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Glossary of Terms

Adequate dose

The dose of a medication at which therapeutic effects occurred when tested in clinical trials in a comparable population of subjects. This dose will differ for each medication and may need to be adjusted in an individual patient to address factors that would influence drug absorption, metabolism, elimination, or other pharmacokinetic properties.

Adequate response

A reduction in symptoms as a result of treatment that is associated with clinically significant benefit in functioning and/or quality of life. A reduction in symptoms of 50% or more is sometimes used as a threshold for adequacy of response.

Agitation

A state of excessive motor activity, verbal aggression, or physical aggression to oneself or others that is associated with observed or inferred evidence of emotional distress (definition adapted from Cummings et al. 2015).

Antipsychotic medication

One of a group of medications used in the treatment of psychosis. Some of the antipsychotic medications are also approved for use in other conditions such as mood disorders or Tourette’s syndrome. The first-generation antipsychotic (FGA) medications, sometimes referred to as “typical” antipsychotic medications, were the initial medications to be discovered. The FGAs include, but are not limited to, chlorpromazine, droperidol, fluphenazine, haloperidol, loxapine, perphenazine, thiothixene, thioridazine, and trifluoperazine. The second-generation antipsychotic (SGA) medications, sometimes referred to as “atypical” antipsychotic medications, include, but are not limited, to aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. Within each group of antipsychotic medications, there is significant variability in the pharmacological properties, presumed mechanisms, and side effect profiles of specific drugs.

Assessment

The process of obtaining information about a patient through any of a variety of methods, including face-to-face interview, review of medical records, physical examination (by the psychiatrist, another physician, or a medically trained clinician), diagnostic testing, or history taking from collateral sources.

Behavioral and psychological symptoms of dementia

Signs and symptoms of disturbed perception, thought content, mood, or behavior that occur in the context of dementia (Finkel et al. 1996). Behavioral and psychological symptoms of dementia (BPSD) are distinct from the cognitive impairments of dementia and include agitation and psychosis as well as apathy, depression, anxiety, irritability, disinhibition, sleep disturbances, wandering, and disruptive or socially inappropriate behaviors (Kales et al. 2015). This set of symptoms has also been referred to as noncognitive neuropsychiatric symptoms of dementia (Kales et al. 2014).

Comprehensive treatment plan

A plan of treatment that is developed as an outgrowth of the psychiatric evaluation and is modified as clinically indicated. A comprehensive treatment plan can include nonpharmacological and pharmacological interventions. It is individualized to the patient’s clinical presentation, safety-related needs, concomitant medical conditions, personal background, relationships, life circumstances, and strengths and vulnerabilities. There is no prescribed format that a comprehensive treatment plan must follow. The breadth and depth of the initial treatment plan will depend on the amount of time and the extent of information that are available. The fully developed treatment plan will also vary in breadth and depth depending upon factors such as the needs of the patient and the setting in which care is occurring. Additions and modifications to the treatment plan are made as additional information accrues (e.g., from family, staff, medical records, and other collateral sources), and the patient’s responses to clinical interventions are observed.

Dementia

A degenerative condition characterized by the development of multiple cognitive deficits that include memory impairment and at least one of the following cognitive disturbances: aphasia, apraxia, agnosia, or a disturbance in executive functioning. The cognitive deficits cannot occur exclusively during the course of a delirium; they must be sufficiently severe to cause impairment in occupational or social functioning, and must represent a decline from a previously higher level of functioning (American Psychiatric Association 2000). The definition of major neurocognitive disorder, as used in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM–5), is somewhat broader than the term dementia, in that individuals with substantial decline in a single domain can receive the diagnosis of neurocognitive disorder (American Psychiatric Association 2013).

Nonpharmacological interventions

Any of a wide variety of interventions other than medications. Nonpharmacological interventions include, but are not limited to, cognitive/emotion-oriented interventions (e.g., reminiscence therapy, validation therapy, simulated presence therapy, cognitive training and rehabilitation), sensory stimulation interventions (e.g., acupuncture, aromatherapy, light therapy, massage and touch therapy, music therapy, Snoezelen multisensory stimulation therapy), individualized behavioral reinforcement strategies, animal-assisted therapy, exercise, environmental modifications (e.g., reducing noise, decreasing clutter, removing access to sharp objects, establishing daily routines, providing orientation, improving lighting, increasing color contrasts), and caregiver support and education (Kales et al. 2015; Brasure et al. 2016). Nonpharmacological interventions do not include restraint or seclusion.

Quantitative measures

Clinician- or patient-administered tests or scales that provide a numerical rating of features such as symptom severity, level of functioning, or quality of life and have been shown to be valid and reliable.

Surrogate decision maker

The individual who is designated to make decisions on behalf of the patient in circumstances where the patient lacks the capacity to do so. The specific designation of and terminology used to describe a surrogate decision maker will depend on state and federal law.

References

Note: References to supporting research evidence are denoted by *. PubMed ID, where applicable, is included at the end of each reference.

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Disclosures

The Guideline Writing Group and Systematic Review Group reported the following disclosures during development and approval of this guideline:

Dr. Reus is employed as a professor of psychiatry at the University of California, San Francisco School of Medicine. He is chairman of the board of the Accreditation Council for Continuing Medical Education (ACCME). He receives travel funds from the ACCME and the American Board of Psychiatry and Neurology (ABPN) for board meetings and test development. He receives research grant support from the National Institute of Mental Health (NIMH) and National Institute on Drug Abuse and honoraria for NIMH grant review service. He reports no conflicts of interest with his work on this guideline.

Dr. Fochtmann is employed as a professor of psychiatry, pharmacological sciences, and biomedical informatics at Stony Brook University. She consults for the American Psychiatric Association on the development of practice guidelines and has received travel funds to attend meetings related to these duties. She has also received travel funds from the American Psychiatric Association to attend the FOCUS self-assessment editorial board meeting. She has received honoraria for serving as a member of NIMH grant review panels, Technical Expert Panels for AHRQ, and Patient-Centered Outcomes Research Institute reviews related to psychiatric topics. She has also received honoraria to present at a meeting of the International Society for ECT and Neurostimulation. She reports no conflicts of interest with her work on this guideline.

Dr. Eyler is employed as a professor of psychiatry and family medicine at the University of Vermont College of Medicine in Burlington, Vermont, and as an attending psychiatrist at the University of Vermont Medical Center and its affiliated hospitals. During the period of preparation of this guideline, honoraria have been received from the University of Vermont College of Medicine, Simmons College, Dartmouth-Hitchcock Medical Center, Dartmouth College, Franklin Pierce University, Greater Manchester [NH] Mental Health Center, and the New Hampshire Department of Corrections. He has provided clinical consultation on gender dysphoria to the department of corrections of the state of New Hampshire, and general psychiatric consultation at The Health Center, a federally qualified health center in Plainfield, Vermont. He is a member of the advisory committee of the Samara Fund, a philanthropic group serving the LGBT communities in Vermont. He has received fees or royalties from Johns Hopkins University Press, Taylor & Francis, and Healthwise, Inc. Travel funds have been provided by the American Psychiatric Association, related to service on the Assembly Executive Committee. He reports no conflicts of interest with his work on this guideline.

Dr. Hilty is employed as a professor of psychiatry at the University of Southern California. He reports no conflicts of interest with his work on this guideline.

Dr. Horvitz-Lennon is employed as a physician scientist at the RAND Corporation and a professor at the Pardee RAND Graduate School. She reports no conflicts of interest with her work on this guideline.

Dr. Jibson is employed as a professor of psychiatry at the University of Michigan. He receives royalties from Up-To-Date for chapters on first- and second-generation antipsychotic medications. He receives grant support and travel funds from the American Board of Psychiatry and Neurology through a Faculty Innovation Fellowship to study the ABPN-mandated Clinical Skills Evaluation in residency programs. He reports no conflicts of interest with his work on this guideline.

