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Original Contribution |

A 24-Week Open-Label Extension Study of Memantine in Moderate to Severe Alzheimer Disease FREE

Barry Reisberg, MD; Rachelle Doody, MD, PhD; Albrecht Stöffler, MD; Frederick Schmitt, PhD; Steven Ferris, PhD; Hans Jörg Möbius, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, New York University School of Medicine, New York (Drs Reisberg and Ferris); Department of Neurology, Baylor College of Medicine, Houston, Tex (Dr Doody); Merz Pharmaceuticals GmbH, Frankfurt, Germany (Drs Stöffler and Möbius); Departments of Neurology and Psychiatry, Sanders-Brown Center on Aging, University of Kentucky, Lexington (Dr Schmitt).


Arch Neurol. 2006;63(1):49-54. doi:10.1001/archneur.63.1.49.
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Published online

Background  This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of memantine in 252 patients with moderate to severe Alzheimer disease.

Objective  To evaluate long-term memantine treatment in moderate to severe Alzheimer disease.

Design, Setting, and Patients  Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting.

Intervention  Twenty mg of memantine was given daily.

Main Outcome Measures  Efficacy assessments from the double-blind study were continued and safety parameters were monitored.

Results  Patients who switched to memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period (P<.05). The completion rate for the extension phase of the study was high (78%) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study.

Conclusion  These results extend previous findings that demonstrated the efficacy and safety of memantine in the treatment of patients with moderate to severe Alzheimer disease.

Figures in this Article

Alzheimer disease (AD) is a progressive neurodegenerative disorder that afflicts millions of people worldwide. Cholinesterase inhibitors are regarded as the standard of care for the symptomatic treatment of mild to moderate AD,1 but there is only 1 published study on cholinesterase inhibitors that specifically included patients with more advanced AD.2

Various mechanisms may contribute to neurodegeneration in AD, including glutamate-mediated excitotoxicity.3 While normal glutamatergic neurotransmission is required for learning and memory processes, excessive glutamatergic activity may cause neuronal dysfunction and eventually degeneration. This excitotoxic effect appears to be mediated, in part, by the N-methyl-D-aspartate receptor.4

Memantine is a mild- to moderate-affinity, uncompetitive, voltage-dependent N-methyl-D-aspartate receptor antagonist with rapid-gating kinetics.4 In 2003, memantine was approved in the United States for the treatment of moderate to severe AD and memantine is also available in the European Union and Australia.

We previously reported results of a 28-week, double-blind, placebo-controlled trial in the United States on outpatients with moderate to severe AD.40433 Memantine treatment resulted in significant benefits compared with placebo in global, functional, and cognitive assessments. In addition, memantine treatment of patients with moderate to severe AD receiving stable doses of donepezil was found to be safe and efficacious.6 Memantine treatment has also shown cognitive benefit in clinical studies on mild to moderate vascular dementia7,8 and efficacy in a study on patients who were severely demented and institutionalized.9

This study evaluated the effects of memantine treatment over a longer time period than previously reported in moderate to severe AD. The majority of patients who completed the 28-week, double-blind study5 were observed for an additional 24 weeks, during which all patients received open-label memantine treatment.

PATIENTS

Thirty centers in the United States enrolled patients to receive open memantine treatment for 24 weeks on completion of a 28-week, double-blind phase.5 At the start of the double-blind phase, patients had to meet criteria for dementia as specified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and for probable AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association, including a recent computerized tomographic scan or a magnetic resonance imaging scan compatible with an AD diagnosis. Furthermore, entry criteria included (1) age of 50 years or older, (2) Mini-Mental State Examination scores of 3 to 14,10 (3) Global Deterioration Scale stages 5 or 6,11 and (4) Functional Assessment Staging score of 6a or greater.12 Participants were also required to have adequate vision and hearing for neuropsychological testing and a reliable caregiver or informant.

STUDY DESIGN

All patients, including participants who had received memantine during the double-blind phase, switched directly from double-blind treatment to an initial dose of 5 mg of memantine daily and were titrated upward (weekly increases of 5 mg/d) to the maintenance dose of 20 mg/d (10 mg twice daily). This procedure maintained the blinding for the treatment assignment during the double-blind phase. Memantine tablets were administered orally for 24 weeks in the open-label phase. Patients were taken off the study medication if, in the opinion of the treating physician, continued treatment posed a potential medical risk or if patients or their caregivers withdrew consent. The study procedures were in accord with the principles in the Helsinki Declaration of 1975 and its amendments. The relevant institutional review boards approved the study protocol.

