Table 3

Efficacy and safety outcomes

InterventionAgitated behaviour measuresEfficacy outcomesSafety outcomes
1. Agitated behaviour as the presenting symptom
Randomised controlled studies
Brooke, et al 31
PropranololOvert aggression scaleSignificant reduction in maximum intensities of agitation per week (p<0.05). No significant difference in average number of agitation episodes per week. Significant reduction in physical restraint use during the study (p<0.05).No safety outcomes reported
Mooney, Haas32
MethylphenidateState-Trait Anger Scale, Belligerence cluster score for the Katz adjustment scale and the Anger-Hostility factor score, Organic Signs and Symptoms InventorySignificant difference in the comparison of methylphenidate and placebo group on all the anger measures before and after 6 weeks in a multivariate analysis (p=0.02).No significant effect on side effects
Yablon, et al 33
AmantadineConfusion assessment protocol (CAP)No significant differences in the number of symptoms of post-traumatic confusional state as measured by the CAP at 14 days (amantadine 2.56 vs placebo 2.7; p=0.57). Mean difference in time to first ‘non-confused’ CAP score between groups approached significance (amantadine 7.7 days and placebo 9.3 days; p=0.053).No patients withdrawn because of safety criteria
Hammond, et al 35
AmantadineNPI-I most aberrant and most problematic
Irritability (NPI-I) and aggressiveness (NPI-A)
Significant reduction in irritability (80.56% improved at least three points on the NPI-I, compared with 44.44% in the placebo group; p=0.0016). Mean change in NPI-I was −4.3 in the amantadine group and −2.6 in the placebo group (p=0.0085). When excluding individuals with minimal to no baseline aggression, mean change in NPI-A was −4.56 in the amantadine group and −2.46 in the placebo group (p=0.046).No difference in adverse events (tremors, appetite, gastrointestinal, aches and pain, sexual problems, disorientation, seizures)
Beresford, et al 37
Valproic acidAgitated Behaviour Scale by spouse or significant otherSignificant others' weekly Agitated Behaviour Scale ratings were statistically lower, indicating less agitation in the valproic acid group, 12.9±4.9, than in the placebo group, 15.5±6.6, with significance at p=0.0367.No safety outcomes reported
Hammond, et al 34
AmantadineNPI-I most problematic by observer and by patient. Global improvement subscale of the Clinical Global Impressions (CGI) by physiciansObserver ratings were not different at day 28 or 60. Participants rating at day 60 showed improvement in NPI-I most problematic (p<0.04; but NS for when adjusted for multiple comparisons). Physician’s assessment of global improvement improved more in the amantadine group than the placebo group at 60 days (p=0.0354).Well tolerated with no significant differences in adverse events between groups
Observational studies
Maturana Waidele, Maturana Rodillo38
OlanzapineRestlessness, irritability, aggressiveness and insomnia. No tool mentionedReduction in irritability (p<0.001), aggressiveness (p=0.008) and insomnia (p=0.011) between weeks 1 and 3 in the patients treated with olanzapine.No safety outcomes reported
Gramish, et al 36
AmantadineRASS score of +2 or higherIncrease in agitation in patients exposed to amantadine (38%) compared with non-exposed (14%); p=0.018. Increase in median ICU length of stay (4.5 vs 3 days; p=0.01). Median hospital length of stay was non-significantly increased (14 days vs 10 days; p=0.051).No safety outcomes reported
2. Agitated behaviour is not the presenting symptom
Randomised controlled studies
Schneider, et al 42
AmantadineNeurobehavioral rating scaleNo significant difference in behaviour scores between amantadine and placebo groups.No safety outcomes reported
Meythaler, et al 41
SertralineAgitated Behaviour ScaleNo difference in decline of ABS over treatment periodNo safety outcomes reported
Meythaler, et al 43
AmantadineAgitated Behaviour ScaleThere were no statistically significant changes or trends in the ABS during the first 6 weeks or the second 6 weeks of the study (p>0.05, Mann-Whitney U test).No detrimental effects in haematology or biochemistry laboratories and no seizures
Baños, et al 39
SertralineAggression self-report and family report according to the Neurobehavioral Function InventoryNo significant differences between sertraline and placebo in patient self-report and family report.No safety outcomes reported
Giacino, et al 40
AmantadineAgitation and restlessness not further definedA total of 12/87 (14%) patients and 11/97 (11%) patients exposed to amantadine and placebo developed agitation (p=NS) over the 4-week period. Restlessness was reported in 8% and 9% of patients exposed to amantadine and placebo, respectively.No differences in adverse events (seizure, nausea, vomiting, constipation, diarrhoea, elevated liver function tests, insomnia, rash, congestive heart failure, involuntary muscle contractions)
/2014/n=22 but 13 patients completed the study
LisdexamfetamineAgitation and restlessness not further definedNo difference in agitation (no cases in each group) or irritability (1/13 case) during placebo) between the lisdexamfetamine and placebo groups.Reduced appetite and weight loss of >5 lbs more frequent with lisdexamfetamine (7 vs 1 case) p=NS
MethylphenidateAggression, restlessness and irritability not further definedNo difference in aggression, restlessness and irritability in patients treated with methylphenidate.A significant increase in heart rate was found. No significant changes were found in blood pressure or QT intervals
SertralineBrief Anger and Aggression Scale and agitation/restlessness not further definedNo difference in the Anger and Aggression Scale. More patients developed agitation/restlessness in the sertraline group (17%) versus the placebo group (7%) p=0.42.No significant difference in safety outcomes. More patients in the sertraline group (17%) developed gas/flatulence versus the placebo group (0%) p=0.052
DextroamphetamineAgitated Behaviour ScaleIncrease in agitation with dextroamphetamine over time compared with placebo (p<0.05).No significant difference in heart rate or blood pressure
  • RASS, Richmond Agitation Sedation Scale.