Dr. Lopez is employed as a professor of neurology at University of Pittsburgh. He has been principal investigator and co-investigator for research funded by the National Institute on Aging (NIA). He has been the site principal investigator in multicenter trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Élan, and NIA, and he has received travel funds to attend meetings related to these clinical trials. Dr. Lopez has received consulting fees from H. Lundbeck A/S and Grifols S.A., and he has received travel funds to attend meetings related to this activity. Dr. Lopez has actively participated in the discussions of the creation of all the items of the guideline. However, because his involvement with the industry and government can be perceived as a conflict of interest, he decided to abstain from voting in Statements 7–15 of the guideline.

Dr. Mahoney is employed as a researcher and clinical nurse specialist at The Menninger Clinic in Houston, Texas. She is also an associate professor in the Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine. Dr. Mahoney receives salary support and travel funds from the Arthur Vining Davis Foundations. She reports no conflicts of interest with her work on this guideline.

Dr. Pasic is employed as a professor of psychiatry at the University of Washington. She is a member of the board of the American Association of Emergency Psychiatry. She reports no conflicts of interest with her work on this guideline.

Dr. Tan is employed as an associate professor of geriatric medicine at the David Geffen School of Medicine, University of California, Los Angeles. He receives publication/writing honoraria from WebMD and has received a speaking honorarium from Optimum Health Education. He reports no conflicts of interest with his work on this guideline.

Dr. Wills is employed as an assistant professor of psychiatry at University Hospitals, Case Medical Center. She also has a private practice in forensic psychiatry. She receives no royalties from any entity. She receives travel funds but no honoraria from the American Academy of Psychiatry and the Law. She provides medicolegal consultation and expert testimony to courts. She reports no conflicts of interest with her work on this guideline.

Dr. Rhoads was employed as an assistant professor of psychiatry at the University of Arizona and as a Medical Director for the University of Arizona Medical Center, South Campus, and the Crisis Response Center (CRC) while consulting for the APA on the development of the practice guideline. He subsequently was employed by ConnectionsAZ, continuing as Medical Director of the CRC. He is currently employed as the chief medical officer for Cenpatico Integrated Care, and he is also employed by Correct Care Solutions to perform evaluations in the jail. He reports no conflicts of interest with his work on this guideline.

Dr. Yager is employed as a professor of psychiatry at the University of Colorado. He reports no conflicts of interest with his work on this guideline.

Individuals and Organizations That Submitted Comments

Vimal M. Aga, M.D.
Rebecca M. Allen, M.D., M.P.H.
James A. Bourgeois, O.D., M.D.
Ryan Carnahan, Pharm.D., BCPP
Lisa K. Catapano-Friedman, M.D.
Huai Y. Cheng, M.D.
Gregory Day, M.D.
D. P. Devanand, M.D.
Brian Draper, M.B.B.S., M.D.
Janel Draxler, R.N., PMHNP
Mary Ann Forciea, M.D.
Norman L. Foster, M.D.
Oliver Freudenreich, M.D.
Wolfang Gaebel, M.D.
Daron Gersch, M.D.
David Goen, R.N., PMHNP
William M. Greenberg, M.D.
Elizabeth Hames, D.O.
Nathan Herrmann, M.D.
Sheila Horras, R.N.
Marilyn Horvath, M.D.
Lee Hyer, Ph.D.
Elie Isenberg-Grzeda, M.D., C.M.
Sefi Knoble, M.D.
Thomas Krajewski, M.D.
John Krystal, M.D.
Amy M. Lewitz, R.N., C.S.
Dinesh Mittal, M.D.
Victor Molinari, Ph.D.
Maureen C. Nash, M.D.
Irene Ortiz, M.D.
David Osser, M.D.
L. Russell Pet, M.D.
Kemuel Philbrick, M.D.
Peter V. Rabins, M.D., M.P.H.
Ryann Rathbone, R.N., PMHNP
Susan Scanland, CRNP, GNP-BC, CDP
Erich Schmidt, Pharm.D., BCPP
Lon S. Schneider, M.D.
Scott Simpson, M.D., M.P.H.
Monica Tegeler, M.D.
Ladislav Volicer, M.D., Ph.D.
Bradley R. Williams, Pharm.D., CGP
Zhan Yang, FNP, PMHNP
APA Council on Geriatric Psychiatry
APA Council on Psychosomatic Medicine
Academy of Psychosomatic Medicine
Alzheimer’s Association
American Academy of Family Physicians
American College of Physicians
American Geriatrics Society
American Medical Directors Association—The Society for Post-Acute and Long-Term Care Medicine
American Psychiatric Nurses Association
American Psychological Association
World Psychiatric Association

Appendix A

Review of Available Evidence

Clinical Questions

Evidence review for this guideline was premised on the following clinical questions:

1A. What is the efficacy and comparative effectiveness of second-generation (“atypical”) antipsychotics for the treatment of overall behavioral symptoms in patients with Alzheimer’s disease and other dementias?
Sub-question: How do second-generation antipsychotic medications compare with other drugs, including first-generation antipsychotics, for the treatment of overall behavioral symptoms?
1B. What are the efficacy and comparative effectiveness of second-generation antipsychotics for the treatment of agitation in patients with Alzheimer’s disease and other dementias?
Sub-question: How do second-generation antipsychotic medications compare with other drugs, including first-generation antipsychotics, for the treatment of agitation in patients with Alzheimer’s disease and other dementias?
1C. What are the efficacy and comparative effectiveness of second-generation antipsychotics for the treatment of psychosis in patients with Alzheimer’s disease and other dementias?
Sub-question: How do second-generation antipsychotic medications compare with other drugs, including first-generation antipsychotics, for the treatment of psychosis in patients with Alzheimer’s disease and other dementias?
2. What are the effective dose and time limit for the use of second-generation antipsychotics for the treatment of agitation, psychosis, or overall behavioral symptoms in patients with Alzheimer’s disease and other dementias?
3. What subset of patients with Alzheimer’s disease and other dementias would potentially benefit from the use of second-generation antipsychotics for the treatment of agitation, psychosis, or overall behavioral symptoms? Do effectiveness and harms differ by race/ethnicity, gender, and age group? by severity of condition and clinical subtype?
4. What are the potential adverse effects and/or complications involved with prescribing of second-generation antipsychotics to patients with Alzheimer’s disease and other dementias for the treatment of agitation, psychosis, or overall behavioral symptoms? How do the potential adverse effects and/or complications compare within the class and with other drugs used?

Review of Supporting Research Evidence

Research evidence related to these clinical questions relies on the 2011 systematic review and meta-analysis conducted by AHRQ on off-label uses of atypical antipsychotic agents (Maglione et al. 2011), which built on a prior AHRQ review (Shekelle et al. 2007). A subsequent systematic review of the literature was conducted by APA staff (see section “Systematic Review Methodology” earlier in this guideline), and ratings of the risk of bias and the quality of the body of research evidence were completed by the Systematic Review Group (see section “Rating the Strength of Supporting Research Evidence” in “Guideline Development Process” earlier in this guideline).

Randomized placebo-controlled trials with sufficient data for standardized mean difference (SMD) calculations of outcome measures were included in the 2011 AHRQ review (Maglione et al. 2011); reported SMD values and summary statistics are from the AHRQ meta-analysis and use Hedges’ g to calculate effect size. Jadad scores of evidence quality (Jadad et al. 1996), which range from a low of 0 to a high of 5, were also taken from the AHRQ review when available or determined by the APA Systematic Review Group.

On the basis of the randomized placebo-controlled efficacy trials, the AHRQ report authors concluded that “aripiprazole, olanzapine, and risperidone have efficacy as treatment for behavioral symptoms of dementia” (Maglione et al., 2011, p. ES-5). The same medications were also noted in the AHRQ report to be superior to placebo for the treatment of agitation, with risperidone superior to placebo for the treatment of psychotic symptoms. However, the report authors also found that the “effect sizes were generally considered to be ’small’ in magnitude” (Maglione et al. 2011, p. ES-5).

