Table 1.
Randomized controlled trials using non-antipsychotic medication for psychosis and/or agitation in persons with dementia
| Authors (year) | Psychotropic (daily dose) | Sample (n) | Outcome Measure | Results | Comments |
|---|---|---|---|---|---|
| Antidepressants | |||||
| Sultzer et al. (1997) | Trazodone (50−250 mg) | Inpatients with dementia and agitation or aggression (28) | CMAI, OAS, CGI | Trazodone = haloperidol (1−5 mg/d); trazodone better tolerated than halodperidol | Small sample size; heterogeneous dementia etiologies included; no PBO control group; chloral hydrate as rescue med |
| Teri et al. (2000) | Trazodone (50−300 mg) | AD patients with agitation (149) | ADCS-CGIC | Trazodone = PBO on efficacy and side effects | 4-armed trial (including PBO, haloperidol, and cognitive behavioral therapy management) failed to distinguish among any treatment group; heterogeneous target symptoms |
| Levkovitz wt al. (2001) | Fluvoxamine (50 mg) | AD patients with psychosis concomitantly treated with perphenazine 12 mg/day (20) | BPRS, CGI | Perphenazine + fluvoxamine better than perphenazine + PBO on total BPRS only | No change in positive symptoms with fluvoxamine augmentation; small sample; fluvoxamine can increase antipsychotic blood levels; little description of concomitant meds or adverse events; crossover design could cause SSRI withdrawal to confound observations; fixed, low dose for brief duration |
| Pollock et al. (2002) | Citalopram (20 mg) | Inpatients with dementia-associated psychosis and/or agitation/aggression (85) | Neuro-behavioral Rating Scale | Citalopram better than PBO for total score and lability + agitation subscales; citalopram = PBO for tolerability | Modest sample size; heterogeneous target symptoms; heterogeneous dementia etiologies; lorazepam as rescue med; relatively high attrition in severely ill population; third arm treated with perphenazine, which did not differ from citalopram or PBO |
| Lanctot et al. (2002) | Sertraline (100 mg) | Institutionalized persons with severe AD with NPI score >7 but without major depression (22) | NPI, CMAI, BEHAVE-AD, CGI | Sertraline = PBO on efficacy and tolerability | Small sample size; limited rescue med with lorazepam; higher prolactin response to fenfluramine challenge somewhat predictive of better reponse to sertraline |
| Finkel et al. (2004) | Sertraline (50−200mg) | AD patients with NPI score >5, taking donepezil 10 mg/d (276) | NPI, CGI, BEHAVE-AD | Sertraline = PBO; more diarrhea in sertraline group | Heterogeneous target symptoms; 8-week open treatment with donepezil as lead-in to sertraline trial could have influenced behavioral symptoms; large sample size and relatively long treatment duration (12 weeks) |
| Anticonvulsants | |||||
| Tariot et al. (1998) | Carbamazepine (CBZ) (mean=304 mg) | Dementia patients with agitation in nursing homes (51) | BPRS, CGI | CBZ better than PBO; more side effects (e.g. ataxia, disorientation) with CBZ | Small sample size; vascular, Alzheimer's, and mixed dementias included; chloral hydrate as rescue med; CBZ dose adjusted by non-blinded physician; some baseline differences between treatment groups |
| Olin et al. (2001) | Carbamazepine (CBZ) (400 mg) | Dementia patients with agitation unresponsive to antipsychotics (21) | BPRS, CGI | CBZ better than PBO but trend for worsened hallucinations with CBZ | Small sample size; chloral hydrate as rescue medication; average CBZ level = 4.9 mcg/ml |
| Porsteinsson et al. (2001) | Divalproex (mean=826 mg) | Dementia patients with agitation in nursing homes (56) | BPRS, CGI | Divalproex=PBO | Modest sample size; average VPA level = 45 mcg/ml; multiple dementia diagnoses included; VPA dose adjusted by non-blinded physician |
| Sival et al. (2001) | Valproate (VPA) (480 mg) | Dementia patients with aggression (42) | SDAS-9, CGI | VPA = PBO | Any dementia type included; secondary beneficial effects on restless/anxious behaviors noted for VPA but with multiple comparisons; treatment duration only 3 weeks |
| Tariot et al. (2005) | Divalproex (mean=800mg) | AD patients with agitation in nursing homes (153) | BPRS (agitation) | Divalproex=PBO | Relatively large sample size with adequate power; average VPA level (52.8 mcg/ml); VPA-treated patients had more diarrhea and “nervous system” side effects; lorazepam and zolpidem allowed as rescue meds |
| Other | |||||
| Coccaro et al. (1990) | Oxazepam (10−60mg) Diphenhydramine (25−200 mg) | Dementia patients with agitation in long-term care facilities (59) | BPRS | Oxazepam, haloperidol, and diphenhydramine were all equivalent | No placebo control; limited assessment of adverse effects; diphenhydramine now often listed among medications to avoid in the elderly because of anticholinergic effects; heterogeneous dementia population |
| Cantillon et al. (1996) | Buspirone (mean 15 mg) | AD patients with agitation/aggression living in a nursing home (26) | BPRS | Buspirone = haloperidol | No placebo comparison; small sample; no concomitant psychotropics except benztropine |
| Christensen and Benfield (1998) | Alprazolam (1 mg) | Dementia patients with agitation living in nursing homes (48) | CGI, SCAG | Alprazolam = haloperidol | Entry criterion was treatment with haloperidol at 1 mg/day or less (not specific symptomatology); cross-over design may create drug withdrawal effects |
| Ballard et al. (2005) | Rivastigmine* (9−12 mg) | AD patients with agitation in long term care facilities (93) | CMAI | Rivastigmine = PBO | Third treatment arm of quetiapine also failed to separate from PBO or rivastigmine; modest sample size; quetiapine may have worsened cognition |
| Hall et al. (2005) | Transdermal estrogen (50−100 mcg) | Male dementia patients with aggressive behaviors (27) | RAGE | Estrogen = PBO | Small sample size; “rebound” worsening when estrogen withdrawn; adverse effects of hormonal treatments may occur over longer term; concomitant antipsychotic and benzodiazepine treatment allowed |
| Peskind et al. (2005) | Propranolol (mean=106mg) | AD patients with agitation (31) | NPI, CGI | Propranolol better than PBO | Small sample size; effects not maintained at 6-month open-label follow-up; participants on average were on two other psychotropics during study |
AD (Alzheimer disease);
ADCS-CGIC (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change);
BEHAVE-AD (Behavioral Pathology in Alzheimer's Disease Rating Scale);
BPRS (Brief Psychiatric Rating Scale);
CBZ (carbamazepine);
CGI (Clinical Golbal Impression);
CMAI (Cohen-Mansfield Agitation Inventory);
NPI (Neuropsychiatric Inventory);
OAS (Overt Aggression Scale);
PBO (placebo);
RAGE (Rating Scale for Aggressive Behavior in the Elderly)
SCAG (Sandoz Clinical Assessment Geriatric scale);
SDAS-9 (Social Dysfunction and Aggression Scale-9);
VPA (valproic acid)
*
We did not include most published trials of cholinesterase inhibitors and memantine that reported behavioral effects, because these trials were designed primarily to assess cognition, with only secondary post-hoc analysis of behavioral symptoms.