EFFICACY EVALUATION

The primary efficacy measures used in the double-blind phase and continued in the extension phase were the change in the 19-item Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale modified for severe dementia13,14 and the New York University version of the Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-Plus), which evaluates change in patients' overall condition between baseline and follow-up.15

Efficacy measures further included a specific cognitive assessment, the Severe Impairment Battery (SIB),16,17 as well as Mini-Mental State Examination,10 Functional Assessment Staging,12 Global Deterioration Scale,11 and Neuropsychiatric Inventory.18

Efficacy assessments were conducted at initiation of the open-label extension (corresponding to the final week 28 visit of the lead-in, double-blind study) and at weeks 40 and 52.

SAFETY EVALUATION

Assessment of safety included reports of adverse events, laboratory examinations (chemistry, hematology, and urinalysis), and vital sign measurements. The World Health Organization Adverse Reaction Terminology dictionary19 was used to code adverse events.

DATA ANALYSIS

All available data for patients who entered the open-label phase were used for an observed cases analysis from week 0 to week 52, without replacement of missing data. In the protocol of the open-treatment extension period, a descriptive data analysis was planned that did not include statistical testing.

A descriptive statistical analysis was performed for the primary efficacy assessments ADCS-ADL and CIBIC-Plus, as well as for the specific cognitive instrument (the SIB), by using log sample z tests. The mean rates of change during the double-blind period (week 0-28) were compared with the mean rates of change in the open label period for the 3 assessments. All P values reported are 2-sided.

Safety analyses were performed on the safety population, which included all patients who received at least 1 dose of study medication during the open-label period.

PATIENT CHARACTERISTICS

Of 181 patients who completed the 28-week, double-blind phase, 80 patients treated with placebo and 95 patients treated with memantine opted to enter the open-label extension. Patient flow through the study is shown in Figure 1. Patients who received placebo during the double-blind phase are hereafter referred to as the PLA-MEM group, and patients who were treated with memantine in the double-blind phase are hereafter referred to as the MEM-MEM group.

Place holder to copy figure label and caption
Figure 1.

Progression of subjects from completion of the double-blind phase to completion of the open-label extension. Asterisk indicates that some patients discontinued for multiple reasons. AE indicates adverse event.

Graphic Jump Location

At the baseline visit of the double-blind phase (week 0), demographic characteristics were similar for the PLA-MEM and the MEM-MEM treatment groups (Table 1).

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics for Enrolled Open-Label Population at Baseline

A total of 11 patients (6 PLA-MEM and 5 MEM-MEM) received, at any time during the extension period, treatment using a cholinesterase inhibitor. Furthermore, 28 patients switched to treatment using a cholinesterase inhibitor at the end of the extension study.

EFFICACY
ADCS-ADL Scores

Mean changes in the ADCS-ADL score from the start of the double-blind period to the end of the open-label phase are presented in Figure 2 and Table 2.

Place holder to copy figure label and caption
Figure 2.

Mean (SEM) change from baseline (week 0) on the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale modified for moderate to severe dementia by treatment week (observed cases analysis). In Figures 2, 3, and 4, double-blind data include only patients who entered the open-label extension and the dotted line represents the projected mean rate of change from week 0 to week 28 (observed cases analysis).

Graphic Jump Location
Table Graphic Jump LocationTable 2. Mean Change in Scores From Initiation of Study Treatment to Week 52 for Major Efficacy Assessments (OC Analysis)

For patients in the PLA-MEM group, switching to memantine treatment resulted in a significantly slower rate of decline during the open-label phase on the ADCS-ADL compared with the mean rate of decline during the double-blind period (weeks 0-28) (P = .021). The rate of decline for the MEM-MEM group, however, was faster during the open-label period than the double-blind period (P = .035).

CIBIC-Plus Ratings

The CIBIC-Plus mean ratings of change from initiation of the double-blind phase to week 52 are presented in Figure 3 and Table 2. Overall, at week 52, an identical percentage of patients (51%) treated with PLA-MEM and patients treated with MEM-MEM had a mean rating of change score of 4 or better (indicating no change or improvement from week 0).

Place holder to copy figure label and caption
Figure 3.

Global score on the Clinician's Interview-Based Impression of Change plus caregiver interview by treatment week (observed cases analysis).

Graphic Jump Location

Switching to memantine treatment significantly decreased the rate of decline on the CIBIC-Plus compared with the mean rate of placebo decline during the double-blind period (P<.001). The rate of decline for the MEM-MEM group during the open-label phase was also significantly slower during the open-label period than during the entire double-blind period (P<.001).

