2008).
sections review these new trials in patients with specific The first study had 990 subjects, the second 1,058. dementias (i.e., Alzheimer's disease, vascular dementia, and Since publication of the 2007 guideline, a 23 mg/day other dementias). formulation of donepezil, a rivastigmine transdermal New systematic reviews and meta-analyses are also patch, and a sustained-release formulation of memantine available, but most of these were not comprehensive, or have become available. they focused on a narrow question (e.g., a pooled analysis In a randomized, double-blind, multisite study that in- of selected outcomes from selected trials). Similarly, anal- cluded 1,371 patients with moderate to severe Alzheimer's yses of partial clinical samples are available but cannot be disease (Farlow et al. 2010), the use of 23 mg/day donepe- considered reliable. One thorough, well-designed sys- zil did not result in a statistically significant difference tematic review by the McMaster University Evidence- from the 10 mg/day dosage on the Clinician Interview- Based Practice Center evaluated 92 publications repre- Based Impression of Change Plus (CIBIC+) scale. The senting 59 studies of pharmacological agents for demen- higher dose of donepezil was associated with a higher pro- tias. The authors concluded, "Treatment of dementia with portion of subjects dropping out of treatment as well as a cholinesterase inhibitors and memantine can result in sta- substantial increase in the rate of adverse events compared tistically significant but clinically marginal improvement with 10 mg/day of donepezil. Thus, in clinical use, the po- in measures of cognition and global assessment of demen- tential cognitive effects of the higher dose of donepezil are tia" (Raina et al. 2008, p. 379). unlikely to outweigh the increase in adverse effects. In a New information is also available on adverse effects of subsequent subgroup analysis (Doody et al. 2012), out- cholinesterase inhibitors when these agents are used on a comes in patients already taking memantine were com- long-term basis. Such effects include anorexia, weight pared with outcomes in patients not taking concomitant loss, syncope (Kim et al. 2011), bradycardia (Hernandez memantine. Although donepezil at 23 mg/day was found et al. 2009), falls, hip fractures, and increased need for a to provide cognitive benefits over the lower dose of donep- cardiac pacemaker (Gill et al. 2009).
ezil at week 24, memantine had no additional effect. A study in patients with severe Alzheimer's disease as- sessed the effects of two doses of rivastigmine transdermal patch in a 24-week prospective, randomized, double-blind The 2007 guideline identifies three cholinesterase inhib- trial (Farlow et al. 2013) and investigated the efficacy, itors—donepezil, rivastigmine, and galantamine—that safety, and tolerability of 13.3 mg/24 hour dosage as com- have been approved by the U.S. Food and Drug Admin- pared with 4.6 mg/24 hour dosage of a rivastigmine patch.
istration (FDA) for treatment of mild to moderate Alz- Individuals who were randomly assigned to receive 13.3 heimer's disease. The guideline notes that donepezil has mg/24 hours (n=356) showed superior effects on cognition been approved for severe Alzheimer's disease. Memantine and function at weeks 16 and 24 as compared with individ- is approved by the FDA for treatment of moderate to severe uals who were assigned to receive a 4.6 mg/24 hour patch Alzheimer's disease. Available evidence for these medica- (n=360). Overall, rates of completion and rates of adverse tions remains modest.
effects were similar in the two groups, although treatment Several new studies of galantamine are available. In a discontinuation (except for skin irritation) and most side ef- trial by Burns and colleagues (2009) of patients with severe fects occurred more frequently in the higher-dose group.
Alzheimer's disease and a mean age of 84 years in a nursing An additional randomized, double-blind, parallel-group home setting, galantamine was found to have minimal clin- study (Cummings et al. 2012) examined the effects, tolera- ical benefit. In this study, participants were randomly as- bility, and safety of the rivastigmine transdermal patch at signed to receive galantamine titrated to 24 mg/day (n=207) two different doses in 567 patients with Alzheimer's disease or placebo (n=200); 168 and 161 individuals completed the who exhibited cognitive and functional decline following study, respectively. The patients who received galan- 24–48 weeks of open-label treatment with 9.5 mg/24 hour tamine had improved cognitive function as measured by rivastigmine patch. There was no cognitive benefit from the Severe Impairment Battery but no benefit on their the change to a 13.3 mg/day dosage of the rivastigmine Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
patch, but there was a statistically significant improvement randomized controlled trials with a total of 1,317 patients.
in the Instrumental Activities of Daily Living domain of the They found that adding memantine to a cholinesterase in- Alzheimer's Disease Cooperative Study–Activities of Daily hibitor had a small impact on patients' Clinical Global Living (ADCS-ADL) in patients receiving 13.3 mg/day as Impression (CGI) score but no benefit on function. They compared with 9.5 mg/24 hours at all study time points.
concluded that clinical relevance of adding memantine "is Adverse events occurred in a larger fraction of patients not robustly demonstrated" (Farrimond et al. 2012).
who received the 13.3 mg/24 hour rivastigmine patch as A clinical trial cited in the 2007 guideline suggested compared with the 9.5 mg/24 hour rivastigmine patch. modest efficacy of memantine for patients with mild to The 2007 guideline notes that "currently available data moderate Alzheimer's disease (Peskind et al. 2006); how- suggest that the combination of a cholinesterase inhibitor ever, the guideline notes that "this result is not conclusive plus memantine is more likely to delay symptom progres- and additional trials should be performed." In more recent sion than a cholinesterase inhibitor alone." The DOMINO studies, memantine was not effective in patients with mild trial conducted by Howard and colleagues (2012) pro- to moderate Alzheimer's disease. In a 24-week double- vides additional information on this issue, but interpreta- blind study, Bakchine and Loft (2008) randomly assigned tion of the findings is limited by important differences 470 patients with mild to moderate Alzheimer's disease to among the groups at baseline and high numbers of drop- receive either 20 mg/day memantine (n=318) or placebo outs, with different dropout rates among the treatment (n=152); 85% and 91%, respectively, completed the study.
groups. The study was designed to follow a community After 24 weeks, patients treated with memantine showed sample of 800 patients, but only 295 were enrolled, and numerically significant but clinically insignificant improve- many of these participants were excluded from the analy- ment relative to placebo on the Alzheimer's Disease Assess- ses because of poor treatment adherence. At the end of the ment Scale–Cognitive Subscale (ADAS-Cog) and the study, sample sizes ranged from 20 to 38 per group. Study CIBIC+. Memantine showed no advantage over placebo in patients had moderate to severe Alzheimer's disease and a similar trial by Porsteinsson and colleagues (2008) in had been treated with donepezil for at least 3 months. They which 433 patients with mild to moderate Alzheimer's dis- were randomly assigned to continue donepezil, switch to ease were randomly assigned to receive placebo or meman- placebo, switch to placebo plus memantine, or continue tine (20 mg/day) for 24 weeks. Primary outcomes were donepezil and start memantine. Patients for whom donep- changes from baseline on the ADAS-Cog and CIBIC+ ezil was discontinued showed worsening on the standard- scores. Similarly, no effect for memantine was found in a ized Mini-Mental Examination (sMMSE) and the Bristol randomized placebo-controlled trial of memantine and vi- Activities of Daily Living Scale (BADLS) compared with tamin E in 613 patients with mild to moderate Alzheimer's patients who continued on donepezil: sMMSE –1.9 points; disease (Dysken et al. 2014), as described in more detail in BADLS +3.0 points. These differences were statistically the section "Alternative Treatments." significant. Patients who received memantine had less pro- Taken together, the bulk of the evidence on the efficacy nounced worsening than patients who received placebo: and effectiveness of cholinesterase inhibitors and meman- sMMSE +1.2 points and BADLS –1.5 points, values that tine in individuals with Alzheimer's disease consists of tri- were also statistically significant. In individuals who con- als of individual medications rather than head-to-head tinued on donepezil, there was no additional benefit of comparator trials. On the basis of the available evidence, adding memantine. one could justify using both memantine and a cholinester- In addition, there are two systematic reviews that show ase inhibitor, using memantine alone, or using a cholines- at best slight effects or unclear clinical significance of me- terase inhibitor alone in treating an individual with Alz- mantine added to cholinesterase inhibitors (Farrimond et heimer's disease. al. 2012; Muayqil and Camicioli 2012). These reviews didnot include the two trials and subanalyses above. Muayqil and Camicioli (2012) pooled data from 13 studies with a Because of inconclusive evidence, the 2007 guideline does total of 971 patients. Small but statistically significant ef- not specifically recommend cholinesterase inhibitors for fect sizes were seen in favor of combination therapy among patients with vascular dementia; however, it notes that in- patients with moderate to severe Alzheimer's disease on dividual patients may benefit from this class of medica- scales of cognition, scales of functional outcomes, and the tions. The guideline states that evidence does not support NPI. The authors noted heterogeneity in scales and pa- the use of memantine in such patients.
