Table 1.

Completed Randomized Controlled Trials (RCTs) of drugs for agitation and aggression in Alzheimer’s Disease^*

Molecule	Mechanism of action	Reference	Design TT period	Primary Aim Definition	Inclusion criteria	Exclusion Criteria	Outcome primary measures	Definition of primary comparison & analysis	Desired clinical difference	Secondary outcomes	Study location & Sites	Start date	End date	N1	Results
Citalopram	Selective serotonin reuptake inhibitor (SSRI)	Portsteinsson et al., 2014	Ph 3 9 wk fixed doses	Agitation NPI A/A ≥4 with s≥2	CD & NH NINCDS-ADRDA MMSE 5–28	Major depression	NBRS modified- ADCS- CGIC	ITT LME model of NBRS	NBRS:3–5 p CGIC: 20%	NPI, CMAI, ADCS-ADL, MMSE, NPI- distress, cumulative lorazepam dose	USA 8	July 2009	Jan 2013	186 169	Positive for NBRS & mADCS- CGIC
Mibampator	AMPA (glutamate receptor) potentiator	Trzepacz et al., 2013	Ph 2 12 wk fixed doses	Agitation Agression NPI≥10 NPI-4-A/A≥4 on 1 domain	CD ≥60 NINCDS-ADRDA DSM MMSE 6–26 NPI-10 ≥10	Delirium Vascular dementia	NPI-4 domain - A/A2 (max score 48)	ITT. Likehood- based, MMRM	Effect size of 0.41 in mean change from baseline to end point	CMAI, NPI- 10, Cornell, FrSBe, Adas- cog, CGI-S- A/A, NPI- distress	USA 16	Feb 2009	June 2011	150 132	Null, positive only or FrSBe
Aripiprazole	Dopamine D2 partial agonist	Rappaport et al., 2009	2 IM fixed doses 24hours	Acute agitation PANNS-EC >14 & <31	NH AD, vascular and mixed		PANNS-EC			ACES, CGI- S, CGI-I	USA 16			129	Positive for all outcomes
Memantine-NH	NMDA agonist	Fox et al., 2012	Ph 4 12 wk fixed doses	Agitation CMAI≥45	NH & Acute psy wards ≥45 y MMSE<19	Previous memantine usage	CMAI at 6 wk	ITT LME model of CMAI	Difference of 6 p from baseline to 6 wk	CMAI at 12wk, NPI, CGI-C, MMSE, SIB	UK	Sept 2007	Jan 2010	153	Null, positive for total NPI
Memantine-CD3	NMDA agonist	Herrmann et al., 2013	Ph 3 24 wk fixed doses	Agitation NPI ≥1 for agitation	CD ≥50 y MMSE 5–15 NINDS-ADRDA & DSM-IV NPI ≥13	Hachinski >4	Total NPI SIB	ANCOVA analyses of the changes from baseline to Week 24 in NPI and SIB total scores	Effet size of 0.31 in mean change from baseline to end point	CMAI, CIBIC plus, ADCS- ADL	Canada 23	Dec 2003	Sept 2010	450 369	Null for all outcomes
Escitalopram vs. Risperidone	SSRI vs. atypical antipsychotic	None	Ph 4 6 wk	NPS: A/A, D/H, AMB NPI f>2, s>1 on 1 domain	Hospitalized 55–95 y DSM-IV MMSE 5–16	Delirium	Total NPI		Not reported	Time to disconinuation drug	Israel 1	April 2008	May 2010	40	None
Topiramate vs. Risperidone	AMPA/GABA modulator vs atypical antipsychotic	Mowla et al., 2010	8 wk fixed doses	NPS: A/A, D, H, Irritability NPI>1 on 1 domain	CD 55–95 y DSM-IV MMSE10–15		Total NPI CMAI CGI	Wilcoxon signed ranks test	Not reported	MMSE	Iran 1	Jan 2008	Mar 2009	48	Null
Valproate	Enhanced GABAergic function	Tariot et al., 2011	24 month fixed doses	Agitation & Psychosis ≥ 3 on 1 or more NPI items A/A, D, H for 2 wks	CD, ≥54 y MMSE10–20 NINDS- ADRDA NPI <1 in A/A, D, H since AD onset		Time to ≥ 3 on 1 or more NPI items A/A, D, H for 2 wks	Time to endpoint Cox proportionl hazard ratio.	33% difference in incidence rate	Total NPI Total CMAI ADCS-CGIC Qol-AD MMSE ADAS-cog ADCS-ADL CDR	USA 46	Nov 2005	Mar 2009	313	Null for all outcomes, Significant adverse events
Prazosin	α1-adreno receptor antagonist	Wang et al., 2009	Pilot 8 wk flexible doses	Agitation & Aggression 2≥/wk BPRS≥4 in at least 1 item	CD & NH No age limit NINDS- ADRDA	hypotension	Total NPI CGIC	LME model (NPI, BPRS) Mann- Whitney test (CGIC)		BPRS SE Blood pressure	USA 1	Jan 2005	Sep 2007	22	Positive for all outcomes
Melatonin	Melatonin receptor agonist	Gerrman et al., 2009	10 days fixed doses	Agitation & Sleep	NH ≥60 y NINDS-ADRDA Severe AD		Sleep: actigraphy Agitation: CMAI & ABRS	Total sleep time. Analysis of variances	Not reported		USA 1			43	Null for all outcomes
Oxcarbazepine	GABA receptor potentiator	Sommer et al., 2009	Ph 3 8 wk fixed doses	Agitation & Agression NPI A/A≥6	NH ≥55 y Vascular or AD; ICD-10 MMSE 5–16	Changes in Psychotropic drugs	NPI-NH A/A	repeated- measures model with an autoregressive covariance structure	difference between treatments of 1.2 p	BARS, NPI- caregiver distress,	Norway 35	Sept 2005	Oct 2006	103	Null for all outcomes