SIB Scores

The mean changes in SIB scores from weeks 0 to 52 are presented in Figure 4 and Table 2.

Place holder to copy figure label and caption
Figure 4.

Mean change from baseline (week 0) on the Severe Impairment Battery by treatment week (observed cases analysis).

Graphic Jump Location

The rate of decline from week 28 to week 52 on the SIB for patients in the PLA-MEM group was significantly less than the projected rate of decline from the double-blind period (P = .049). The rate of decline for the MEM-MEM group during the open-label phase did not differ significantly from the mean rate during the double-blind memantine-treatment period (P = .086).

SAFETY

The most commonly reported adverse events (AEs) during the extension study are listed in Table 3. Overall, the types of AEs reported were consistent with observations from the double-blind phase.5

Table Graphic Jump LocationTable 3. Most Frequently Reported Treatment-Emergent Adverse Events During the Open-Label Extension Phase

The majority of AEs for both treatment groups were considered either mild or moderate in severity (88% and 87% of patients, respectively). Adverse events that fulfilled criteria as serious events were reported by 27 (15%) of the 175 patients in the open-label extension (only 4 of these patients had AEs judged to be possibly related to administration of study medication). This serious event frequency was similar to that noted in the double-blind study.5

There were no clinically meaningful differences in changes from the study baseline (week 0) in vital signs or laboratory parameters for either of the 2 treatment groups.

This open-treatment extension provides further efficacy and safety data that add to the findings of the double-blind phase of the study.5

A strength of this study is the continuation of the same efficacy measures used in the double-blind phase. We were therefore able to continue to examine the clinically relevant domains that show deterioration with AD progression. During the open memantine treatment phase (weeks 28-52), observations by both clinicians and caregivers (ADCS-ADL, CIBIC-Plus) as well as a measurement of cognition (SIB) indicated that treatment initiation with memantine was effective. The benefits of memantine seen in the double-blind phase were again observed when patients treated with placebo were switched to memantine treatment in the open extension. For the patients who were randomized to memantine treatment during the double-blind phase, these clinically relevant benefits also appeared to be maintained in sum; compared with the double-blind period, decline was faster for the ADCS-ADL and slower for the CIBIC-Plus, with no significant change on the SIB. Patients who were untreated (baseline Mini-Mental State Examination scores of 0-15 in the ADCS instrument study) experienced greater mean annual declines on the SIB17 and on the ADCS-ADL (unpublished data, Douglas Galasko, MD, 2002) than both the PLA-MEM and MEM-MEM groups in this study.

Whether open treatment extension studies show disease-modifying properties (in contrast to symptomatic effects) is often linked to the question of whether patients switching from placebo to active treatment catch up with those who continued on active treatment. Our data indicate that patients treated with PLA-MEM did not completely catch up in the ADCS-ADL or the SIB, but did nearly catch up in the CIBIC-Plus ratings. Definitive conclusions regarding this differentiation require prospective, randomized, double-blind trials.

Memantine treatment was safe and well tolerated during the course of the study and the safety profile in the open-label phase was similar in both the PLA-MEM and the MEM-MEM patient groups. Adverse events noted with the administration of memantine were consistent with previous observations, including an earlier study on patients with severe AD and vascular dementia9 and studies in vascular dementia.7,8 The high patient retention rate (78% overall) during this open-label study supported the good tolerability of memantine. It might be useful for future investigations to examine the efficacy of memantine in earlier stages of AD and other forms of dementia.

Correspondence: Barry Reisberg, MD, William and Sylvia Silberstein Aging and Dementia Research and Treatment Center, New York University School of Medicine, 550 First Ave, New York, NY 10016 (barry.reisberg@med.nyu.edu).

Accepted for Publication: May 16, 2005.

Author Contributions:Study concept and design: Reisberg, Doody, Stöffler, Schmitt, Ferris, and Möbius. Acquisition of data: Reisberg, Doody, Schmitt, and Ferris. Analysis and interpretation of data: Reisberg, Stöffler, Schmitt, and Möbius. Drafting of the manuscript: Reisberg, Stöffler, and Möbius. Critical revision of the manuscript for important intellectual content: Reisberg, Doody, Schmitt, and Ferris. Statistical analysis: Schmitt. Obtained funding: Reisberg. Administrative, technical, and material support: Reisberg, Stöffler, Ferris, and Möbius. Study supervision: Reisberg and Ferris.