tient characteristics and concluded that the clinical signif- New trials of the cholinesterase inhibitors in patients with icance of their findings is uncertain (Muayqil and Camici- vascular dementia have not found them to be effective.
oli 2012). Farrimond et al. (2012) pooled data from three For example, a 24-week double-blind, randomized, placebo- APA Guideline Watch controlled study of 710 patients with probable vascular dementia (FTD), except for two small trials and two case dementia showed no effect of rivastigmine (Ballard et al.
series showing that either trazodone or one of a variety of 2008b). Similarly, in a multinational, double-blind, paral- selective serotonin reuptake inhibitors may be beneficial lel-group clinical trial, 788 patients with probable vascular in decreasing problematic behaviors or agitation. In a more dementia were randomly assigned to receive galantamine or recent study, 36 patients with behavioral variety FTD and placebo (Auchus et al. 2007). Galantamine showed no clear primary progressive aphasia were treated in an open-label effect on activities of daily living or global functioning. fashion with galantamine for 18 weeks and then were ran- Kavirajan and Schneider (2007) conducted a meta- domly assigned to receive an additional 8 weeks of either analysis of randomized controlled trials of cholinesterase galantamine or placebo (Kertesz et al. 2008). Galantamine inhibitors and memantine in vascular dementia. Three showed no effect on behavior or language.
donepezil, two galantamine, one rivastigmine, and two Similarly, memantine did not improve cognition in memantine trials, comprising 3,093 patients taking the study randomized placebo-controlled trials of patients with drugs and 2,090 patients taking placebo, met selection cri- DLB or PDD (Aarsland et al. 2009; Emre et al. 2010). In teria. Overall, the donepezil trials showed questionable, the study by Aarsland and colleagues (2009), 72 patients not clinically significant, or not statistically significant effects with PDD or DLB were randomly assigned to receive on cognition. This meta-analysis concluded that available memantine (n=34) or placebo (n=38). Sixteen patients did evidence does not support use of galantamine, rivastig- not complete the study because of adverse events (the pro- mine, donepezil, or memantine in vascular dementia.
portion of withdrawals was similar in both groups). In the Dichgans and colleagues (2008) conducted a multicenter, study by Emre and colleagues (2010), 199 patients were 18-week, placebo-controlled, double-blind, randomized randomly assigned to treatment; 34 with DLB and 62 parallel-group trial to determine whether donepezil im- with PDD were given memantine, and 41 with DLB and proves cognition in patients with cerebral autosomal 58 with PDD were given placebo. The study was com- dominant arteriopathy with subcortical infarcts and leu- pleted by 159 (80%) patients: 80 in the memantine group coencephalopathy (CADASIL; N = 168). The primary and 79 in the placebo group.
endpoint was change from baseline in the score on the In two randomized, double-blind, placebo-controlled vascular ADAS-Cog. Donepezil showed no effect in sub- trials, memantine was not found to be effective for FTD cortical vascular cognitive impairment.
(Boxer et al. 2013; Vercelletto et al. 2011). In the trial byVercelletto and colleagues (2011), no significant differ- ences were found between patients who received meman- The 2007 guideline states that cholinesterase inhibitors tine (n=23) and those who received placebo (n=26) on the should be considered for patients with mild to moderate CIBIC+ or on secondary measures of cognitive function Parkinson's disease dementia (PDD). Supporting evidence, or illness burden. In the trial by Boxer and colleagues however, remains weak. The guideline describes a single (2013), patients with FTD and patients with aphasias were trial of rivastigmine, leading to an FDA indication for this randomly assigned to treatment with memantine (n=33 condition. Donepezil was subsequently studied for PDD and 8) or placebo (n=31 and 8). After 26 weeks, there were in a randomized double-blind trial (Dubois et al. 2012). In no statistically significant differences between the groups this 24-week study in 550 patients, donepezil had no effect on measures of cognitive function or clinical global im- on activities of daily living or behavior. There was also no effect on the protocol-specified analyses of cognition, al- A randomized, double-blind, placebo-controlled trial though post hoc analyses found benefit on some measures by Hanney and colleagues (2012) found that memantine of cognitive function.
is not effective for adults over 40 years of age who have The 2007 guideline suggests that cholinesterase inhib- Down's syndrome and dementia. In this study, 88 patients itors can be considered for patients with dementia with received memantine and 85 received placebo for 52 weeks.
Lewy bodies (DLB) and describes two randomized con- Both groups declined in cognition and function, with no trolled trials, one of rivastigmine and one of donepezil. An differences between the groups for any outcomes.
additional trial is now available: Mori and Kosaka (2012)randomly assigned 140 patients with DLB to receive OTHER PHARMACOLOGICAL TREATMENTS FOR
donepezil or placebo for 12 weeks. Donepezil at 5 and10 mg/day was superior to placebo on measures of cogni- tive function and behavior.
In addition to cholinesterase inhibitors and memantine, The 2007 guideline noted little evidence overall to the 2007 guideline reviews other medications used to de- support the use of any particular agent for frontotemporal lay the progression of cognitive symptoms in dementia, Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
including statins, nonsteroidal anti-inflammatory drugs and colleagues (2011) conducted a placebo-controlled, (NSAIDs), estrogen supplements, and other marketed double-blind, parallel-group study of the effect of trans- and experimental agents. Since 2007, a number of studies dermal estradiol in postmenopausal women with mild to have examined whether reducing risk factors for cerebro- moderate Alzheimer's disease. Forty-three postmeno- vascular disease, primarily with antihypertensive drugs, pausal women with Alzheimer's disease were assessed over might delay or prevent development of dementia or slow 12 months; there was a 49% dropout rate during this pe- its progression (McGuinness et al. 2009, 2010; Peters et riod. Results showed favorable effects of hormone therapy al. 2008; Shah et al. 2009). The results have been incon- on visual memory and semantic memory. A 12-month clusive, and there is no new basis for recommending these randomized, double-blind, placebo-controlled study of types of treatments solely in the context of dementia treat- low-dose estradiol and norethisterone on 65 female outpa- ment or prevention.
tients with probable Alzheimer's disease by Valen-Sendstadand colleagues (2010) found that women without an apo- lipoprotein E 4 allele may show better mood and cogni- The 2007 guideline recommends against the use of statins tion with hormone therapy. Tierney and colleagues (2009) for dementia because of a lack of efficacy in the prevention conducted a 2-year double-blind placebo-controlled trial or treatment of cognitive decline; subsequent evidence is of 142 women randomly assigned to receive low-dose estra- consistent with this conclusion. A large randomized con- diol and norethindrone or a placebo. On the basis of scores trolled trial on the use of pravastatin in 5,804 at-risk el- on the short-delay verbal recall tasks of the California Ver- derly patients found no difference between statins and bal Learning Test, the study results suggested that the ben- placebo in the prevention of cognitive decline after a efits of estrogen exposure may be limited to those women mean follow-up period of 42 months (Trompet et al.
with average to above average performance.