Research evidence for efficacy of second-generation antipsychotics (SGAs) from placebo-controlled trials

Antipsychotic	Symptom domain	Confidence	Effect	SMD (95% CI)
Aripiprazole	BPSD	Moderate	Small	0.20 (0.04, 0.35)
Aripiprazole	Agitation	Low	Small	—
Aripiprazole	Psychosis	Low	Nonsignificant	0.14 (− 0.02, 0.29)
Olanzapine	Overall BPSD	Low	Very small	0.12 (0.00, 0.25)
Olanzapine	Agitation	Moderate	Very small	0.10 (0.07, 0.31)
Olanzapine	Psychosis	Insufficient	Nonsignificant	0.05 (− 0.07, 0.17)
Quetiapine	Overall BPSD	Low	Nonsignificant	0.13 (− 0.03, 0.28)
Quetiapine	Agitation	Insufficient	Nonsignificant	0.06 (− 0.14, 0.25)
Quetiapine	Psychosis	Insufficient	Nonsignificant	0.04 (− 0.11, 0.19)
Risperidone	Overall BPSD	Moderate	Very small	0.19 (0.00, 0.38)
Risperidone	Agitation	Moderate	Small	0.22 (0.09, 0.35)
Risperidone	Psychosis	Moderate	Small	0.20 (0.05, 0.36)
SGAs overall	Overall BPSD	High	Very small	—
SGAs overall	Agitation	Moderate	Small	—
SGAs overall	Psychosis	Low	Very small	—
Note. BPSD = behavioral and psychological symptoms of dementia; CI = confidence interval; SMD = standardized mean difference. Source. Adapted from Maglione et al. 2011.