The Memantine Study Group: Jeffrey T. Apter, MD, Princeton Biomedical Research, Princeton, NJ; Barry Baumel, MD, Baumel-Eisner Neuromedical Institute, Fort Lauderdale, Fla; Charles Bernick, MD, Nevada School of Medicine, Las Vegas, Nev; John S. Carman, MD, Carman Research, Smyrna, Ga; Jody Corey-Bloom, MD, PhD, Department of Neurosciences, University of California, San Diego; Howard Cummins, PhD, Institute for Advanced Clinical Research, Elkins Park, Pa; Charles DeCarli, MD, University of Kansas Medical Center, Kansas City, Kan; Ranjan Duara, MD, Wien Center for Alzheimer's Disease, Miami Beach, Fla; Eugene DuBoff, MD, Denver Center for Medical Research, Denver, Colo; Neil Edwards, MD, University of Tennessee, Memphis; Larry Eisner, MD, Baumel-Eisner Neuromedical Institute, Fort Lauderdale, Fla; Martin R. Farlow, MD, Indiana University Center for Alzheimer's Disease, Indianapolis; Stephen Flitman, MD, Neurology Group Ltd, Phoenix, Ariz; Ari Kiev, MD, Life Span Develop Mental Systems, Poughkeepsie, NY; Louis C. Kirby II, MD, Pivotal Research Centers, Peoria, Ariz; David Margolin, MD, Fresno, Calif; Charles Merideth, MD, Affiliated Research Institute, San Diego, Calif; Jacobo E. Mintzer, MD, Alzheimer's Research & Clinical Program, Charleston, SC; Eric Pfeiffer, MD, University of South Florida Suncoast Gerontology Center, Tampa; Ralph Richter, MD, St. John's Doctors Building, Tulsa, Okla; Carl H. Sadowsky, MD, Premiere Research Institute, West Palm Beach, Fla; Paul Solomon, PhD, The Memory Clinic, Bennington, Vt; Steven Targum, MD, Clinical Studies, Wayne, Pa; Harvey A. Tilker, PhD, Four Rivers Clinical Research, Paducah, Ky; Mahmood Usman, MD, Alzheimer's Center of Pittsburgh, Pittsburgh, Pa.

Financial Disclosure: Dr Reisberg has received honoraria and travel support for lectures from Merz Pharmaceuticals and Lundbeck, distributors of memantine in various worldwide jurisdictions. He has also received grant support from Forest Laboratories and has served as a consultant to Merz Pharmaceuticals. Dr Doody has received compensation for consulting services and honoraria for lectures from Forest Laboratories. Drs Stöffler and Möbius are full-time employees at Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany. Dr Schmitt has been a speaker for Pfizer, consulted for Forest Laboratories, Pfizer, and Wyeth, and received grant support from Pfizer and Forest Laboratories (ongoing clinical trials with Dr Schmitt as a subinvestigator). Dr Ferris has been an investigator, consultant, and paid speaker for Forest Laboratories, and a consultant and paid speaker for Merz Pharmaceuticals and Lundbeck Pharmaceuticals.

Funding/Support: This study was funded by Merz Pharmaceuticals GmbH, Frankfurt, Germany. Development of measurements used in this study was supported by grants AG-03051, AG-08051, and I-U02 AG-10483 from the National Institute of Aging of the US National Institutes of Health.

Acknowledgments: We thank Wei Zhu, PhD, New York University School of Medicine, for the statistical analysis of the data.

Doody  RSStevens  JCBeck  C  et al.  Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;561154- 1166
PubMed
Feldman  HGauthier  SHecker  JVellas  BSubbiah  PWhalen  E A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57613- 620
PubMed
Olney  JWWozniak  DFFarber  NB Excitotoxic neurodegeneration in Alzheimer disease: new hypothesis and new therapeutic strategies. Arch Neurol 1997;541234- 1240
PubMed
Parsons  CGDanysz  WQuack  G Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 1999;38735- 767
PubMed
Reisberg  BDoody  RStöffler  ASchmitt  FFerris  SMöbius  HJ Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;3481333- 1341
PubMed
Tariot  PNFarlow  MRGrossberg  GTGraham  SMMcDonald  SGergel  I Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291317- 324
PubMed
Orgogozo  JMRigaud  ASStöffler  AMöbius  HJForette  F Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;331834- 1839
PubMed
Wilcock  GMöbius  HJStöffler  A A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002;17297- 305
PubMed
Winblad  BPoritis  N Memantine in severe dementia: results of the M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14135- 146
PubMed
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;1391136- 1139
PubMed
Sclan  SGReisberg  B Functional Assessment Staging (FAST) in Alzheimer's disease: reliability, validity, and ordinality. Int Psychogeriatr 1992;4(Suppl 1)55- 69
PubMed
Galasko  DBennett  DSano  M  et al.  An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11(Suppl 2)S33- S39
PubMed
Galasko  DRSchmitt  FAJin  S  et al.  Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer's disease. Neurobiol Aging 2000;21(Suppl 1)S168
Reisberg  BSchneider  LDoody  R  et al.  Clinical global measures of dementia: position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11(Suppl 3)8- 18
PubMed
Panisset  MRoudier  MSaxton  JBoller  F Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994;5141- 45
PubMed
Schmitt  FAAshford  WErnesto  CBoller  F The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11(Suppl 2)S51- S56
PubMed
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DAGornbein  J The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMed
World Health Organization The WHO Adverse Reaction Terminology.  Uppsala, Sweden: UMC Products, 1997/Q3

Figures

Place holder to copy figure label and caption
Figure 1.

Progression of subjects from completion of the double-blind phase to completion of the open-label extension. Asterisk indicates that some patients discontinued for multiple reasons. AE indicates adverse event.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean (SEM) change from baseline (week 0) on the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale modified for moderate to severe dementia by treatment week (observed cases analysis). In Figures 2, 3, and 4, double-blind data include only patients who entered the open-label extension and the dotted line represents the projected mean rate of change from week 0 to week 28 (observed cases analysis).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Global score on the Clinician's Interview-Based Impression of Change plus caregiver interview by treatment week (observed cases analysis).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Mean change from baseline (week 0) on the Severe Impairment Battery by treatment week (observed cases analysis).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics for Enrolled Open-Label Population at Baseline
Table Graphic Jump LocationTable 2. Mean Change in Scores From Initiation of Study Treatment to Week 52 for Major Efficacy Assessments (OC Analysis)
Table Graphic Jump LocationTable 3. Most Frequently Reported Treatment-Emergent Adverse Events During the Open-Label Extension Phase

References

Doody  RSStevens  JCBeck  C  et al.  Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;561154- 1166
PubMed
Feldman  HGauthier  SHecker  JVellas  BSubbiah  PWhalen  E A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57613- 620
PubMed
Olney  JWWozniak  DFFarber  NB Excitotoxic neurodegeneration in Alzheimer disease: new hypothesis and new therapeutic strategies. Arch Neurol 1997;541234- 1240
PubMed
Parsons  CGDanysz  WQuack  G Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 1999;38735- 767
PubMed
Reisberg  BDoody  RStöffler  ASchmitt  FFerris  SMöbius  HJ Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;3481333- 1341
PubMed
Tariot  PNFarlow  MRGrossberg  GTGraham  SMMcDonald  SGergel  I Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291317- 324
PubMed
Orgogozo  JMRigaud  ASStöffler  AMöbius  HJForette  F Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;331834- 1839
PubMed
Wilcock  GMöbius  HJStöffler  A A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002;17297- 305
PubMed
Winblad  BPoritis  N Memantine in severe dementia: results of the M-Best Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14135- 146
PubMed
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;1391136- 1139
PubMed
Sclan  SGReisberg  B Functional Assessment Staging (FAST) in Alzheimer's disease: reliability, validity, and ordinality. Int Psychogeriatr 1992;4(Suppl 1)55- 69
PubMed
Galasko  DBennett  DSano  M  et al.  An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11(Suppl 2)S33- S39
PubMed
Galasko  DRSchmitt  FAJin  S  et al.  Detailed assessment of cognition and activities of daily living in moderate to severe Alzheimer's disease. Neurobiol Aging 2000;21(Suppl 1)S168
Reisberg  BSchneider  LDoody  R  et al.  Clinical global measures of dementia: position paper from the International Working Group on Harmonization of Dementia Drug Guidelines. Alzheimer Dis Assoc Disord 1997;11(Suppl 3)8- 18
PubMed
Panisset  MRoudier  MSaxton  JBoller  F Severe impairment battery: a neuropsychological test for severely demented patients. Arch Neurol 1994;5141- 45
PubMed
Schmitt  FAAshford  WErnesto  CBoller  F The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer's disease. Alzheimer Dis Assoc Disord 1997;11(Suppl 2)S51- S56
PubMed
Cummings  JLMega  MGray  KRosenberg-Thompson  SCarusi  DAGornbein  J The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;442308- 2314
PubMed
World Health Organization The WHO Adverse Reaction Terminology.  Uppsala, Sweden: UMC Products, 1997/Q3

Correspondence

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