2010). Last, two randomized controlled trials found no An additional study of magnetic resonance imaging benefit of statins in the treatment of Alzheimer's disease, (MRI) in 1,403 women (Espeland et al. 2009) suggested as measured by scales of cognition (ADAS-Cog) and global that treatment with conjugated equine estrogens was as- function (Feldman et al. 2010; Sano et al. 2011). Several sys- sociated with brain volume loss and that hippocampal and tematic reviews (Beri et al. 2009; Muangpaisan and Brayne total brain volumes were smaller in women who had been 2010) and a meta-analysis (Zhou et al. 2007) of statins have prescribed conjugated equine estrogen and developed cog- also noted that data for the use of statins in dementia is in- nitive impairment. However, the clinical significance of these findings is unclear. Given the lack of benefit on cognitive outcome mea- Nonsteroidal Anti-Inflammatory Drugs
sures and the adverse vascular and cancer risks, the 2007 The 2007 guideline also recommends against the use of guideline recommendation against the use of hormone re- NSAIDs, and subsequent evidence supports this. There placement therapy is unchanged.
have been numerous studies since 2007 on the potential ofNSAIDs to delay or prevent emergence of mild cognitive Other Agents
impairment or dementia in cognitively normal older per- Since publication of the 2007 guideline, several other agents sons, delay or prevent conversion of mild cognitive im- have been studied for their effects in dementia. None of pairment to dementia, or slow progression of dementia these agents are considered appropriate for clinical use at (Aisen et al. 2008b; Breitner et al. 2011; De Jong et al. 2008; present, and more research is necessary. Martin et al. 2008; Pasqualetti et al. 2009; Salpeter et al.
Lithium was previously studied for its potential to re- 2006; Soininen et al. 2007; Soni et al. 2009). Overall, no duce psychopathological features of dementia, and since clinically meaningful benefit has been seen, with mixed ev- 2007 its neuroprotective potential has been investigated.
idence regarding excess toxicity. Two studies have examined lithium's effects on biomark-ers relevant to Alzheimer's disease (Forlenza et al. 2011; Hampel et al. 2009). In one study comparing random as- Hormone replacement therapy is also not recommended signment to receive lithium or placebo in 71 individuals in the 2007 guideline. A number of small studies since 2007 with mild Alzheimer's disease, there were no effects of continue to show mixed results of estrogen treatment in lithium at serum levels of 0.5–0.8 mmol/L in terms of women with Alzheimer's disease (Valen-Sendstad et al.
global cognitive performance, depressive symptoms, or 2010; Wharton et al. 2011) or to slow or prevent cognitive cerebrospinal fluid biomarkers (Hampel et al. 2009) with decline in older women (Tierney et al. 2009). Wharton 6 weeks of dose titration followed by 4 weeks of treatment APA Guideline Watch at therapeutic levels. In another relatively small study of RSG XR, 8 mg RSG XR, or 10 mg donepezil as an active low-dose lithium (with serum levels of 0.25–0.5 mmol/L), comparator. Co-primary endpoints were change from base- individuals with mild amnestic cognitive impairment line to week 24 on the ADAS-Cog and CIBIC+. RSG XR showed a decrease in cerebrospinal fluid concentrations of showed no effect in either dose. Harrington and col- p-tau and some improvement in performance on cogni- leagues (2011) conducted two double-blind, placebo-con- tive and attentional tasks with a year of treatment. Given trolled phase III studies in which subjects with mild to the small sample sizes and varying duration of these stud- moderate probable Alzheimer's disease were randomly ies, as well as the known side effects and potential toxicity assigned to receive once-daily placebo, 2 mg RSG XR, or of lithium, particularly in older individuals, use of lithium 8 mg RSG XR for 48 weeks. No statistically or clinically to treat or prevent dementia is not recommended. How- significant effect was detected for either dose, using the ever, further study of lithium's potential neuroprotective ADAS-Cog subscale and Clinical Dementia Rating–Sum effects may be warranted. A small (N=92), 6-month trial of Boxes scores. A randomized, double-blind, placebo- of atomoxetine (Mohs et al. 2009) failed to show clinically controlled pilot study of intranasal insulin—with primary significant benefit in patients with Alzheimer's disease measures consisting of delayed story recall score and the measured on the ADAS-Cog, although there were hints of Dementia Severity Rating Scale score and secondary mea- possible benefit in secondary measures. A 6-month dou- sures including the ADAS-Cog score and the ADCS- ble-blind pilot study of transdermal nicotine in people ADL scale—suggested benefit in patients with mild cog- (N=74) with mild cognitive impairment indicated possi- nitive impairment or Alzheimer's disease (Craft et al. 2012).
ble cognitive benefit (Newhouse et al. 2012), with primary A well-designed trial is under way to test efficacy.
outcome variables being attentional improvement as as- A large number of experimental agents, many targeting sessed with the Connors' Continuous Performance Test the amyloid pathway such as bapineuzumab, tarenflurbil, and clinical improvement as measured by CGI. Safety and and tramiprosate, have failed to show benefit (Aisen et al.
tolerability were noted to be excellent. 2007, 2011; Gauthier et al. 2009; Green et al. 2009; Sallo- Rosiglitazone failed to show benefit in three large way et al. 2009; Saumier et al. 2009; Sperling et al. 2012). In phase III trials after showing possible benefit in a phase II a phase III trial of solanezumab in patients with mild to trial (Risner et al. 2006), which measured the effects of 2, moderate severity of Alzheimer's disease, no benefits were 4, or 8 mg of extended-release rosiglitazone (RSG XR) us- seen on primary outcomes; however, secondary analyses ing the ADAS-Cog and the CIBIC+. In one of these phase showed trends for improvement in participants with mild III trials, Gold and colleagues (2010) conducted a double- Alzheimer's disease (Doody et al. 2014). Intravenous im- blind placebo-controlled study in which 693 subjects were munoglobulin showed possible benefit in pilot studies but randomly assigned to receive a once-daily placebo, 2 mg not in more definitive studies (Relkin et al. 2009).
PHARMACOLOGICAL TREATMENTS FOR AGITATION AND PSYCHOSIS Since 2007, new randomized controlled trials of anti- The 2007 guideline recommends with moderate clinical psychotics have been published. Although some of these confidence the use of antipsychotic medications for the trials involved large samples, few trials included head-to- treatment of psychosis in patients with dementia and for head comparisons of antipsychotic agents that would in- the treatment of agitation but only after addressing poten- form the choice of a specific medication for an individual tial underlying causes and after trying environmental mea- patient. Additional limitations in the newer trials affecting sures, including reassurance and redirection. The guideline their external validity and potential for translation into also states that antipsychotics must be used with caution practice included rates of attrition and variability in eligibil- and at the lowest effective dosage because they are associ- ity criteria, outcome measures, treatment protocols, con- ated with severe adverse events. As noted in the 2007 guide- trol conditions, and masking procedures. line, all second-generation ("atypical") antipsychotics carry Unpublished summaries of some of the new trials were a black box warning about increased risk of mortality in el- reviewed during development of the 2007 guideline, spe- derly patients. In 2008, the FDA extended this warning to cifically two aripiprazole trials (Mintzer et al. 2007; Streim all first-generation agents.
et al. 2008). In addition, results from a quetiapine trial Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
(Zhong et al. 2007) were reviewed as the guideline was be- potential benefit of treatment (Katz et al. 2007; Kryzhanov- ing finalized for publication. Since the publication of the skaya et al. 2006). 2007 guideline, a small (N=40) 6-week randomized pla- In summary, new trials and studies better define adverse cebo-controlled trial of quetiapine at a median dosage of effects, but they do not strengthen the evidence for effi- 200 mg/day has been completed (Paleacu et al. 2008). No cacy of antipsychotic drugs in treating psychosis or agita- consistent differences were found in behavioral or psy- tion. Rather, they demonstrate minimal or no efficacy chological symptoms of dementia for patients treated with strong placebo effects as well as variations in response with quetiapine as compared with placebo. Together with with trial duration. These findings strengthen the support the large 10-week double-blind fixed-dose study of Zhong for using nonpharmacological inventions and environ- and colleagues (2007) and other small quetiapine trials mental measures to attempt to reduce psychosis and agi- (Ballard et al. 2005), which were already described in the tation prior to initiation of medications. 2007 guideline, available evidence suggests weak efficacyof quetiapine with increases in sedation at dosages above Discontinuation Trials
200–300 mg/day.