Comparison	Symptom domain	Confidence	Effect
SGA vs. haloperidol	Overall BPSD	Low	No difference
SGA vs. haloperidol	Agitation	Low	No difference
SGA vs. haloperidol	Psychosis	Insufficient	Unable to determine
Olanzapine or quetiapine vs. risperidone	Overall BPSD	Low	No difference
Olanzapine or quetiapine vs. risperidone	Agitation	Low	No difference
Olanzapine or quetiapine vs. risperidone	Psychosis	Insufficient	Unable to determine
SGA vs. other comparators	Overall BPSD	Insufficient	Unable to determine
SGA vs. other comparators	Agitation	Insufficient	Unable to determine
SGA vs. other comparators	Psychosis	Insufficient	Unable to determine
Lower doses vs. higher doses		Insufficient	Unable to determine
Continue on antipsychotic vs. change to placebo		Moderate	Small benefit for continued antipsychotic
Note. BPSD = behavioral and psychological symptoms of dementia; SGA = second-generation antipsychotic. Source. Adapted from Maglione et al. 2011.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1A	Breder et al. 2004; Mintzer et al. 2007	Nursing home residents with MMSE scores 6–22 and NPI or NPI-NH score > 5 for hallucinations and delusions Interventions: placebo and three fixed doses of aripiprazole (2 mg, 5 mg, 10 mg) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in long-term care facilities internationally, including the United States and Canada	487 subjects enrolled; data for 284 were analyzed	10 weeks	Aripiprazole vs. placebo: total SMD = 0.16 (− 0.05, 0.37); psychosis SMD = 0.24 (0.03, 0.45); agitation SMD = 0.31 (0.10, 0.52)	1, 2
1A	De Deyn et al. 2005	Non-institutionalized subjects with Alzheimer’s disease and psychosis Interventions: placebo and aripiprazole at doses ranging from 2 to 15 mg/day (average dose: 10 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in the United States, Canada, Western Europe, and Australia/New Zealand	208 subjects; 83% completed the trial with no difference in dropouts between placebo and aripiprazole	10 weeks	Aripiprazole vs. placebo: total SMD = 0.06 (− 0.21, 0.34); psychosis SMD = 0.16 (− 0.12, 0.43)	3
1A	Streim et al. 2008	Subjects with Alzheimer’s disease, residing in nursing homes, with psychosis Interventions: placebo, aripiprazole at doses ranging from 0.7 to 15 mg/day (average dose: 8.6 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in long-term care facilities in the United States	256 subjects enrolled; data for 151 were analyzed	10 weeks, after 1-week washout	Aripiprazole vs. placebo: total SMD = 0.36 (0.11, 0.61); psychosis SMD = − 0.02 (− 0.27, 0.23); agitation SMD = 0.30 (0.05, 0.55)	2
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BPSD = behavioral and psychological symptoms of dementia; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1A	Deberdt et al. 2005	Subjects with Alzheimer’s dementia, vascular dementia, or mixed dementia, in outpatient or residential settings, with NPI or NPI-NH score > 5 on hallucination and delusion items Interventions: placebo vs. flexibly dosed olanzapine (2.5–10 mg/day; mean dose: 5.2 mg/day) or risperidone (0.5–2 mg/day; mean dose: 1.0 mg/day) Design: double-blind randomized trial Industry-sponsored multicenter trial in the United States	494 subjects, with 94 receiving placebo, 204 receiving olanzapine, and 196 receiving risperidone	10 weeks	Olanzapine vs. placebo: total SMD = − 0.02 (− 0.27, 0.23); psychosis SMD = − 0.12 (− 0.36, 0.13); agitation SMD = 0.09 (− 0.16, 0.34)	2
1A	De Deyn et al. 2004	Subjects with Alzheimer’s disease (MMSE scores 5–26), in long-term care settings, with hallucinations or delusions Interventions: placebo or fixed doses of olanzapine (1, 2.5, 5, or 7.5 mg/day) Design: double-blind randomized trial in Europe, Israel, Lebanon, Australia/New Zealand, and South Africa Industry-sponsored multicenter trial	652 subjects; 65%–75% of subjects in each study arm completed the trial	10 weeks	Olanzapine vs. placebo: total SMD = 0.14 (− 0.05, 0.34); psychosis SMD = 0.17 (− 0.02, 0.37); agitation SMD = 0.14 (− 0.05, 0.33)	2
1A	Schneider et al. 2006; Sultzer et al. 2008	Subjects with Alzheimer’s disease or probable Alzheimer’s disease (MMSE scores 5–26), ambulatory and residing at home or in assisted living, with moderate or greater levels of psychosis, aggression, or agitation Interventions: placebo vs. masked, flexibly dosed olanzapine (mean dose: 5.5 mg/day), quetiapine (mean dose: 56.5 mg/day), or risperidone (mean dose: 1.0 mg/day) Stable doses of cholinesterase inhibitor were permitted. Design: multicenter, federally funded CATIE-AD trial—Phase 1	421 subjects randomly assigned to treatment group, with 142 receiving placebo, 100 receiving olanzapine, 94 receiving quetiapine, and 85 receiving risperidone	Median duration on Phase 1 treatment was 7.1 weeks; clinical outcomes assessed for those continuing to receive antipsychotic at 12 weeks	Olanzapine vs. placebo: total SMD = 0.15 (− 0.11, 0.40); psychosis SMD = 0.07 (− 0.19, 0.33); agitation SMD = 0.28 (0.02, 0.53)	1
1A	Street et al. 2000	Subjects with possible or probable Alzheimer’s disease, residing in a nursing facility, with NPI-NH score > 2 Interventions: placebo vs. fixed doses of olanzapine (5, 10, or 15 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial in the United States	206 subjects; 66%–80% of subjects in each study arm completed the trial	6 weeks	Olanzapine vs. placebo: total SMD = 0.30 (− 0.03, 0.63); psychosis SMD = 0.17 (− 0.17, 0.50); agitation SMD = 0.39 (0.05, 0.72)	5
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BPSD = behavioral and psychological symptoms of dementia; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1A	Brodaty et al. 2003, 2005	Subjects with DSM-IV diagnosis of dementia of the Alzheimer’s type, vascular dementia, or mixed dementia, residing in nursing homes, with MMSE score < 24 and significant aggressive behavior Interventions: placebo vs. risperidone (flexibly dosed up to 2 mg/day; mean dose: 0.95 mg/day). Design: double-blind randomized trial Industry-sponsored multicenter trial in Australia/New Zealand	345 subjects	12 weeks	Risperidone vs. placebo: total SMD = 0.46 (0.23, 0.69); psychosis SMD = 0.36 (0.13, 0.59); agitation SMD = 0.37 (0.14, 0.59)	3
1A	Deberdt et al. 2005	Subjects with Alzheimer’s dementia, vascular dementia, or mixed dementia, in outpatient or residential settings, with NPI or NPI-NH score > 5 on hallucination and delusion items Interventions: placebo vs. flexibly dosed olanzapine (2.5–10 mg/day; mean dose: 5.2 mg/day) or risperidone (0.5–2 mg/day; mean dose: 1.0 mg/day) Design: double-blind randomized trial Industry-sponsored multicenter trial in the United States	494 subjects, with 94 receiving placebo, 204 receiving olanzapine, and 196 receiving risperidone	10 weeks	Risperidone vs. placebo: total SMD = − 0.13 (− 0.38, 0.12); psychosis SMD = − 0.03 (− 0.34, 0.16); agitation SMD = 0.14 (− 0.11, 0.39)	2
1A	De Deyn et al. 1999	Hospitalized or institutionalized subjects with MMSE score < 24 and BEHAVE-AD score > 7 Interventions: placebo vs. flexibly dosed haloperidol (0.5–4 mg/day; mean dose: 1.2 mg/day) or risperidone (0.5–4 mg/day; mean dose: 1.1 mg/day) Design: randomized trial Industry-sponsored multicenter trial in the United Kingdom and Europe	344 subjects; 68 of 115 subjects treated with risperidone, 81 of 115 subjects treated with haloperidol, and 74 of 114 subjects receiving placebo completed the trial	12 weeks	Risperidone vs. placebo: total SMD = 0.12 (− 0.14, 0.38); agitation SMD = 0.31 (0.05, 0.57)	4
1A	Katz et al. 1999	Subjects with DSM-IV diagnosis of Alzheimer’s disease, vascular dementia, or mixed dementia, residing in a nursing home or chronic care facility, with MMSE score < 24 and significant psychotic and behavioral symptoms (BEHAVE-AD score > 7) Interventions: placebo vs. fixed doses of risperidone (0.5 mg/day, 1 mg/day, or 2 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in the United States	625 subjects; 70% of whom completed the study	12 weeks	Risperidone vs. placebo: total SMD = 0.32 (0.11, 0.53); psychosis SMD = 0.20 (− 0.01, 0.41); agitation SMD = 0.38 (0.17, 0.60)	4
1A	Mintzer et al. 2006	Subjects with symptoms meeting criteria for Alzheimer’s dementia (MMSE scores 5–23), residing in nursing homes or long- term care facilities, who were mobile and had psychosis Interventions: placebo vs. flexibly dosed risperidone (0.5–1.5 mg/day; mean dose: 1.03 mg/day) Design: randomized controlled trial Industry-sponsored multicenter trial conducted in the United States	473 subjects randomly assigned to treatment group, with 238 receiving placebo and 235 receiving risperidone; 354 of the subjects completed the study	8 weeks, after 1–16 days of placebo run-in/washout	Risperidone vs. placebo: total SMD = −0.01 (− 0.21, 0.18); psychosis SMD = 0.17 (− 0.02, 0.36); agitation SMD = 0.04 (− 0.16, 0.23)	3
1A	Schneider et al. 2006; Sultzer et al. 2008	Subjects with Alzheimer’s disease or probable Alzheimer’s disease (MMSE scores 5–26), ambulatory and residing at home or in assisted living, with moderate or greater levels of psychosis, aggression, or agitation Interventions: placebo vs. masked, flexibly dosed olanzapine (mean dose: 5.5 mg/day), quetiapine (mean dose: 56.5 mg/day), or risperidone (mean dose: 1.0 mg/day) Stable doses of cholinesterase inhibitor were permitted. Design: multicenter, federally funded CATIE-AD trial—Phase 1	421 subjects randomly assigned to treatment group, with 142 receiving placebo, 100 receiving olanzapine, 94 receiving quetiapine, and 85 receiving risperidone	Median duration on Phase 1 treatment was 7.1 weeks; clinical outcomes assessed for those continuing to receive antipsychotic at 12 weeks	Risperidone vs. placebo: total SMD = 0.40 (0.13, 0.68); psychosis SMD = 0.38 (0.11, 0.66); agitation SMD = 0.10 (− 0.17, 0.37)	1
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease; BPSD = behavioral and psychological symptoms of dementia; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; MMSE = Mini-Mental State Examination; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1	Chan et al. 2001	Inpatients or outpatients with DSM-IV diagnosis of dementia of Alzheimer’s type or vascular dementia associated with behavioral symptoms Interventions: flexibly dosed haloperidol (0.5–2 mg/day; mean dose: 0.90 mg/day) vs. risperidone (0.5–2 mg/day; mean dose: 0.85 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in Hong Kong	58 subjects	3 months	Haloperidol vs. risperidone: change in BEHAVE-AD dementia (aggressiveness): SMD = 0.057 (− 0.472, 0.585); change in BEHAVE-AD dementia (psychosis): SMD = − 0.383 (− 0.917, 0.15) Scores on the CMAI and BEHAVE-AD were significantly improved by both haloperidol and risperidone, with no significant differences between the two treatments. Patients treated with haloperidol, but not those treated with risperidone, showed an increase in EPS on the SAS.	3
