Efficacy and safety outcomes
| Study /year/n | Intervention | Agitated behaviour measures | Efficacy outcomes | Safety outcomes |
| 1. Agitated behaviour as the presenting symptom | ||||
| Randomised controlled studies | ||||
| Brooke, et al
31
/1992/n=21 | Propranolol | Overt aggression scale | Significant 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
/1993/n=38 | Methylphenidate | State-Trait Anger Scale, Belligerence cluster score for the Katz adjustment scale and the Anger-Hostility factor score, Organic Signs and Symptoms Inventory | Significant 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
/2010/n=79 | Amantadine | Confusion 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 | No patients withdrawn because of safety criteria |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
/2014/n=76 | Amantadine | NPI-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
/2015/n=50 | Valproic acid | Agitated Behaviour Scale by spouse or significant other | Significant 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
/2015/n=168 | Amantadine | NPI-I most problematic by observer and by patient. Global improvement subscale of the Clinical Global Impressions (CGI) by physicians | Observer 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
/2009/n=31 | Olanzapine | Restlessness, irritability, aggressiveness and insomnia. No tool mentioned | Reduction 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
/2017/n=139 | Amantadine | RASS score of +2 or higher | Increase 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
/1994/n=10 | Amantadine | Neurobehavioral rating scale | No significant difference in behaviour scores between amantadine and placebo groups. | No safety outcomes reported |
| Meythaler, et al
41
/2001/n=9 | Sertraline | Agitated Behaviour Scale | No difference in decline of ABS over treatment period | No safety outcomes reported |
| Meythaler, et al
43
/2002/n=35 | Amantadine | Agitated Behaviour Scale | There 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
/2010/n=99 | Sertraline | Aggression self-report and family report according to the Neurobehavioral Function Inventory | No significant differences between sertraline and placebo in patient self-report and family report. | No safety outcomes reported |
| Giacino, et al
40
/2012/n=184 | Amantadine | Agitation and restlessness not further defined | A 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) |
| Tramontana44
/2014/n=22 but 13 patients completed the study | Lisdexamfetamine | Agitation and restlessness not further defined | No 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 |
| Johansson46
/2014/n=48 | Methylphenidate | Aggression, restlessness and irritability not further defined | No 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 |
| Fann45
/2017/n=62 | Sertraline | Brief Anger and Aggression Scale and agitation/restlessness not further defined | No 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 |
| Hart47
/2017/n=32 | Dextroamphetamine | Agitated Behaviour Scale | Increase 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.