In a long-term, randomized, placebo-controlled discon- Several small randomized controlled trials comparing tinuation trial, Dementia Antipsychotic Withdrawal Trial– two antipsychotics or an antipsychotic with an antidepres- Alzheimer's Disease (DART-AD), 165 patients were ran- sant showed no differences between the drugs. However, domly assigned to continue or discontinue their anti- none of these studies included a placebo control group.
psychotic medications. This trial showed a continuing Among these studies were comparisons between olanza- increase in the risk for death among patients who contin- pine and haloperidol (Verhey et al. 2006), quetiapine and ued to take antipsychotics compared with patients for risperidone (Rainer et al. 2007), risperidone and citalo- whom antipsychotics were tapered and changed to placebo pram (Pollock et al. 2007), and risperidone and escitalopram (Ballard et al. 2009). There was a reduction in survival in (Barak et al. 2011). The latter two trials showed fewer ad- the patients who continued to receive antipsychotics. When verse events and dropouts with the antidepressant. Because compared with individuals who received placebo, those the trials were not placebo controlled, they provide no ev- who continued to receive antipsychotics showed a reduc- idence that either drug in the trial was actually superior to tion in survival that was apparent at 12 months of follow- placebo; however, they do provide evidence that there is lit- up, with a strong and persistent effect for up to 4 years.
tle to distinguish between the drugs in terms of efficacy, Because the majority of patients were initially treated with although adverse events appear to be different. risperidone (67%) or haloperidol (26%), the results apply Additional analyses of data from the Clinical Antipsy- primarily to these drugs. The results support the concern chotic Trials of Intervention Effectiveness–Alzheimer's that an increased risk for death continues if patients re- Disease (CATIE-AD), a comparison of olanzapine, que- main on antipsychotic medications and is not just a short- tiapine, and risperidone, showed modest effects on symp- term effect seen for 10–12 weeks after initiation of antipsy- tom scales that were similar to effects observed in other tri- chotic medication (Schneider et al. 2005).
als (Sultzer et al. 2008). As in the primary analysis of the Another objective of this discontinuation trial was to CATIE-AD data, however, the small advantages were off- assess clinical change associated with withdrawal of anti- set by adverse events. In terms of effectiveness, placebo psychotic medication (Ballard et al. 2008a). Here, results treatment in CATIE-AD was associated with lower health over the 1-year follow-up period showed that there were care costs (Rosenheck et al. 2007); further cognitive im- no detrimental effects of antipsychotic discontinuation on pairment was associated with antipsychotics (Vigen et al.
either cognition or behavioral measures. However, there 2011); and the antipsychotics were associated with "weight was evidence to suggest that patients with higher levels of gain in women, with olanzapine and quetiapine in partic- behavioral symptoms prior to randomized discontinua- ular, and with unfavorable change in HDL cholesterol and tion may have had some benefits from continued treat- girth with olanzapine" (Zheng et al. 2009, p. 583). ment with antipsychotics, which were mainly risperidone Post hoc pooled analysis of trials of risperidone sug- and haloperidol. gests improvement in a number of behavioral symptoms In a randomized discontinuation trial in Norway, 55 pa- but not individual items on hallucinations or delusions tients taking risperidone, olanzapine, or haloperidol were (Rabinowitz et al. 2007). Another meta-analyis suggested randomly assigned to continue or discontinue medication that benefits of risperidone may be more notable in patients (Ruths et al. 2008). At 4 weeks follow-up, 23 of the 27 pa- with more severe behavioral symptoms (Katz et al. 2007).
tients (85%) who were assigned to discontinue the anti- However, meta-analyses also indicated that increased ad- psychotic remained off medication. No differences in verse effects with antipsychotic treatment may offset any NPI scores were found between the group who continued APA Guideline Watch treatment and the group who discontinued antipsychot- 2007 guideline to discontinue antipsychotic medications ics, with scores generally remaining stable or improving.
when possible and particularly when the physician is un- Patients who exhibited worsening of behavioral symp- certain that a patient is benefiting from treatment. toms with cessation of the antipsychotic were receivingdaily drug doses at baseline that were higher than average.
A recently published discontinuation trial (Devanand et Several randomized trials clearly indicate that antipsy- al. 2012) treated 180 patients with risperidone for 16 weeks chotic medications can worsen cognition. Deberdt et al.
in an open-label design. Next, 110 individuals who re- (2008) combined data from three trials of olanzapine in el- sponded to treatment were randomly assigned to contin- derly patients with behavioral and psychiatric symptoms uation of risperidone or to withdrawal of risperidone and associated with dementia. For the olanzapine group as a administration of placebo. Sixteen weeks later, some of whole there was a trend for worsening on the MMSE, which the patients who continued on risperidone were randomly was significant in the subgroup of subjects with lower assigned to receive placebo while others continued to re- MMSE scores. In an additional study of olanzapine, Ken- ceive risperidone for another 16 weeks. The primary out- nedy et al. (2005) reported a 2.6 point difference in ADAS- come was time to relapse, defined by the investigators as a Cog score compared with placebo and a 1.5 point differ- minimum of a 5-point or 30% increase in the NPI psy- ence on the MMSE over 6 months. With quetiapine, Bal- chosis and agitation score. Patients who continued to take lard et al. (2005) reported substantial worsening on the risperidone were less likely to relapse than those whose Severe Impairment Battery compared with placebo over risperidone was changed to placebo, with relapse rates of 26 weeks. With second-generation antipsychotics overall, 33% on risperidone as compared with 60% with placebo Vigen et al. (2011) reported a worsening of scores on the for the initial randomization and 15% and 48%, respec- MMSE and ADAS-Cog compared with placebo. tively, for those changed to placebo at 16 weeks. Never-theless, a large proportion of patients who met the inves- tigators' definition of response in the initial 16 weeks and The 2007 guideline notes that antidepressants have not who continued to receive risperidone in the double- been well studied for symptoms other than depression in blinded, randomized, placebo-controlled phase had a re- patients with dementia. The Citalopram for Agitation in lapse or dropped out of the study. The rates of discontin- Alzheimer Disease (CitAD) study was a randomized, pla- uation of risperidone treatment were 38% in the 16-week cebo-controlled, double-blind, multisite trial of citalo- initial open phase, 68% in one randomized risperidone pram for agitation in patients with probable Alzheimer's group during 32 weeks of follow-up, and 29% in the sec- disease (Porsteinsson et al. 2014). Participants received a ond risperidone group during 16 weeks of risperidone and psychosocial intervention plus either citalopram (n=94) 16 weeks of placebo. Indeed, only 10 of 32 patients (31%) or placebo (n=92) for 9 weeks. Citalopram was initiated at assigned to continue risperidone for 32 weeks completed a dosage of 10 mg/day with planned titration to 30 mg/day the study as compared with 10 of 40 patients (25%) assigned over 3 weeks on the basis of response and tolerability. Par- to 16 weeks of placebo. There were no differences in ad- ticipants who received citalopram showed significant im- verse events and ratings, cognitive function, or behavior provement compared with those who received placebo on rating scales between the patients assigned to 16 weeks of the Neurobehavioral Rating Scale Agitation Subscale and continuing risperidone and those assigned to 16 weeks of on the modified Alzheimer's Disease Cooperative Study– withdrawal from risperidone followed by placebo. Thus, Clinical Global Impression of Change. Caregiver distress there was a sizeable rate of treatment dropout or symptom was also reduced. As noted by the study authors, cognitive relapse in individuals who were maintained on risperi- and cardiac adverse effects of citalopram may limit its use done, but the risk of symptomatic relapse was even higher at the dosage of 30 mg/day.