1A	De Deyn et al. 1999	Hospitalized or institutionalized subjects with MMSE score < 24 and BEHAVE-AD score > 7 Interventions: placebo vs. flexibly dosed haloperidol (0.5–4 mg/day; mean dose: 1.2 mg/day) or risperidone (0.5–4 mg/day; mean dose: 1.1 mg/day) Design: randomized trial Industry-sponsored multicenter trial in the United Kingdom and Europe	344 subjects; 68 of the 115 risperidone, 81 of the 115 subjects treated with haloperidol, and 74 of the 114 subjects receiving placebo completed the trial	12 weeks	Risperidone vs. haloperidol: total SMD = − 0.19 (− 0.45, 0.07); agitation SMD = − 0.07 (− 0.19, − 0.33)	4
1	Suh et al. 2004, 2006	Subjects in a nursing facility with a diagnosis of Alzheimer’s disease, vascular dementia, or mixed dementia associated with behavioral disturbance FAST > 3, BEHAVE-AD score > 7, and CMAI score > 2 on at least two items Interventions: flexibly dosed risperidone (0.5–1.5 mg/day; mean dose: 0.80 mg/day) vs. haloperidol (0.5–1.5 mg/day; mean dose: 0.83 mg/day) Design: randomized double-blind crossover trial Industry-sponsored trial at a single center in Korea	120	18 weeks	Compared with treatment with haloperidol, risperidone treatment was associated with greater clinical improvement on total and subscale scores of the Korean version of BEHAVE-AD, total and subscale scores of the Korean version of CMAI, and the CGI-C as well as a lower frequency of EPS.	4
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease; BPSD = behavioral and psychological symptoms of dementia; CGI-C = Clinical Global Impression of Change; CMAI = Cohen-Mansfield Agitation Inventory; EPS = extrapyramidal side effects; FAST = Functional Assessment Staging; MMSE = Mini-Mental State Exam; SAS = Simpson-Angus Scale; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1	Ballard et al. 2005	Subjects with a diagnosis of Alzheimer’s disease, residing in nursing care facilities in England, with clinically significant agitation Interventions: placebo vs. rivastigmine (3–6 mg BID by week 12 and > 8 mg daily by week 26) vs. quetiapine (25–50 mg BID by week 12 and 50 mg BID by week 26) Design: double-blind randomized controlled trial Funded by general donations to the principal investigator’s research program and profits from prior industry-sponsored trials	93 subjects; 80 started treatment (25 receiving rivastigmine, 26 receiving quetiapine, and 29 receiving placebo), and 71 tolerated the maximum protocol dose (22 rivastigmine, 23 quetiapine, 26 placebo); 56 had a baseline score of > 10 on the SIB, and 46 of these subjects were included in the analysis at 6-week follow up (14 receiving rivastigmine, 14 receiving quetiapine, and 18 receiving placebo).	26 weeks total; primary outcome was agitation at 6 weeks	Rivastigmine vs. quetiapine: change in CMAI dementia (agitation) SMD = − 0.051 (− 0.601, 0.499) When treated with either rivastigmine or quetiapine as compared with placebo, subjects failed to show an improvement in agitation. Relative to placebo, quetiapine, but not rivastigmine, was associated with greater cognitive decline as measured by the SIB score.	4
1	Barak et al. 2011	Inpatients with Alzheimer’s dementia who had been admitted for behavioral symptoms, including psychosis and agitation Interventions: risperidone 1 mg/day vs. escitalopram 10 mg/day Design: double-blind randomized trial Trial conducted in Israel	40 subjects	6 weeks	Degree of improvement as measured by the NPI was comparable in those treated with risperidone as compared with those treated with escitalopram. Premature discontinuation occurred in 45% of risperidone-treated subjects and 25% of escitalopram-treated subjects, primarily because of adverse events. Serious adverse effects, including severe extrapyramidal side effects and acute illness requiring hospitalization, occurred in 6 risperidone-treated patients.	5
1	Culo et al. 2010	Subjects with dementia with Lewy body (DLB) or Alzheimer’s disease (AD) who were hospitalized for behavioral disturbance Interventions: risperidone (started at 0.5 mg/day for 3 days, then increased to two capsules/day for 2 weeks, with two additional dosage increases up to four capsules/day allowed) vs. citalopram (started at 10 mg/day for 3 days, then increased to two capsules/day for 2 weeks, with two additional dosage increases up to four capsules/day allowed) Design: double-blind randomized controlled trial Trial conducted at Western Psychiatric Institute and Clinic in Pittsburgh, PA	31 patients with DLB and 66 patients with AD; of the 408 patients who were prescreened, 111 signed consent and were screened, and 103 were randomly assigned to treatment group	Up to 12 weeks	Efficacy of citalopram or risperidone was comparable for subjects overall, but AD patients showed improved scores on the NPI and CGI-C, whereas DLB patients showed a worsening on both measures. Discontinuation rates were similar for DLB patients who were treated with citalopram (71%) or risperidone (65%). However, premature discontinuation rates were higher in participants with DLB (68%) than in those with AD (50%), and treated DLB subjects who had been randomly assiged to receive risperidone had more side effects.	4
1	De Deyn et al. 2012	Subjects age 65 years or older with Alzheimer’s disease, residing in nursing homes or equivalent institutions, with symptoms of psychosis and/or agitation Interventions: XR vs. IR quetiapine; doses were 50 mg/day XR and 25 mg/day IR. Treatment was escalated to 100 mg/day by day 4 (for both XR and IR). At day 8, a period of flexible dosing (50–300 mg/day) began when dose adjustment was made at the investigator’s discretion Design: double-blind, double-dummy, parallel-group randomized controlled trial Trial conducted at 14 sites in Australia, Belgium, Canada, Norway, and South Africa	Of the 109 patients screened, 100 were randomly assigned to receive quetiapine XR (n = 68) or quetiapine IR (n = 32); 90 patients completed the study (1 patient receiving quetiapine XR withdrew because of an adverse event).	6 weeks; enrollment and screening were conducted between May 2002 and February 2003	Relative to baseline, both the IR and the XR formulations of quetiapine were associated with improvements in NPI frequency x severity total score and the NPI disruption score, as well as improvements in the CMAI score. Global ratings using the CGI–Severity of Illness and CGI–Improvement scores also showed benefit from both formulations.	3
1	Freund-Levi et al. 2014a, 2014b	Subjects with a diagnosis of dementia and associated neuropsychiatric symptoms who were being treated on an inpatient or outpatient basis at a university hospital in Sweden Interventions: galantamine (target dose: 24 mg) vs. risperidone (target dose: 1.5 mg) Design: open-label randomized trial Trial conducted at a single center in Sweden	100 subjects (50 in each group); 91 completed the study	12 weeks	Treatments with galantamine and with risperidone were associated with decreases in agitation. However, improvement was more pronounced with risperidone than with galantamine (mean difference in total CMAI score: 3.7 points at 3 weeks [P = 0.03] and 4.3 points at 12 weeks [P = 0.01]). NPI domains of irritation and agitation also showed greater benefit with risperidone (F(1,97) = 5.2, P = 0.02). However, galantamine treatment was associated with an improvement in MMSE scores, with an increase of 2.8 points compared with baseline (95% CI: 1.96, 3.52). No severe treatment-related side effects were reported with either treatment.	0
1A	Holmes et al. 2007	Subjects with severe probable Alzheimer’s disease, residing in nursing home setting, with MMSE score < 6 and CMAI score> 3 for at least 6 weeks Interventions: fixed titration with rivastigmine 3–6 mg/day vs. risperidone 0.5 mg/day Exclusion criteria included prior exposure to cholinesterase inhibitor or antipsychotic (> 20 mg thioridazine equivalents per day). Design: double-blind randomized controlled trial Trial conducted in the United Kingdom	27 subjects	6 weeks	Rivastigmine vs. risperidone: change in CMAI (agitation) SMD = 1.31 (0.47–2.15)	3
1	Mowla and Pani 2010	Subjects with mild to moderate DSM-IV Alzheimer’s disease and behavioral disturbance Interventions: flexibly dosed topiramate (average dose: 44 mg/day) or risperidone (average dose: 1.9 mg/day) Design: randomized controlled trial Multisite trial; Bushehr University of Medical Sciences, Iran	48 subjects, with 25 receiving topiramate and 23 receiving risperidone; 41 total subjects completed the trial	8 weeks	Topiramate vs. risperidone: change in NPI (total) SMD = 0.23 (− 0.38, 0.85); change in CMAI (agitation) SMD = 0.06 (− 0.56, 0.67) Both topiramate and risperidone were associated with significant improvements in all outcome measures.	5
1	Pollock et al. 2007	Subjects with dementia admitted to hospital for moderate to severe agitation or psychosis but no significant depressive symptoms or recent depressive episodes and no unstable physical illness Interventions: flexibly dosed citalopram (average dose: 29.4 mg/day) or risperidone (average dose: 1.25 mg/day) Subjects could continue taking cholinesterase inhibitors or memantine if they had been taking them for at least 12 weeks at a stable dose; lorazepam at up to 2 mg/day was also permitted for extreme agitation or aggression. Design: Double-blind randomized trial Trial conducted in Canada; funding by U.S. Public Health Service and Sandra A. Rotman Program in Neuropsychiatry, Toronto, Ontario, Canada	408 subjects were screened; 103 were randomly assigned (citalopram, n = 53; risperidone, n = 50); 45 completed treatment (citalopram, n = 25; risperidone, n = 20)	12-week trial conducted between February 2000 to June 2005	No significant differences were seen between citalopram and risperidone in outcomes or time to dropout. On the NRS, there were significant decreases in psychosis scores for both medications (32.3% and 35.2% decreases for citalopram and risperidone, respectively). The decrease in agitation scores was significant for citalopram (12.5%) but not for risperidone (8.2%).	5