^*completed RCT registered in a clinical trial registry between 2008 and 2013 and/or published between 2008 and 2013

¹randomized, completed

²The NPI-4 A/A is a 4-domain subscale chosen which combines from the NPI-10 four domains: agitation/aggression; aberrant motor behavior; irritability/emotional lability; and disinhibition

³This study was prematurely terminated due to recruitment problems

Abbreviations: Ph= phase; TT= Treatment; y= years; wk= week; NPS= neuropsychiatric symptoms; A/A=agitation/aggression; D/H= delusions/hallucinations; AMB= Aberrant Motor Behavior; s= severity; f= frequency; AAN= American Academy of Neurology; CD= community-dwelling; NH= nursing home; ITT= intention to treat; NINDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, DSM= Diagnostic and Statistical Manual of Mental Disorders ; NPI=Neuropsychiatric Inventory; CMAI=Cohen-Mansfield Agitation Inventory; ADCS-ADL= Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-CGIG=Alzheimer’s disease Cooperative Study-Clinical Global Impression of change; FrSBe= Frontal Systems Behaviors Scale; CGI-C= Clinical Global Impression of change; CGI-I= Clinical Global Impression Improvement Score; CGI-S= Clinical Global Impression Severity of Illness Score; PANSS-EC = Positive and Negative Syndrome Scale – Excited Component; ACES= Agitation-Calmness Evaluation Scale; BPRS = Brief Psychiatric Rating Scale; SIB= Severe Impairment Battery; CIBIC-plus= Clinician’s Interview-Based Impression of Change-Plus Version; ABRS= Agitation Behavior Rating Scale; NIA= National Institute of aging; QoL-AD=quality of life-AD; p= points; IN= intramuscular; LME model= linear mixed effects model; ANCOVA=analysis of covariance; MMRM= mixed-effects model repeated measures analysis