when risperidone was discontinued. Taken together, these trials suggest that many patients with Alzheimer's disease who are receiving antipsychotics CHOLINESTERASE INHIBITORS AND MEMANTINE
can have these medications tapered and discontinued with- Pharmacological alternatives to antipsychotics are lacking out return of behavioral symptoms. A small minority of pa- for the treatment of agitation in individuals with demen- tients may show increased behavioral symptoms when an- tia. Since the 2007 guideline, the evidence is clearer that tipsychotics are withdrawn, and the physician will need to cholinesterase inhibitors and memantine do not have ben- decide whether or not to restart medications. These obser- efits in reducing agitation, although they may have bene- vations further strengthen the recommendation of the fits on other clinically relevant behaviors. Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
Since 2007, two trials in patients with Alzheimer's dis- use of valproate to delay or prevent behavioral symptoms ease have addressed this issue. In patients with Alz- has also been studied. In a 2-year multicenter trial, 313 in- heimer's disease who had clinically significant agitation dividuals with moderate Alzheimer's disease who had not and no response to a brief psychosocial treatment pro- yet experienced agitation or psychosis were randomly as- gram, 272 subjects were randomly assigned to receive 10 signed to receive valproate treatment or placebo; there was mg/day of donepezil (128 patients) or placebo (131 pa- no difference between groups in time to emergence of ag- tients) (Howard et al. 2007). After 12 weeks, the two groups itation or psychosis (Tariot et al. 2011). The study also found showed no significant differences on the Cohen-Mans- no attenuation of cognitive or functional decline, and val- field Agitation Inventory (CMAI) or other agitation scales.
proate was associated with significant toxic effects. Addi- Furthermore, adverse effects of donepezil include agita- tionally, 89 of the 313 patients in the study received MRI tion and insomnia. scans at baseline and 12 months; there was greater hippo- In a similar trial of memantine, Fox et al. (2012) randomly campal and whole brain volume loss after 1 year of treat- assigned 149 patients with moderate to severe Alzheimer's ment with divalproex versus placebo (Fleisher et al. 2011).
disease and clinically significant agitation to receive me-mantine or placebo. After 6 weeks, improvement in cogni-tion was observed, but the two groups showed no signifi- OTHER AGENTS
cant differences on the CMAI or other agitation scales.
A number of medications have been used to manage pain The efficacy of memantine for behavioral symptoms was in individuals with dementia, with the goal of reducing ag- examined in a 2008 meta-analysis that included five of six itation and other behavioral symptoms. The 2007 guide- available trials that reported NPI outcomes (Maidment et line also notes that new or worsening agitation can be a al. 2008). Patients had mild to severe Alzheimer's disease sign of untreated or undertreated pain, among other un- without significant agitation or psychosis and were being derlying medical conditions. Importantly, a randomized treated with memantine to improve cognition, not behav- controlled trial showed positive effects of adequate pain ior. The authors found a small effect size but questioned management on behavioral symptoms in 352 Norwegian whether the 1.99 point difference (p=0.041) on the NPI nursing home residents with moderate to severe dementia was clinically beneficial, especially in light of the sixth trial, and significant behavioral disturbances (Husebo et al.
which was not included in the meta-analysis but showed no 2011). A study of 3,000 mg acetaminophen daily that had significant benefit of memantine.
multiple outcomes, including behavior, social engage-ment, and emotion, reported benefit on social behavior (Chibnall et al. 2005). In contrast, other adequately de- There are no new studies since 2007 to augment the mod- signed trials of acetaminophen (Buffum et al. 2004) and est data demonstrating benefit of benzodiazepines.
vitamin D (Bjorkman et al. 2008) for pain showed no ben-efit. A meta-analysis of studies of procaine as a treatmentfor dementia found clear evidence of adverse effects and weaker evidence for benefits, suggesting that the harm of The 2007 guideline notes that there is some evidence for some pain-related interventions may outweigh the bene- modest benefit of low doses of carbamazepine in patients fits (Szatmari and Bereczki 2008).
with dementia who have agitation. There are no new data No evidence for prazosin was available to inform rec- since 2007 regarding carbamazepine. As described in the ommendations in the 2007 guideline. A pilot study of pra- 2007 guideline, carbamazepine is not recommended for zosin has now been published (Wang et al. 2009). Twenty- routine use for agitation in patients with dementia be- two patients with probable or possible Alzheimer's disease cause of weak evidence and known risks such as drug-drug and with agitation or aggression were randomly assigned interactions and poor tolerability with long-term use. to receive placebo or prazosin titrated to an average dos- Oxcarbazepine was studied in an 8-week multicenter age of about 6 mg/day. Although prazosin had some ben- randomized controlled trial in 103 patients with Alzhei- efit, available evidence was not sufficient to support use. A mer's disease with agitation and aggression (Sommer et al.
larger trial is planned by the Alzheimer's Disease Cooper- 2009). The investigators found no differences between ative Study.
oxcarbazepine and placebo. Other agents reviewed in the 2007 guideline for the The 2007 guideline also recommends against routine treatment of agitation and psychosis in dementia include use of valproate in any formulation to treat behavioral trazodone, buspirone, lithium carbonate, hormonal agents, symptoms in dementia on the basis of inconsistent results and beta-blockers. There is no new evidence since 2007 to from several randomized controlled trials. Since 2007, the support the benefit of these agents. APA Guideline Watch PHARMACOLOGICAL TREATMENTS FOR DEPRESSION There have been additional clinical trials of antidepres- studies, there were more adverse effects associated with ac- sants in dementia since 2007, but the evidence for efficacy tive treatment than placebo.
remains mixed. For example, a review and meta-analysis Overall, the evidence for the efficacy of antidepressant of seven trials with 330 subjects found that the odds ratio pharmacotherapy for people with depression and dementia for treatment response was 2.12 (95% CI 0.95–4.70; is weak, mostly because trials were underpowered and con- p=0.07) (Nelson and Devanand 2011). Most of the new ev- founded by variability in presenting symptoms, trial meth- idence comes from two relatively large trials. One trial was ods, and presence of comorbid conditions and differences conducted in 326 people with Alzheimer's disease and de- among treatments and doses used. However, as noted in the pression and failed to show benefit of either sertraline (at 2007 guideline, clinical consensus still supports undertak- a target dosage of 150 mg/day) or mirtazapine (at a target ing one or more trials of an antidepressant to treat clinically dosage of 45 mg/day) in comparison with placebo (Baner- significant and persistent depressed mood in patients with jee et al. 2011). The other trial included 135 people with dementia because of the increased rates of disability, im- Alzheimer's disease and depression and also failed to show paired quality of life, and greater mortality associated with benefit of sertraline (at a target dosage of 100 mg/day) in comparison with placebo (Rosenberg et al. 2010). In both PHARMACOLOGICAL TREATMENTS FOR APATHY The 2007 guideline describes a small amount of evidence nificant improvement in two of three efficacy outcomes that psychostimulants may aid in the treatment of severe and a trend toward improved global cognition with min- apathy in patients with dementia. Further support is pro- imal adverse events. In contrast, modafinil was not asso- vided by a 6-week, randomized, double-blind, placebo- ciated with reductions in apathy or improvements in controlled multicenter trial by Rosenberg et al. (2013), in activities of daily living in a randomized, double-blind, which 60 patients with Alzheimer's disease and apathy were placebo-controlled trial of 23 subjects who were also re- assigned to receive methylphenidate 20 mg/day or pla- ceiving stable doses of a cholinesterase inhibitor (Frakey cebo. Methylphenidate treatment was associated with sig- Since 2007, publication of a number of high-quality meta- ventions to optimize the cognitive, affective, behavioral, analyses, systematic reviews, and randomized controlled and functional capacities of persons with dementia. These trials has increased the overall quality of evidence that psy- interventions, which include caregiver education and chosocial interventions improve or maintain cognition, skills training (Gitlin 2012), can be delivered in the home function, adaptive behavior, and quality of life. The avail- and in institutional settings and constitute the foundation able research does not conclusively determine whether any of treatment for persons with Alzheimer's disease and other one intervention is more effective than another or which dementias. Although in actual practice clinicians and intervention works best for which service setting, specific caregivers use a wide array of overlapping psychosocial in- behavior, disease stage, or caregiver and patient profile.
terventions, the 2007 guideline characterizes psychosocial With the exception of possible frustration in patients who interventions as behavior-oriented, emotion-oriented, receive cognition-oriented therapies, there are no plausible cognition-oriented, and stimulation-oriented. The guide- harms associated with these interventions. Thus, despite line recommends behavior-, emotion-, and stimulation- limitations in supporting research, common sense contin- oriented approaches with moderate confidence and cog- ues to support their use in the care of all persons with de- nition-oriented approaches with less confidence. Limita- mentia, as recommended in the 2007 guideline. tions of the research reviewed in the guideline included Principles of rehabilitation, clinical practice, and re- small samples; attrition; variability in eligibility criteria, search studies also support the use of psychosocial inter- outcome measures, treatment protocols, control condi- Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
tions, and masking procedures; and uncertainty about long- tioning), higher levels of care recipients' activity engage- term benefits and the potential for translating these ap- ment, and enhanced caregiver skills and self-efficacy, al- proaches into practice. though this benefit did not persist after 9 months.