1	Teranishi et al. 2013	Subjects with DSM-IV Alzheimer’s dementia admitted to hospital for unmanageable behavioral symptoms Interventions: flexibly dosed risperidone (average dose: 1.1 mg/day), yokukansan (average dose: 7 mg/day), or fluvoxamine (average dose: 83 mg/day) Subjects could continue taking donepezil and could receive anticholinergic medications for EPS and zopiclone or brotizolam for insomnia. Design: rater-blinded randomized trial Trial conducted at a psychiatric hospital in Japan	90 subjects screened; 82 enrolled and data for 76 analyzed (risperidone, n = 25; yokukansan, n = 26; fluvoxamine, n = 25)	8 weeks, preceded by 1-week washout, with data collected between January 2009 and August 2010	All three drugs significantly reduced NPI-NH total scores from 26.20 (SD, 15.77) to 17.72 (SD, 11.49), with no significant differences among groups. Single-item scores were significantly reduced for delusions, agitation, disinhibition, aberrant motor behavior, and nighttime behavior disturbances, again with no significant group differences. MMSE scores and FIM scores showed no significant change during the study. Constipation was the most common adverse event in all groups, with a significant increase in frequency with risperidone. EPS and muscle rigidity were also significantly increased in frequency with risperidone (19.2% of that treatment group).	2
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BPSD = behavioral and psychological symptoms of dementia; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; CGI = Clinical Global Impression; CGI-C = Clinical Global Impression of Change; CI = confidence interval; CMAI = Cohen-Mansfield Agitation Inventory; EPS = extrapyramidal side effects; FIM = Functional Independence Measure; IR = immediate release; MMSE = Mini-Mental State Exam; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; NRS = Neurobehavioral Rating Scale; SIB = Severe Impairment Battery; SAS = Simpson-Angus Scale; SD = standard deviation; SMD = standardized mean difference; XR = extended release. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1	Ballard et al. 2004	Nursing home residents with probable or possible Alzheimer’s disease (by NINCDS/ADRDA criteria) who had no severe behavioral disturbances and had been taking neuroleptics for longer than 3 months Interventions: prescriptions written, in a twice-daily regimen, allocating the closest dose to participant’s preexisting prescription from the doses encapsulated (risperidone 0.5 mg, chlorpromazine 12.5 mg, thioridazine 12.5 mg, trifluoperazine 0.5 mg, haloperidol 0.25 mg) After randomization, study medication replaced existing medication on the day of commencement. Design: double-blind, placebo-controlled randomized discontinuation study Multicenter trial in the United Kingdom	100 subjects enrolled, with 82 completing 1-month assessment (36 receiving placebo, 46 receiving active treatment)	3 months	Subjects with higher baseline NPI scores (> 14) were significantly more likely to develop marked behavioral problems when antipsychotic medication was discontinued (χ² = 6.8, P = 0.009). Similar proportions of antipsychotic- and placebo-treated subjects withdrew from the study prematurely, overall and because of worsening behavioral symptoms.	3
1	Ballard et al. 2008, 2009	Subjects with dementia, residing in nursing facilities, who had been receiving antipsychotic medication for at least 3 months for behavioral or psychiatric disturbance Interventions: continuation of antipsychotic (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) or change to receiving placebo Design: Blinded, placebo-controlled, parallel-group randomized discontinuation trial Multicenter trial (Dementia Antipsychotic Withdrawal Trial) in the United Kingdom	165 subjects randomly assigned to treatment group (83 to antipsychotic treatment group; 82 to placebo group); 128 initiated intervention (64 in each condition); 13 were lost to follow-up in each study arm. 51 subjects per condition completed the study.	12 months	Continuation treatment and placebo groups had no significant difference in the estimated mean change between baseline and 6 months in SIB scores (estimated mean difference in deterioration favoring placebo: − 0.4 [95% CI: − 6.4, 5.5]) or NPI scores (estimated mean difference in deterioration favoring continued treatment: − 2.4 [95% CI: − 8.2, 3.5]). There continued to be no difference between continuation treatment and placebo groups at 12 months, although some evidence suggested that subjects with initial NPI scores ≥ 15 showed reduced neuropsychiatric symptoms with continuing treatment. Subjects who continued to receive antipsychotic treatment had a lower cumulative probability of survival at 12 months, with 70% (95% CI: 58%, 80%) survival in the continued treatment group versus 77% (95% CI: 64%, 85%) in the placebo group for subjects receiving at least one dose of drug or placebo. Differences between groups were more pronounced at longer periods of follow-up (24-month survival: 46% vs. 71%; 36-month survival: 30% vs. 59%) with an HR of 0.58 (95% CI: 0.35, 0.95).	5
1	Devanand et al. 2011	Outpatients with Alzheimer’s disease with psychosis or agitation who had responded to 20 weeks of open-label haloperidol (0.5–5 mg/day) as defined by a minimum of a 50% reduction in three target symptoms, and improvement in CGI-C score for psychosis/agitation Interventions: randomization to placebo vs. continuation of haloperidol Design: double-blind randomized trial in the United States	44 patients at trial entry; of the 22 responders to haloperidol, 21 entered the randomized portion of the trial, and 20 had at least one follow-up visit.	6 months	Open-label haloperidol was associated with a significant decrease in symptoms but a significant increase in EPS. 4 of 10 patients who continued to take haloperidol relapsed as compared with 8 of 10 patients receiving placebo, but this difference was not statistically significant. (Relapse criteria required 50% worsening in target symptoms and CGI-C scores.) Time to relapse was shorter for placebo than for haloperidol (P = 0.04).	3
1	Devanand et al. 2012	Patients with Alzheimer’s disease and psychosis or agitation-aggression, 50–95 years of age, who were recruited from memory clinics (including Alzheimer’s research centers), geriatric psychiatry clinics, and clinics at Veterans Affairs medical centers; through physician referrals and advertising; or from assisted-living facilities (outpatient or residents) or nursing homes Interventions: 16-week open-label risperidone phase, then randomization to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3) Design: double-blind randomized controlled trial	180 patients received open-label risperidone (mean dose, 0.97 mg/day). Criteria for response to treatment were met in 112 patients; 110 of these subjects underwent randomization.	32 weeks in randomized phase (after the 16-week open-label phase)	Outcome measures: time to relapse of psychosis or agitation, adverse events, mortality. 16-week relapse rate was higher in patients receiving placebo than in those treated with risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P = 0.004; HR with placebo = 1.94; 95% CI: 1.09, 3.45; P = 0.02). 32-week relapse rate was higher in group 2 than in group 1 (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P = 0.02; HR = 4.88; 95% CI: 1.08, 21.98; P = 0.02).	5
1	Ruths et al. 2004, 2008	Subjects with dementia, residing in nursing homes, who were taking haloperidol, risperidone, or olanzapine for nonpsychotic symptoms for at least 3 months Interventions: continuation of treatment with antipsychotic medication or change to placebo Design: double-blind, placebo-controlled randomized trial Multicenter trial in Norway	55 subjects; 27 of the subjects had antipsychotic medication discontinued, and 28 had antipsychotic medication continued.	4 weeks	In subjects who had antipsychotic discontinued, the proportion of individuals who continued not to take an antipsychotic medication was 85%, 46%, and 33% at 1, 2, and 5 months after drug discontinuation. In a subset of 30 patients, antipsychotic discontinuation was associated with reduced sleep efficiency and greater activity levels as measured by actigraphy.	4
1	van Reekum et al. 2002	Subjects with dementia, residing in nursing facilities, who had been receiving antipsychotic medication (risperidone, olanzapine, haloperidol, thioridazine, or loxapine) for more than 6 months, and had behavioral symptoms that were currently stable Interventions: continue treatment or change to placebo Design: randomized trial of antipsychotic discontinuation Multicenter trial in Canada; not industry sponsored	34 subjects; 10 of the 16 subjects receiving placebo and 6 of the 16 subjects receiving active treatment withdrew from the trial before completion.	6 months	About one-quarter of subjects in each group showed a worsening of behavioral symptoms. More subjects in the placebo group withdrew from the study for worsening behavior, but this difference was not statistically significant. Data suggested that subjects taking a higher baseline dose of antipsychotic were more likely to have a worsening of behavior upon discontinuation of antipsychotic medication.	3
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; ADRDA = Alzheimer’s Disease and Related Disorders Association; CGI-C = Clinical Global Impression of Change; CI = confidence interval; EPS = extrapyramidal side effects; HR = Kaplan-Meier hazard ratio; NINCDS = National Institute of Neurological and Communicative Diseases; NPI = Neuropsychiatric Inventory; NPI-Q = NPI-Questionnaire; SIB = Severe Impairment Battery. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1	Chan et al. 2001	Inpatients or outpatients with a DSM-IV diagnosis of dementia of Alzheimer’s type or vascular dementia associated with behavioral symptoms Interventions: flexibly dosed haloperidol (0.5–2 mg/day; mean dose: 0.90 mg/day) vs. risperidone (0.5–2 mg/day; mean dose: 0.85 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial in Hong Kong	58 subjects	3 months	Haloperidol vs. risperidone: change in BEHAVE-AD dementia (aggressiveness) SMD = 0.057 (− 0.472, 0.585); change in BEHAVE-AD dementia (psychosis) SMD = − 0.383 (− 0.917, 0.15) Scores on the CMAI and BEHAVE-AD were significantly improved by both haloperidol and risperidone, with no significant differences between the two treatments. Haloperidol-treated patients, but not risperidone-treated patients, showed an increase in EPS on the SAS.	3
