Table 2 Summary of studies on pharmacological interventions for managing agitation and behavioral symptoms of dementia

Ballard et al.⁵

165 participants

Continue neuroleptic treatment for 12 months or a switch to placebo.

12 months

Neuropsychiatric symptoms evaluated with the Neuropsychiatric Inventory (NPI).

At 6 months: No significant difference between the continue treatment and placebo groups. Estimated mean change in Severe Impairment Battery (SIB) scores between baseline and 6 months showed estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (P=0.9). For neuropsychiatric symptoms, the estimated mean difference in deterioration (favouring continued treatment) was 2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (P=0.4).

At 12 months: clinically important but no statistically significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 12 months. Estimated mean difference in deterioration (favouring placebo) 8.4 (95% CI −18.6 to 1.7), adjusted for baseline value (P ¼ 0.1). For the NPI, there was a significant difference between the continue treatment and placebo groups in the estimated mean change in NPI scores between baseline and 12 months, with 11.4 points (s.d. 17.7) deterioration for the placebo group compared with a 1.4 (s.d. 22.1) deterioration for the continue treatment group. Estimated mean difference in deterioration (favouring continued treatment) 10.9 (95% CI 20.1–1.7), adjusted for baseline value (P ¼ 0.02).

Rappaport et al.²³

129 participants

IM aripiprazole (5, 10, or 15 mg) versus IM placebo.

24 h

Efficacy analyses done included the Positive and Negative Syndrome Scale-Excited Component (PEC) scores, Agitation–Calmness Evaluation Scale (ACES), Clinical Global Impressions–Severity of Illness (CGI-S) and Clinical Global Impressions–Improvement (CGI-I) rating scales.

PEC scores showed greater improvements in agitation with IM aripiprazole 10 mg and 15 mg compared with IM placebo. Mean CGI-I score was lower for all 3 IM aripiprazole dose groups versus IM placebo. Generally, there were significant improvements on the PEC, CGI-I, CGI-S and ACES rating scales with IM aripiprazole compared with IM placebo

Likewise, more adverse effects (AEs) were reported with IM aripiprazole (50% to 60%) than IM placebo (32.0%), but over 90% were mild or moderate in severity.

Cakir and Kulaksizoglu²⁴

16 participants

Mirtazapine (15–30 mg)

12 weeks

Changes in Cohen-Mansfield Agitation Inventory-Short form (CMAI-SF) scores and Impression-Severity scale (CGI-S) scores with tolerability-safety profile were the primary and secondary outcome measurements respectively.

Statistically significant improvement between baseline and 12th week in both CGI-S and CMAI-SF scores (P<0.001). The mean change in CMAI-SF was −11.0 (s.d.±7.5) and −2.0 (s.d.±0.9) in CGI-S, P value was<0.001 in both.

Mirtazapine demonstrated some efficacy in treating agitated patients with Alzheimer's disease.

Side-effect profile of mirtazapine reported includes sedation, headache, increased appetite (but no weight gain) and mild hypotension.

Wang et al.²⁵

22 participants

Prazocin versus Placebo

8 weeks

Brief Psychiatric Rating Scale (BPRS) and Neuropsychiatric Inventory (NPI) at Weeks 1, 2, 4, 6 and 8; and the Clinical Global Impression of Change (CGIC) at Week 8 were measured.

Participants that had prazosin (mean dose: 5.7±0.9 mg/day) show more improvements than those that had placebo (mean dose: 5.6±1.2 mg/day) on the NPI (mean change: −19±21 versus -2±15, chi=6.32, df=1, P=0.012) and BPRS (mean change: -9±9 versus -3±5, chi=4.42, df=1, P=0.036) based on linear mixed effects models and the CGIC (mean: 2.6±1.0 versus 4.5±1.6, z=2.57, P=0.011 [Mann–Whitney test]).

The AEs reported by both prazosin and placebo groups were similar.

Lockhart et al.²⁶

6 studies (1393 participants)

Donepezil and memantine monotherapy versus Placebo in managing the behavioral and psychological symptoms of dementia (BPSD)

24 weeks

Absolute change in NPI score were compared with baseline NPI score.