A nursing home–based clinical trial evaluated the effec- tiveness of a staff education intervention to reduce behav- BEHAVIOR-ORIENTED INTERVENTIONS
ior disorders (Deudon et al. 2009). The education and The 2007 guideline notes that behavioral interventions training program, involving 16 nursing homes and 306 have not been shown to improve the overall functioning of patients with a diagnosis of dementia, included personal- patients with dementia, although there is some evidence ized staff training, advice, and feedback as well as easily that they can lessen or eliminate specific problem behaviors carried cards with "how-to" instructions for dealing with or be somewhat beneficial for improving mood and disrup- behavioral symptoms. Compared with the usual-care con- tive behavior. Still, "with some exceptions, the limited avail- trol treatment, the active intervention significantly re- able follow-up data have suggested that the benefits do not duced global CMAI scores and the CMAI subscale scores persist beyond the duration of interventions" (American for physically nonaggressive and verbally nonaggressive Psychiatric Association, 2007). Since the 2007 guideline was behaviors at 8 weeks postbaseline. This positive effect was issued, O'Connor and colleagues (2009a) conducted two sustained 3 months after the end of the program.
systematic reviews of studies of behavior-oriented psycho-social treatments to reduce behavioral disturbances in de- EMOTION-ORIENTED INTERVENTIONS
mentia and, in a separate analysis (O'Connor et al. 2009b), Emotion-oriented treatments (e.g., supportive psycho- to reduce psychological symptoms such as anxiety and de- therapy, reminiscence therapy) aim to improve mood, pression. All studies met quality research standards (e.g., cognition, and quality of life. Logsdon et al. (2010) con- control for attention). Treatments with moderate or large ducted a large randomized controlled trial testing the effi- effect sizes for behavioral symptoms included caregiver ed- cacy of a support group program for persons with early- ucation, aromatherapy, muscle relaxation training, and pre- stage dementia and their caregivers (142 dyads). Com- ferred music. Treatments for psychological symptoms with pared with a wait-list control condition, treated persons moderate effect sizes included music and recreational ther- had improved quality of life, mood, and family communi- apies. Maintenance effects were brief, suggesting that treat- cation. Small clinical trials of reminiscence groups report ment works best in specific, time-limited situations and positive effects on these outcomes as well (Haslam et al.
when tailored to individuals' preferences. 2010; Wang et al. 2007). A meta-analysis of studies on the Brodaty and Arasaratnam (2012) conducted a meta-anal- efficacy of simulated presence (i.e., a personalized videotape ysis of studies evaluating the efficacy of interventions deliv- of family and friends) yielded limited support (Zetteler ered by family caregivers to reduce neuropsychiatric symp- 2008). No systematic reviews, however, have been con- toms. The studies represented 3,279 caregiver-recipient ducted to support or demonstrate the efficacy or risks of dyads and tested a variety of interventions, often in com- emotion-oriented treatments. bination, including skills training for caregivers (e.g., man-aging behavioral symptoms, improving communication),activity planning, home modifications, and increasing COGNITION-ORIENTED INTERVENTIONS
care recipients' participation in meaningful activities. The Cognition-oriented treatments include reality orientation interventions were effective in reducing behavioral and and cognitive stimulation, training, and rehabilitation.
psychological symptoms, with an overall effect size of 0.34 The 2007 guideline described modest improvements with (95% CI=0.20–0.48; p<0.01), as well as in improving care- some of these cognition-oriented treatments but con- giver reactions to these behaviors, with an overall effect size cluded that transient benefits may not justify the cost of of 0.15 (95% CI=0.04–0.26; p=0.006). A notable random- treatment or the risk of adverse effects, such as increased ized controlled trial of an in-home tailored activity pro- frustration in some patients. New evidence remains con- gram showed positive results in 60 patient-caregiver dyads sistent with that recommendation. (Gitlin et al. 2008). The eight-session occupational ther- Kurz et al. (2011) conducted a systematic review of ran- apy intervention customized activities to match partici- domized controlled trials evaluating cognition-focused pants' cognitive and physical capabilities and enabled interventions in participants with mild cognitive impair- caregivers to support these activities. At 4 months, com- ment or dementia and used meta-analytic strategies to cal- pared with wait-list controls, intervention participants culate effect sizes. Cognition-focused interventions con- had, according to caregiver reports, reduced frequency of ferred small and inconsistent effects on trained cognitive problem behaviors (e.g., shadowing and repetitive ques- skills, which, in some studies, translated into gains on gen- APA Guideline Watch eral cognitive ability. However, convincing evidence of 2011) found that physical activity improved physical func- clinical significance (i.e., mild short-term improvements tion (e.g., walking, timed get-up-and-go) but had uncer- in selected cognitive domains) was observed only in single tain effects on mood and quality of life. Some, but not all, trials with small sample sizes. In a single community- clinical trials of music therapy (Cooke et al. 2010; Raglio based randomized controlled trial, Clare et al. (2010) com- et al. 2008; Sung et al. 2006) report positive outcomes pared the efficacy of cognitive rehabilitation with relax- (e.g., reduced agitation), but small samples, uncertain ad- ation therapy or no treatment in 69 persons with early-stage herence to treatment protocols, and other limitations in Alzheimer's disease. The eight weekly cognitive rehabili- research methods preclude strong recommendations. On tation sessions consisted of personalized interventions to the other hand, the lack of adverse effects supports their use.
achieve participants' goals using practical aids and strate- As in the 2007 guideline, studies of multisensory stimula- gies, techniques for learning new information, practice in tion, including Snoezelen rooms, have shown mixed results, maintaining attention and concentration, and techniques and there is not enough new evidence to make conclu- for stress management. Cognitive rehabilitation pro- sions about efficacy (Klages et al. 2011; Milev et al. 2008). duced improvement in goal performance and satisfaction,whereas the control treatments were not associated withany gains. In a nursing home–based randomized con- PSYCHOSOCIAL INTERVENTIONS FOR CARE
trolled trial, Graessel et al. (2011) tested the efficacy of a DELIVERY AND END-OF-LIFE CARE
group intervention comprising motor stimulation, prac- There is moderately strong evidence supporting interven- tice in activities of daily living, and cognitive stimulation tions to improve different aspects of end-of-life care (Lorenz on cognition and function. At 12 months, compared with et al. 2008; Sampson et al. 2011), and as discussed in the usual-care, the 98 intervention participants remained sta- 2007 guideline, a palliative care referral for patients with ble in cognitive and functional capacities, whereas controls end-stage dementia should be considered. Case manage- declined. A literature review and meta-analysis of cogni- ment and coordinated care have shown encouraging but tive stimulation therapy for individuals with mild to mod- not definitive results (Callahan et al. 2006; Duru et al.
erate dementia found only a trend toward delayed cognitive 2009; Lam et al. 2010; Pimouguet et al. 2010; Spijker et al.
decline (Yuill and Hollis 2011). 2011). An integrated psychiatric nursing home programshowed positive effects on behavior (Bakker et al. 2011), STIMULATION-ORIENTED INTERVENTIONS
and implementing new nursing guidelines for depression Stimulation-oriented treatments (e.g., physical activity, showed benefit as well (Verkaik et al. 2011). High-calorie music therapy, and multisensory stimulation) create op- feeding helped maintain weight in individuals with advanced portunities for socialization; improve cognition and func- dementia, but there was no benefit of enteral tube feedings tion; and aim to reduce behavior disorders, anxiety, and (Candy et al. 2009; Hanson et al. 2011). In the aggregate, apathy. A meta-analysis of studies identified in the Co- these data support the use of interventions to improve co- chrane database (Forbes et al. 2008) found insufficient ev- ordination of care at all stages of illness and to integrate idence of effectiveness for physical activity to improve fundamental nursing precepts, particularly in more ad- cognition, function, behavior, or depression. A more re- vanced stages of dementia.