1A	De Deyn et al. 1999	Hospitalized or institutionalized subjects with MMSE score < 24 and a BEHAVE-AD score > 7 Interventions: placebo vs. flexibly dosed haloperidol (0.5–4 mg/day; mean dose: 1.2 mg/day) or risperidone (0.5–4 mg/day; mean dose: 1.1 mg/day) Design: randomized trial Industry-sponsored multicenter trial in the United Kingdom and Europe	344 subjects	12 weeks	Risperidone vs. haloperidol: total SMD = − 0.19 (− 0.45, 0.07); agitation SMD = − 0.07 (− 0.19, 0.33)	4
1A	Savaskan et al. 2006	Inpatients with ICD-10 Alzheimer’s disease and associated behavioral symptoms Interventions: haloperidol (0.5–4 mg/day; mean dose: 1.9 mg/day) vs. quetiapine (25–200 mg/day; mean dose: 125 mg/day); fixed titration schedule with weekly dose increments to final dose Design: open-label randomized controlled trial Trial conducted in Switzerland; two of the three investigators were noted to be supported by an industry-sponsored grant.	30 subjects enrolled; 4 dropped out, and 4 had missing data; data for 22 analyzed	5 weeks, after run-in period of up to 7 days	Quetiapine vs. haloperidol: total SMD = 0.99 (0.10, 1.88); agitation SMD = 0.06 (− 0.78, 0.89)	2
1	Suh et al. 2004, 2006	Subjects residing in a nursing facility with a diagnosis of Alzheimer’s disease, vascular dementia, or mixed dementia associated with behavioral disturbance (FAST score > 3, BEHAVE-D score > 7, CMAI score > 2 on at least two items) Interventions: flexibly dosed risperidone (0.5–1.5 mg/day; mean dose: 0.80 mg/day) vs. haloperidol (0.5-1.5 mg/day; mean dose: 0.83 mg/day) Design: double-blind, crossover, randomized trial Industry-sponsored trial at a single center in Korea	120 subjects	18 weeks	Compared with haloperidol treatment, risperidone treatment was associated with greater clinical improvement on total and subscale scores of the Korean version of BEHAVE-AD, on total and subscale scores of the Korean version of CMAI, and on the CGI-C, as well as a lower frequency of EPS.	4
1A	Tariot et al. 2006	Subjects with DSM-IV Alzheimer’s disease (MMSE score > 4), residing in a nursing facility, with psychosis and BPRS score > 23 Interventions: placebo vs. flexibly dosed haloperidol (0.5–12 mg/day; mean dose: 1.9 mg/day) or quetiapine (25–600 mg/day; mean dose: 96.9 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial in the United States	284 subjects; data for 180 analyzed	10 weeks	Quetiapine vs. haloperidol: total SMD = 0.16 (− 0.16, 0.47); agitation SMD = 0.04 (− 0.26, 0.34)	4
1A	Verhey et al. 2006	Subjects with DSM-IV diagnosis of dementia, living in nursing homes or their own homes, who were judged to be in need of treatment for clinically significant agitation (CMAI score > 44) Interventions: haloperidol (1–3 mg/day; mean dose: 1.75 mg) vs. olanzapine (2.5–7.5 mg/day; mean dose: 4.71 mg) Design: double-blind, two-arm randomized controlled study Randomization took place after a 3- to 11-day washout. Multicenter trial conducted in the Netherlands; funding source not noted	59 subjects; 1 excluded for missing data; 3 patients, all of whom were in the olanzapine group, withdrew from the study	5 weeks total; titration for up to 2 weeks, and at least 3 weeks at stable dose	Olanzapine vs. haloperidol: total SMD = − 0.18 (− 0.77, 0.41); agitation SMD = − 0.21 (− 0.73, 0.31) AHRQ does not report SMD for psychosis comparison, but the change in the NPI psychosis item showed no significant difference in the scores for the two treatments.	3
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease; BPRS = Brief Psychiatric Rating Scale; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; CGI-C = Clinical Global Impression of Change; CMAI = Cohen-Mansfield Agitation Inventory; EPS = extrapyramidal side effects; FAST = Functional Assessment Staging; MMSE = Mini-Mental State Exam; NPI = Neuropsychiatric Inventory; SAS = Simpson-Angus Scale; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1A	Breder et al. 2004; Mintzer et al. 2007	Nursing home residents with MMSE scores 6–22 and NPI or NPI-NH score >5 for hallucinations and delusions Interventions: placebo vs. three fixed doses of aripiprazole (2 mg, 5 mg, 10 mg) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in long-term care facilities internationally, including the United States and Canada	487 subjects enrolled; data for 284 analyzed	10 weeks	Aripiprazole vs. placebo: total SMD = 0.16 (− 0.05, 0.37); psychosis SMD = 0.24 (0.03, 0.45); agitation SMD = 0.31 (0.10, 0.52)	1, 2
1A	De Deyn et al. 2005	Non-institutionalized subjects with Alzheimer’s disease and psychosis Interventions: placebo vs. aripiprazole (2–15 mg/day) Design: double-blind randomized controlled trials Industry-sponsored multicenter trial conducted in the United States, Canada, Western Europe, and Australia/New Zealand	208 subjects	10 weeks	Aripiprazole vs. placebo: total SMD = 0.06 (− 0.21, 0.34); psychosis SMD = 0.16 (− 0.12, 0.43)	3
1A	Streim et al. 2008	Nursing home residents with Alzheimer’s disease and psychosis Interventions: placebo vs. aripiprazole (0.7–15 mg/day; average dose: 8.6 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in long-term care facilities in the United States	256 subjects enrolled; data for 151 analyzed	10 weeks, after 1-week washout	Aripiprazole vs. placebo: total SMD = 0.36 (0.11, 0.61); psychosis SMD = − 0.02 (−0.27, 0.23); agitation SMD = 0.30 (0.05, 0.55)	2
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; MMSE = Mini-Mental State Exam; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Study type	Study	How subjects were recruited and what intervention(s) were performed^a	Sample size^b	How long subjects were followed	Outcome measures and main results	Rating of quality of evidence
1A	Brodaty et al. 2003, 2005	Subjects with a DSM-IV diagnosis of dementia of the Alzheimer’s type, vascular dementia, or mixed dementia, residing in nursing homes, with MMSE score < 24 and significant aggressive behavior Interventions: placebo vs. flexibly dosed risperidone (up to 2 mg/day; mean dose: 0.95 mg/day) Design: double-blind randomized trial Industry-sponsored multicenter trial in Australia/ New Zealand	345 subjects	12 weeks	Risperidone vs. placebo: total SMD = 0.46 (0.23, 0.69); psychosis SMD = 0.36 (0.13, 0.59); agitation SMD = 0.37 (0.14, 0.59)	3
1A	Deberdt et al. 2005	Subjects with Alzheimer’s dementia, vascular dementia, or mixed dementia, in outpatient or residential settings, with NPI or NPI-NH score > 5 on hallucination and delusion items Interventions: placebo vs. flexibly dosed olanzapine (2.5–10 mg/day; mean dose: 5.2 mg/day) or risperidone (0.5–2 mg/day; mean dose: 1.0 mg/day) Design: double-blind randomized trial Industry-sponsored multicenter trial in the United States	494 subjects, with 94 receiving placebo, 204 receiving olanzapine, and 196 receiving risperidone	10 weeks	Risperidone vs. placebo: total SMD = − 0.13 (− 0.38, 0.12); psychosis SMD = − 0.03 (− 0.34, 0.16); agitation SMD = 0.14 (− 0.11, 0.39)	2
1A	De Deyn et al. 1999	Hospitalized or institutionalized individuals with MMSE score < 24 and BEHAVE-AD score > 7 Interventions: placebo vs. flexibly dosed haloperidol (0.5–4 mg/day; mean dose: 1.2 mg/day) or risperidone (0.5–4 mg/day; mean dose: 1.1 mg/day) Design: randomized trial Industry-sponsored multicenter trial in the United Kingdom and Europe	344 subjects; 68 of the 115 subjects receiving risperidone, 81 of the 115 subjects receiving haloperidol, and 74 of the 114 subjects receiving placebo completed the trial	12 weeks	Risperidone vs. placebo: total SMD = 0.12 (− 0.14, 0.38); agitation SMD = 0.31 (0.05, 0.57)	4
1A	Katz et al. 1999	Subjects with DSM-IV diagnosis of Alzheimer’s disease, vascular dementia, or mixed dementia, residing in a nursing home or chronic care facility, with MMSE score <24 and significant psychotic and behavioral symptoms (BEHAVE-AD score > 7) Interventions: placebo vs. fixed doses of risperidone (0.5, 1, or 2 mg/day) Design: double-blind randomized controlled trial Industry-sponsored multicenter trial conducted in the United States	625 subjects; 70% of the subjects completed the study	12 weeks	Risperidone vs. placebo: total SMD = 0.32 (0.11, 0.53); psychosis SMD = 0.20 (− 0.01, 0.41); agitation SMD = 0.38 (0.17, 0.60)	4
1A	Mintzer et al. 2006	Subjects with presentation that met criteria for Alzheimer’s dementia (MMSE scores 5–23), residing in nursing homes or a long-term care setting, who were mobile and had psychosis Interventions: placebo vs. flexibly dosed risperidone (0.5-1.5 mg/day; mean dose: 1.03 mg/day) Design: randomized controlled trial Industry-sponsored multicenter trial conducted in the United States	473 subjects randomly assigned to treatment group, with 238 receiving placebo and 235 receiving risperidone; 354 subjects completed the study	8 weeks, after 1–16 days of placebo run-in/washout	Risperidone vs. placebo: total SMD = − 0.01 (−0.21, 0.18); psychosis SMD = 0.17 (−0.02, 0.36); agitation SMD = 0.04 (− 0.16, 0.23)	3
1A	Schneider et al. 2006; Sultzer et al. 2008	Subjects with Alzheimer’s disease or probable Alzheimer’s disease (MMSE scores 5–26), ambulatory and residing at home or in assisted living facilities, with moderate or greater levels of psychosis, aggression, or agitation Interventions: placebo vs. masked flexibly dosed olanzapine (mean dose: 5.5 mg/day), quetiapine (mean dose: 56.5 mg/day), or risperidone (mean dose: 1.0 mg/day) Stable doses of cholinesterase inhibitor were permitted. Design: multicenter, federally funded CATIE-AD trial—Phase 1	421 subjects randomly assigned to treatment group, with 142 receiving placebo, 100 receiving olanzapine, 94 receiving quetiapine, and 85 receiving risperidone	Median duration on Phase 1 treatment was 7.1 weeks; clinical outcomes assessed for those who continued to take antipsychotic at 12 weeks	Risperidone vs. placebo: total SMD = 0.40 (0.13, 0.68); psychosis SMD = 0.38 (0.11, 0.66); agitation SMD = 0.10 (− 0.17, 0.37)	1
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; MMSE = Mini-Mental State Exam; NPI = Neuropsychiatric Inventory; NPI-NH = Neuropsychiatric Inventory—Nursing Home; SMD = standardized mean difference. ^aIncludes additional notes that may impact quality rating. ^bWhere applicable. Note overall N as well as group n for control and intervention.

Adverse effect	Strength of evidence (from the 2011 AHRQ review^a)	Summary of studies since the 2011 AHRQ review	Overall strength of evidence
Mortality	High for SGAs relative to placebo Moderate for FGAs relative to SGAs	Moderate for FGAs relative to SGAs Moderate for haloperidol relative to risperidone and for risperidone relative to quetiapine	High for SGAs relative to placebo High for FGAs relative to SGAs Moderate for haloperidol relative to risperidone and for risperidone relative to quetiapine
Stroke	Low	Low	Low
Myocardial infarction and other cardiovascular events	Low	Insufficient	Low
Pulmonary-related adverse effects	Insufficient	Low	Low
Cognitive changes	Low	Insufficient	Low
Sedation/fatigue	Moderate	N/A	Moderate
Extrapyramidal side effects (excluding tardive dyskinesia)	Moderate	Low	Moderate
Tardive dyskinesia	Insufficient	N/A	Insufficient
Falls and hip fractures	Insufficient	Low	Low
Development of diabetes	Low	Insufficient	Low
Weight gain	Moderate for elderly and those with dementia High for all uses and ages	N/A	Moderate
Urinary symptoms	Low	N/A	Low
Note. FGA = first-generation antipsychotic; N/A = not applicable; SGA = second-generation antipsychotic. ^aMaglione et al. 2011.

Adverse effect	Drug	Number of studies	Drug (adverse events/ sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
Death	Aripiprazole	3	8/340	3/253	2.37	(0.55, 14.18)	NC
Death	Olanzapine	2	2/278	4/232	0.48	(0.04, 3.62)	NC
Death	Quetiapine	2	5/185	7/241	0.91	(0.22, 3.41)	NC
Death	Risperidone	5	39/1,561	17/916	1.19	(0.63, 2.31)	NC
Note. CI = confidence interval; NC = not calculated; NNH = number needed to harm; OR = odds ratio. Source. Adapted from Maglione et al. 2011.

Adverse effect	Drug	Number of studies	Drug (adverse events/ sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
Stroke	Aripiprazole	3	2/340	2/253	0.70	(0.05, 10.48)	NC
Stroke	Olanzapine	2	6/278	4/232	1.46	(0.33, 7.44)	NC
Stroke	Quetiapine	2	3/185	6/241	0.65	(0.10, 3.08)	NC
Stroke	Risperidone	4	24/1,099	8/753	3.12	(1.32, 8.21)	53
Note. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; NC = not calculated; NNH = number needed to harm; OR = odds ratio. