Table 1. Characteristics of included trials.
| Study | Total n | Patients | Diagnosis | Duration | Age (years) (mean ± SD) | Male, % | Race (%) | Drug | n | Dose (mg/day) | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Reisberg 2003 (USA), industry | 252 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 28 weeks | 76.1 ± 8.07 | MEM: 28, PLA: 37 | MEM: White 89, Black 4, Other 7, PLA: White 91, Black 5, Other 4 | MEM | 126 | MEM 20 mg | MEM > PLA: SIB, ADCS-ADL (sev), FAST, MEM = PLA: CIBIC-Plus, MMSE, GDS, NPI |
| Inclusion: age ≥50 years, MMSE 3–14, GDS 5–6, FAST ≥ 6a, MRI or CT consistent with a diagnosis of probable AD (within 12 months) | |||||||||||
| Exclusion: any neurodegenerative disorder or MDD other than AD, modified HIS <4, clinically significant coexisting medical conditions or laboratory abnormalities, receiving specific concomitant medications (anticonvulsant, antiparkinsonian, hypnotic, anxiolytic, neuroleptic, cholinomimetic, or any other investigational compounds) | PLA | 126 | PLA | ||||||||
| Peskind 2006 (USA), industry | 403 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA | 24 weeks | MEM: 78.0 ± 7.3, PLA: 77.0 ± 8.2 | MEM: 40, PLA: 43 | MEM: White 92, Other 8, PLA: White 91, Other 9 | MEM | 201 | MEM 20 mg (fixed dose) | MEM > PLA: ADAS-cog, CIBIC-Plus, NPI, MEM = PLA: ADCS-ADL23 |
| Inclusion: MMSE 10–22, age ≥50 years, MRI or CT consistent with a diagnosis of probable AD (within 12 months), MADRS <22 | PLA | 202 | PLA | ||||||||
| Exclusion: significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular disease; clinically significant B12 or folate deficiency; evidence of any psychiatric or neurological disorder other than probable AD; HIS <4; screening; delusions or delirium (DSM-IV); treatment with a depot neuroleptic within 6 months of screening; previous treatment with MEM; treatment within 30 days of screening with a ChEI or any investigational drug | |||||||||||
| Study | Total n | Patients | Diagnosis | Duration | Age (years) (mean ± SD) | Male, % | Race (%) | Drug | n | Dose (mg/day) | Outcomes |
| van Dyck 2007 (USA), industry | 350 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA | 24 weeks | MEM: 78.1 ± 8.2, PLA: 78.3 ± 7.6 | MEM: 27.5, PLA: 29.7 | MEM: White 80, Other 20, PLA: White 82, Other 18 | MEM | 178 | MEM 20 mg | MEM = PLA: SIB, ADCS-ADL19, CIBIC-Plus, NPI, BGP, FAST |
| Inclusion: MMSE 5–14, age ≥50 years, MRI or CT consistent with a diagnosis of probable AD (within 12 months), stable dose of following concomitant medication were allowed: antihypertensives, anti-inflammatories, diuretics, laxatives, antidepressants, atypical antipsychotics, and tocopherol | PLA | 172 | PLA | ||||||||
| Exclusion: significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular disease; clinically significant B12 or folate deficiency; evidence of any psychiatric or neurological disorder other than probable AD; HIS <4; delusions or delirium (DSM-IV); active malignancy; history of substance abuse within 10 years; treatment with a depot neuroleptic within 6 months of screening; previous treatment with MEM; treatment within 30 days of screening with a ChEI or any investigational drug | |||||||||||
| Bakchine 2007 (Austria, Belgium, Denmark, Finland, France, Greece, Lithuania, the Netherlands, Poland, Spain, Sweden, and United Kingdom), industry | 470 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 24 weeks | MEM: 74.0 ± 7.4, PLA: 73.3 ± 6.9 | MEM: 35, PLA: 40 | MEM: White 100, PLA: White 100 | MEM | 318 | MEM 20 mg (fixed dose) | MEM = PLA: ADAS-cog, CIBIC-Plus, ADCS-ADL23, NPI |
| Inclusion: MMSE 11–23, age ≥50 years, MRI or CT consistent with a diagnosis of probable AD (within 12 months); SSRIs, estrogens, anti-inflammatory drugs, β-blockers, insulin, and H2 blockers were allowed if the dose and medication had been stable for at least 3 months and were kept stable during the study; vitamin E, coenzyme Q, and atypical antipsychotics were allowed if the dose and medication had been stable for at least 30 days and kept stable during the study; atypical antipsychotics were not to be taken 3 days before a visit | PLA | 152 | PLA | ||||||||
| Exclusion: any neurodegenerative disorder or MDD other than AD; modified HIS <4; significant coexisting medical conditions or laboratory abnormalities; receiving anticonvulsants, antiparkinsonian agents, classical and depot antipsychotics, anxiolytics, hypnotics, non-SSRI antidepressants, ChEI | |||||||||||
| Study | Total n | Patients | Diagnosis | Duration | Age (years) (mean ± SD) | Male, % | Race (%) | Drug | n | Dose (mg/day) | Outcomes |
| Schmidt 2008 (Austria), industry | 36 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 52 weeks | MEM: 76.5 ± 4.8, PLA: 75.8 ± 5.7 | MEM: 27.8, PLA: 44.4 | NR | MEM | 18 | MEM 20 mg | NR |
| Inclusion: age ≥50 years; HIS ≥4; MMSE 14–22; patients who had either failed to respond to ChEI or experienced severe side effects leading to termination of such treatment and had MMSE scores >14, which, at the time of study conduct, had excluded them from other approved antidementia treatment once ChEI had been stopped; generally good health; ChEI had to be terminated at least 4 weeks before screening; low-dose atypical neuroleptics, SSRI, non-centrally active antihypertensives, anti-inflammatory drugs, platelet antiaggregants and anticoagulants, laxatives, diuretics, and sedatives/hypnotics were permitted to continue on stable dose at least 3 months before screening | PLA | 18 | PLA | ||||||||
| Exclusion: primary diagnosis of psychiatric disorders other than AD; cerebrovascular disease; any unstable medical condition; using anticonvulsants, antiparkinsonian agents, barbiturates, Ginkgo biloba and nootropics, systemic corticosteroids, and insulin | |||||||||||
| Kitamura 2011 (Japan), industry | 315 | AD: Outpatient (100%) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 24 weeks | MEM (20 mg): 73.2 ± 9.9, MEM (10 mg): 73.2 ± 9.6, PLA: 73.6 ± 8.9 | MEM (20 mg): 26, MEM (10 mg): 35, PLA: 31 | Japanese: 100% | MEM (20 mg) | 100 | MEM 20 mg (fixed dose) | MEM > PLA: SIB (20 mg), MMSE(20 mg), FAST (20 mg), MEM = PLA: ADCS-ADL19, SIB (10 mg), CIBIC-Plus, NPI, MMSE (10 mg), FAST (10 mg) |
| Inclusion: age ≥50 years, MMSE 5–14, FAST 6a–7a | MEM (10 mg) | 107 | MEM 10 mg (fixed dose) | ||||||||
| Exclusion: MDD (DSM-IV) other dementia with AD, other severe neurological disorder | PLA | 108 | PLA | ||||||||
| Study | Total n | Patients | Diagnosis | Duration | Age (mean ± SD) | Male, % | Race (%) | Drug | n | Dose (mg/day) | Outcomes |
| Nakamura 2011 (Japan), industry | 432 | AD: Outpatient (100%) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 24 weeks | MEM: 74.4 ± 8.5, PLA: 74.9 ± 8.4 | MEM: 36.2, PLA: 35.1 | Japanese: 100% | MEM | 221 | MEM 20 mg (fixed dose) | MEM > PLA: SIB, Behave-AD, MEM = PLA: CIBIC-Plus, AST, MENFIS |
| Inclusion: age ≥50 years, MMSE 5–14, FAST 6a–7a | PLA | 211 | PLA | ||||||||
| Exclusion: MDD (DSM-IV) other dementia with AD, other severe neurological disorder | |||||||||||
| Howard 2012 (United Kingdom), no industry | 149 | AD: Outpatient (NR) | Probable or possible AD: NINCDS-ADRDA criteria | 52 weeks | MEM: 76.2 ± 8.9, PLA: 7.7 ± 8.0 | MEM: 39, PLA: 36 | MEM: White 96, Black 3, Other 1, PLA: White 97, Black 3, Other 0 | MEM | 76 | MEM 20 mg | MEM > PLA: SMMSE, BADLS, MEM = PLA: NPI, DEMQOL-proxy, GHQ-12 |
| Inclusion: continuously treatment with DON for at least 3 months (treatment with DON 10 mg for at least the previous 6 weeks), SMMSE 5–13, each eligible patient’s prescribing clinician was considering a change in drug treatment on the basis of NICE guidelines at the time, discussions with the patient and caregivers, and the physician’s clinical judgment | PLA | 73 | PLA | ||||||||
| Exclusion: severe or unstable medical conditions, current prescription of MEM, contraindications or previous adverse or allergic reactions to trial drugs | |||||||||||
| Wang 2013 (China), industry | 26 | AD: Outpatient (NR) | Probable AD: NINCDS-ADRDA and DSM-IV criteria | 24 weeks | MEM: 65.7 ± 12.5, PLA: 64.7 ± 11.5 | MEM: 36, PLA: 36 | NR | MEM | 13 | MEM 20 mg | MEM > PLA: SIB, MEM = PLA: MMSE, ADAS-cog, NPI |
| Inclusion: age 50–90 years, MMSE 4–20, HIS ≥4, BP 160–95/95–60 | PLA | 13 | PLA | ||||||||
| Exclusion: diabetes, renal impairment, significant systemic condition, psychiatric disorder, seizures, traumatic brain injuries, using approved or investigational antidementia drugs in the previous 3 months |
AD: Alzheimer’s Disease, ADAS-cog: Alzheimer’s Disease Assessment Scale cognitive subscale, ADCS-ADL (sev): Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (modified for more severe dementia), Behave-AD: Behavioral Pathology in Alzheimer’s Disease Rating Scale, BGP: Behavioral Rating Scale for Geriatric Patients, BP: Blood pressure, ChEI: Cholinesterase Inhibitors, CIBIC-Plus: Clinician’s Interview-Based Impression of Change Plus Caregiver Input, CT: computed tomography, DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders-4th edition-text revision, FAST: Functional Assessment Staging instrument, GDS: Global Deterioration Scale, GHQ-12: General Health Questionnaire 12, HIS: Hachinski Ischemic Score, MADRS: Montgomery Asberg Depression Rating Scale, MDD: Major Depressive Disorder, MEM: memantine, MENFIS: Mental Function Impairment Scale, MMSE: Mini-Mental State Examination, MRI: magnetic resonance imaging, NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association, NPI: Neuropsychiatric Inventory, NR: Not reported, PET: positron emission tomography, PLA: placebo, SD: standard deviation, SIB: Severe Impairment Battery, SMMSE: Standardized Mini-Mental State Examination, SSRI: Selective Serotonin Reuptake Inhibitors.