cent systematic review with meta-analysis (Potter et al.
givers' distress and burden. One such intervention, Project Providing education to the patient and his or her family Care, teaches informal caregivers specific behavioral about dementia is an important aspect of care, as noted in techniques to manage patients' neuropsychiatric symp- the 2007 guideline. Patients differ in their ability and de- toms in the home environment (Gonyea et al. 2006). In a sire to understand their diagnosis, so it is important that randomized controlled trial involving 80 caregivers, five the family understands the diagnosis and available treat- weekly sessions helped caregivers with the stress of man- ment options.
aging neuropsychiatric symptoms in patients with demen- Interventions have been designed to help informal care- tia when compared with a control intervention but did not givers manage neuropsychiatric problems in care recipi- affect caregivers' overall burden. Other studies published ents with dementia, with additional goals of reducing care- since the 2007 guideline suggest that the benefits of psy- Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
choeducation and support for caregivers are seen across that often accompany dementia is important, but there is cultures. In India, a multidisciplinary intervention with limited evidence that education alone is adequate in de- counselors and psychiatrists focused on supporting the creasing caregiver distress and burden. Consequently, inter- caregiver by providing information on dementia, helping ventions that are specifically designed for the caregiver may with management of behavioral problems in the patient, be necessary. Distress is common in those caring for pa- and prescribing psychotropic medications if needed (81 tients with dementia and may result from physical burdens, families enrolled in the trial; 41 were randomly assigned financial strain, or psychological issues such as anxiety and to the intervention; 59 completed the trial; and 18 died depression. The recommendation that clinicians be vigilant during the trial). When compared with control subjects, for distress remains unchanged from the 2007 guideline. scores on the General Health Questionnaire scale and Interventions to address caregiver distress have been Neuropsychiatric Inventory–Distress scale were signifi- developed and can have positive effects on the well-being cantly reduced in the caregivers who participated in the of caregivers. Thompson and colleagues (2007) systemat- intervention (Dias et al. 2008). Likewise, in Hong Kong, a ically reviewed interventions designed to improve overall pilot intervention was developed with a treatment pro- quality of life for people caring for someone with demen- gram consisting of 13 weekly sessions teaching cognitive- tia. Unfortunately, they found little evidence that inter- behavioral strategies to handle caregiver stress resulting ventions aimed at supporting or providing information to from disruptive behaviors of the care recipients. Twenty- caregivers individually were effective. However, they did seven female primary caregivers were randomly assigned find evidence that group-based supportive interventions to the treatment group or wait-list control group. The care- influence psychological morbidity. givers in the intervention were significantly better able to Selwood and colleagues (2007) systematically reviewed use problem-focused and emotion-focused coping strate- the effect of various psychological interventions on the psy- gies to handle the disruptive behaviors of the care recipi- chological health of caregivers. They found that six or more ents (Au et al. 2010). sessions of behavioral management therapy improved the Psychoeducational approaches have also been devel- caregivers' psychological health. Cooper and colleagues oped to help families and patients cope with decisions re- (2007) systematically reviewed interventions designed to lated to driving. Although the 2007 guideline recommends address anxiety in caregivers of people with dementia. They that the risks of driving be discussed with patients with de- found a paucity of randomized controlled trials directly tar- mentia and their families, restrictions on driving can pro- geting anxiety. One of the few studies meeting inclusion duce significant stress. Family caregivers must frequently criteria reported reduced anxiety in caregivers who re- make the final decision to restrict a cognitively impaired ceived CBT and relaxation-based interventions.
loved one from driving. However, they are often reluctant Interventions designed to help family caregivers with to do so. Stern and colleagues (2008) developed a group in- care planning, such as Tailored Caregiver Assessment and tervention consisting of four 2-hour manualized educational Referral (Kwak et al. 2011), have been found to often have support group meetings to assist caregivers in addressing a positive effect on caregiver stress, burden, and depres- patients' driving issues. Two months after the intervention sive symptoms. Interventions directly targeting depres- was completed, a battery of self-report and interview-based sion in caregivers have also been shown to be beneficial.
questionnaires showed that caregivers in the intervention One study assessed the efficacy of a 12-session cognitive- group (n = 31) scored significantly higher on self-efficacy, behavioral therapy–based program for improving caregiv- communication, and preparedness than participants who ers' dysfunctional thoughts. This intervention improved were assigned to a control condition (31 participants re- both dysfunctional thoughts and depressive symptoms in ceived written materials only after a pretest; 12 participants the caregivers participating in the study (Losada et al. 2010; received written materials after a posttest). This type of Marquez-Gonzalez et al. 2007). Technology-based psy- assistance for caregivers may reduce their stress in ad- choeducational interventions for family caregivers have dressing issues related to their cognitively impaired loved also been found to reduce levels of depression in caregiv- one's driving, but the sample size was small and the inter- ers (Finkel et al. 2007).
vention is not widely available.
In addition to affecting emotional health, caregiving has an impact on physical well-being and sleep. A ran-domized controlled trial by Hirano and colleagues (2011) assessed the influence of regular exercise, defined as three Educating the patient and family about dementia, the stages exercise sessions per week for 12 weeks, on subjective sense of progression of the illness, and the associated symptoms of burden and physical symptoms in a community-based APA Guideline Watch caregiver sample in 31 elderly caregivers. They found de- NURSING HOME PLACEMENT
creased caregiver burden and frequency of feeling fatigued Despite resources and programs available for caregivers as well as an improvement in self-reported quality of sleep.
managing loved ones with dementia at home, many care- Elliott and colleagues (2010) developed a structured mul- givers are unable to prevent institutionalizing the patient.
ticomponent skills training intervention, Resources for The 2007 guideline notes that psychiatrists can be a valu- Enhancing Alzheimer Caregiver Health. In a randomized, able resource in assisting patients and caregivers with de- multisite clinical trial involving 495 dementia caregiver cisions about nursing home placement, and some new and recipient dyads, caregivers reported improved self- research provides continuing support. In a randomized rated health, quality of sleep, and both physical and emo- controlled trial, Gaugler and colleagues (2008) provided tional well-being. enhanced counseling and support to 406 spouse caregiv- Other research suggests that patients who are trained ers of persons with Alzheimer's disease during transition in a memory compensation strategy have greater indepen- to a nursing home and followed the spouse caregivers for dence and require less care. In a randomized trial, Green- up to 16 years. After six supportive counseling group ses- away et al. (2013) trained individuals with mild cognitive sions followed by ongoing ad hoc telephone counseling, impairment and their care partners in the use of a note- the burden and depressive symptoms in caregivers in the book/calendar system to help compensate for their mem- intervention program were significantly lower than those ory difficulties. At follow-up, the calendar training group in a usual-care control group, both before and after insti- (n=20) demonstrated significantly improved function in tutionalization. Spijker et al. (2008) conducted a system- memory-dependent daily activities compared with con- atic review with meta-analysis of high-quality studies, with a trols (n=20). They also had improvement in memory self- total of 9,043 patients, on the impact of caregiver support efficacy. Moreover, mood improved for care partners of programs on delaying institutionalization and found that the notebook/calendar trainees, whereas caregiving bur- these programs reduced the odds of institutionalization den worsened for control group partners over time.
