Table 2.

Randomized, controlled withdrawal trials of agents for neuropsychiatric symptoms as of 2004

Study; funding sponsor	Study design (N); study length	Drug	Pt residence	Dementia type and severity	Outcomes	Outcomes related to specific symptoms	AEs
Ruths et al. [118]; NR	RAN, PC, DB trial (N = 30); 4 wk	HAL, RIS, or OLA	Nursing homes	Dementia diagnosis per ICD-10	Effects of antipsychotic withdrawal assessed with NPI-Q, which showed ND between groups, and actigraphy. Antipsychotic discontinuation associated with reduced average sleep efficiency	On individual items of the NPI-Q, differences between groups observed in restlessness (aberrant motor behavior)	AE associated with antipsychotic discontinuation: one pt restarted antipsychotic due to increased leg movements. AE for pts remaining on antipsychotics NR
Ballard et al. [82]; The Alzheimer’s Research Trust	RAN, blinded, PC, 2-group discontinuation (N = 128); 12 months	THI, CHL, HAL, TRI, or RIS	Nursing or residential home	Possible or probable AD per NINCDS-ADRDA; MMSE score > 6 or SIB > 30	ND between discontinuation and continuation groups on primary outcome measure of total SIB score change from baseline to 6 months. ND between groups in NPI or M-UPDRS estimated mean changes and CGI-C over 6 months. Analysis at 12 months limited due to missing data but show no significant difference between groups in SIB score changes at 12 months. NPI estimated mean change in scores showed differences between groups in favor of continuation though a test of interaction was not statistically significant	Specific symptom outcomes NR	ND in cognitive function changes as measured by SMMSE
Ruths et al. [88]; NR	RAN, MC, DB, controlled (N = 55); 4 wk	HAL, RIS, or OLA	Nursing home	Dementia per ICD-10	Primary outcome measure of successful antipsychotic discontinuation, which was described as 23 of 27 pts remaining off antipsychotics at wk 4	ND on individual items or total NPI scores between antipsychotic discontinuation and continuation group	NR
Bergh et al. [86]; Innlandet Hospital Trust, the Research Council of Norway, and the South-Eastern Norway Regional Health Authority	DB, RAN, PG, MC, PC (N = 128); 25 wk	SSRIs (ESC, CIT, SER, or PAR)	Nursing homes	AD, dementia, or vascular dementia per ICD-10 criteria	ND observed in primary efficacy endpoint was CSDD and NPI scores between groups	No particular subscale of the CSDD (e.g., mood or non-mood) or NPI (e.g., agitation, psychotic, apathy) showed differences between groups	ND between groups on UPDRS. More pts in discontinuation (20%) vs. PL group (6%) withdrew from study due to increased depressive or neuropsychiatric symptoms
Devanand et al. [80]; NIH and the Department of Veterans Affairs; Jannsen provided medication only	RAN, DB (N = 110); 32 wk	RIS	Outpatients and nursing home/ALF	Dementia criteria per DSM-IV and probable AD per NINCDS-ADRDA criteria; MMSE score 5–26 in outpatients or 2–30 in nursing home residents	Primary outcome measure was time to relapse during wk 0–16 of phase B (pts responding to RIS during phase A); pts receiving PL had increased risk of relapse at 16 wk. Pts discontinuing RIS at 16 wk and switched to PL had an increased risk of relapse vs. PL	Specific symptom outcome NR	No significant differences in reported AE rating scales
Ballard et al. [84]; Lundbeck pharmaceutical company and National Institute for Health Research	RAN, DB, PC, MC, double-dummy, PG (N = 199); 24 wk	MEM, antipsychotics	Care facilities	Probable or possible AD according to NINCDS-ADRDA criteria	ND between groups on primary outcome measure of agitation on the CMAI and function using BADLS. ND between groups on NPI or CGI-C	Specific symptom outcomes NR	Statistical significance NR. In antipsychotic group, 193 pts had AE (25 SAE) and in MEM group, 167 pts had AE (18 SAE)

AD Alzheimer’s disease, AE adverse event, ALF assisted living facility, BADLS Bristol Activities of Daily Living Scale, CGI-C Clinical Global Impression of Change, CHL chlorpromazine, CIT citalopram, CMAI Cohen-Mansfield Agitation Inventory, CSDD Cornell Scale for Depression in Dementia, DB double blind, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, ESC escitalopram, HAL haloperidol, ICD-10 International Statistical Classification of Diseases – tenth revision, MC multicenter, MEM memantine, MMSE Mini-Mental State Examination, M-UPDRS Modified Unified Parkinson’s Disease Rating Scale, ND no difference(s), NIH National Institutes of Health, NINCDS-ADRDA National Institute of Neurological and Communication Disorders and Stroke-Alzheimer Disease and Related Disorders Association criteria, NPI neuropsychiatric inventory, NPI-Q neuropsychiatric inventory Questionnaire, NR not reported, OLA olanzapine, PAR paroxetine, PC placebo controlled, PG parallel group, PL placebo, RAN randomized, RIS risperidone, SAE serious adverse event, SER sertraline, SIB Severe Impairment Battery, SMMSE Standardized Mini-Mental State Examination, THI thioridazine, TRI trifluoperazine, UPDRS Unified Parkinson’s disease rating scale, wk week