Results from the total NPI measured showed that BPSD demonstrated statistically significant improvement with donepezil monotherapy within its licensed indication compared with placebo [weighted mean difference (WMD) in NPI -3.51, 95% confidence interval (CI) −5.75, −1.27]. Contrarily, there was no statistically significant difference between memantine monotherapy used within its license compared with placebo (WMD −1.65, 95% CI −4.78, 1.49).

Also, WMD in NPI for donepezil versus memantine favored donepezil but this was not statistically significant (−1.86, 95% CI −5.71, 1.99; P=0.34).

Fox et al.²⁷

153 participants

Memantine versus Placebo.

12 weeks

Primary outcome was 6 weeks Cohen-Mansfield Agitation Inventory (CMAI) and Secondary outcomes included 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery.

No significant difference in the primary outcome, 6 weeks CMAI between memantine and placebo (memantine lower −3.0; −8.3 to 2.2, P = 0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favored memantine at weeks 6 (−6.9; −12.2 to −1.6; P = 0.012) and 12 (−9.6; −15.0 to −4.3 P = 0.0005).

Memantine was significantly better than placebo for cognition, but failed to show any significant benefits over placebo at improving agitation in AD people.

Herrmann et al.²⁸

369 participants

Efficacy of Memantine versus Placebo.

24 weeks

Total NPI and Severe Impairment Battery (SIB) scores for behavior and cognition respectively, were the primary outcome measured. Other endpoints included the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and the Cohen-Mansfield Agitation Inventory (CMAI) total score.

There were no statistically significant differences between memantine and placebo in mean change from baseline in NPI (P=0.42), SIB (P=0.60), or in any of the secondary outcome measured. Behavior improved in both groups (total NPI change scores -3.90±1.24 for memantine and −5.13±1.23 for placebo).

Li et al.²⁹

42 participants

Efficacy of 10 mg memantine on neuropsychiatric symptoms of patients with mild and moderate-to-severe form of behavioral variant fronto-temporal dementia (bvFTD).

6 months

Primary and secondary endpoints included Neuropsychiatric Inventory Questionnaire (NPI-Q); Clinic Dementia Rating (CDR) scores; Inventory Caregiver Distress Scale (NPI-D), MMSE, Montreal Cognitive Assessment (MoCA) and Hamilton Depression Rating Scale (HAMD) scores.

In both baseline and final visit, no statistically significant differences were detected in the NPI-D and HAMD scores. However, following 6 months of memantine treatment, the subgroup of patients with moderate-to-severe bvFTD exhibited significantly improved total NPI-Q scores (Z=−2.488, P=0.013), and improvements in the subscales of agitation (Z=−2.058, P=0.04) compared with those at baseline. By contrast, memantine caused no significant changes in patients with mild bvFTD with regard to the total NPI-Q score (14.50±2.82 baseline versus 15.70±3.00 after 6 months, P=0.192) or individual subscale scores.

Trzepacz et al.³⁰

132 participants

Mibampator versus Placebo

12 weeks

Primary endpoints included 4-domain A/A subscale of the Neuropsychiatric Inventory(NPI-4- A/A), and Secondary measures were Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimer's Disease Assessment Scale-Cognitive.

Both mibampator and placebo groups improved on the NPI-4- A/A. However, among secondary endpoints measured, mibampator was significantly better (P=.007) than placebo only on the FrSBe. Both groups had similar adverse effects.

Porsteinsson et al.³¹

186 participants

Citalopram versus Placebo.

9 weeks

18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Cohen-Mansfield Agitation Inventory (CMAI), and Neuropsychiatric Inventory (NPI), were among the outcome measured.

Citalopram showed significant improvement compared with placebo on all outcomes measured including the total NPI, except on the NPI agitation subscale. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = 0.04. Also, mADCS-CGIC showed 40% of citalopram participants having significant improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = 0.01.

Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = 0.03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = 0.01) were seen in the citalopram group.

Cummings et al.³²

220 participants

Combination of dextromethorphan-quinidine treatment versus placebo.

10 weeks

The efficacy endpoints were changes from baseline in the NPI total scores.

Analysis combining all participants showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine compared with placebo (ordinary least squares z statistic, −3.95; P < .001).

Most commonly reported AEs (>3% and greater than placebo) were falls (8.6% versus 3.9%), diarrhea (5.9% versus 3.1%), urinary tract infection (5.3% versus 3.9%) and dizziness (4.6% versus 2.4%) for dextromethorphan-quinidine versus placebo respectively.