(odds ratio =0.60, 95% CI =0.43–0.85; p=0.004). Com-pared with ineffective interventions, effective programs REFERRAL FOR CARE AND SUPPORT
allowed greater caregiver involvement in choosing among Caring for a family member with dementia can be over- treatment options for their family member.
whelming; thus, the 2007 guideline recommends that cli- Nursing home placement of a family member with de- nicians refer family members to appropriate sources of mentia often leads to stress and guilt for the caregiver.
care and support. There are a number of community- Helping family caregivers adjust to the change and main- based support services for caregivers; however, a connec- tain a good working relationship with the nursing home tion between these services and the professional medical staff is important. In a study by Davis and colleagues (2011) services available is often lacking. Fortinsky and colleagues assessing a telephone-based psychosocial intervention, (2009) designed a process to improve collaboration between caregivers were randomly assigned to the group receiving primary care physicians and community-based support 10 telephone contacts over 3 months (n=24) or to a non- services. Eighty-four caregivers participated in total, and contact control group (n=22). Those in the intervention randomization was based on the patient's primary care group showed a reduction in feelings of guilt related to physician. Dementia care consultants located at an Alz- the nursing home placement and more positive percep- heimer's Association chapter provided individualized tion of the nursing home staff compared with controls. In counseling and support over a 12-month period to caregiv- a randomized controlled trial, Robison and colleagues ers in the intervention group and sent copies of the care (2007) studied a nursing home–based intervention for 384 plans to the referring primary care physicians. Although family members of residents with dementia and 384 staff no significant benefit to caregivers was reported in the in- members recruited from 20 nursing homes. Training ses- tervention group as compared with controls, the caregiv- sions for improved communication and conflict resolu- ers did report a greater satisfaction with the intervention tion individually and jointly with families and staff re- and felt more equipped to manage the patient's behavior.
sulted in positive outcomes. Both the families and the staff Only 27% of those in the intervention group reported dis- believed communication improved, families were more cussing these care plans with their physicians, but nursing involved in the nursing home care, and nursing home staff home placement was less likely for patients whose caregiv- experienced less depression and burnout compared with ers were in the intervention group. the control group. Guideline Watch for the Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias
ALTERNATIVE TREATMENTS The past decade has seen widespread interest in dietary, comparison with the placebo group. All-cause mortality nutraceutical, and alternative medication therapies for and safety analyses showed a difference only on the serious Alzheimer's disease and other dementias. Many of these adverse event of "infections or infestations," with greater studies lack rigor and are plagued by the lack of a specified frequencies in the memantine (31 events in 23 participants) primary a priori outcome, multiple outcomes (often across and combination groups (44 events in 31 participants) com- domains of cognition, behavior, and function), lack of pared with the placebo group (13 events in 11 participants).
power to exclude type 2 error, and lack of randomization or Patients taking warfarin were excluded from the study. a placebo comparison group. There is not enough defini- Ginkgo biloba has been widely studied since publica- tive new evidence to warrant a change to the 2007 guideline tion of the guideline, with both positive (Ihl et al. 2010; statement that alternative agents are not generally recom- Napryeyenko and Borzenko 2007) and negative (McCar- mended because of uncertain efficacy and safety. ney et al. 2008) findings. Two Cochrane reviews, one pub- Although cohort and case control studies have found lished in 2007 (Birks and Grimley Evans 2007) and an up- Mediterranean diet, elevated homocysteine, and greater dated review in 2009 (Birks and Grimley Evans 2009), intake of fish or fatty acids and folate to be associated with found the evidence for ginkgo biloba in individuals with lower dementia incidence, no adequately designed pro- cognitive impairment or dementia to be inconsistent and spective trial has demonstrated cognitive benefit in indi- unreliable. Studies assessing whether ginkgo biloba pre- viduals with Alzheimer's disease or other dementias (Aisen vents cognitive decline or dementia have also shown no et al. 2008a; Kwok et al. 2011). Dangour et al. (2010) stated benefit (DeKosky et al. 2008; Snitz et al. 2009; Vellas et al.
that "the available evidence is insufficient to draw definitive 2012). A single, small randomized controlled trial of saf- conclusions on the association of B vitamins and fatty acids fron (Akhondzadeh et al. 2010) showed benefit on the with cognitive decline or dementia" (p. 205). Other reviews ADAS-Cog. One randomized controlled trial of soybean- of B vitamins and antioxidants (Jia et al. 2008), homocys- derived phosphatidylserine in elderly patients with mild teine-lowering B-vitamin supplementation (Balk et al.
cognitive impairment showed some preliminary evidence 2007; Ford and Almeida, 2012) and omega-3 fatty acids for memory improvement, but more research is needed (Issa et al. 2006) have come to similar conclusions. A meta- (Kato-Kataoka et al. 2010). analysis of trials of omega-3 fatty acids also found no effect Trials of melatonin for cognitive and noncognitive symp- on cognition in participants (Mazereeuw et al. 2012). toms have provided insufficient evidence of clinical effi- In the 2007 guideline, vitamin E was not recommended cacy and safety (De Jonghe et al. 2010; Jansen et al. 2006).
for the treatment of cognitive symptoms of dementia be- Studies indicated that vitamin D2 (Stein et al. 2011), oral cause of safety concerns and limited evidence for efficacy.
copper (Kessler et al. 2008), docosahexaenoic acid (Quinn Nevertheless, the guideline also noted that some physicians et al. 2010), and Huperzine A (Rafii et al. 2011; Xu et al.
and their patients may elect to use vitamin E after consid- 2012) did not improve cognition. Reviews of selenium (Loef ering its potential risks and benefits. More recently, possi- et al. 2011) and ginseng (Lee et al. 2009b) also found no ev- ble benefit for vitamin E was found in a double-blind, pla- idence for efficacy.
cebo-controlled, randomized clinical trial involving 613 Trials of multiple medical foods for cognition in demen- patients with mild to moderate Alzheimer's disease at 14 tia, including yamabushitake mushroom extract (Mori et Veterans Affairs medical centers (Dysken et al. 2014). Par- al. 2009) and yi-gan san [yokukan in Japanese] (Iwasaki et ticipants received either 2,000 IU/day of alpha-tocopherol al. 2005; Mizukami et al. 2009; Okahara et al. 2010), did (n=152), 20 mg/day of memantine (n = 155), the combi- not show cognitive benefits. No adverse effects were ob- nation (n=154), or placebo (n=152). Data from 52 partic- served in these studies. ipants were excluded from analysis because of lack of fol- Since 2007, systematic reviews of available literature low-up. Among those patients with mild to moderate AD, found no consistent benefit of shiatsu or acupressure (Lee 2,000 IU/day of alpha-tocopherol compared with placebo et al. 2009a; Robinson et al. 2011); of reflexology, despite resulted in a slower functional decline of 6.2 months at some encouraging small studies (Burns et al. 2011; Ernst mean follow-up of 2.27 years. Caregiver burden also de- 2009; Ernst et al. 2011; Hodgson and Andersen 2008; Lin creased, but no significant differences were observed for et al. 2007); of transcranial magnetic stimulation, despite other outcomes. Furthermore, there were no significant some positive smaller studies (Ahmed et al. 2012; Cotelli differences in any outcomes for the groups receiving me- et al. 2011; Freitas et al. 2011); of cranial electrical stimu- mantine alone or memantine plus alpha-tocopherol in lation (Rose et al. 2009); or of peripheral electrical stimu- APA Guideline Watch lation (Scherder et al. 2007). However, a pilot study of a lessness but not for aggression in nursing home patients multimodal intervention consisting of Taiji exercises, cog- with dementia (Hawranik et al. 2008; Woods et al. 2009). nitive-behavioral therapies, and support group participa- Taken together, the evidence supporting most of these tion showed encouraging results in patients with mild de- alternative management strategies is not sufficient to war- mentia (Burgener et al. 2008). In addition, a relatively large rant their routine adoption, but future evidence could study of therapeutic touch showed positive results for rest- change this perspective.
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Helicobacter pylori infection and the use of nsaids

Best Practice & Research Clinical Gastroenterology Vol. 15, No. 5, pp. 775±785, 2001 doi:10.1053/bega.2001.0234, available online at on6 Helicobacter pylori infection and the use of Franco Bazzoli MDLuca De Luca MD Department of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S. Orsola, Italy David Y. Graham* MDDepartment of Medicine, Veterans' A€airs Medical Center and Baylor Col ege of Medicine, Houston, Texas,

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Translating cell biology intotherapeutic advancesin Alzheimer's diseaseDennis J. Selkoe Studies of the molecular basis of Alzheimer's disease exemplify the increasingly blurred distinction between basic andapplied biomedical research. The four genes so far implicated in familial Alzheimer's disease have each been shown toelevate brain levels of the self-aggregating amyloid-b protein, leading gradually to profound neuronal and glialalteration, synaptic loss and dementia. Progress in understanding this cascade has helped to identify specifictherapeutic targets and provides a model for elucidating other neurodegenerative disorders.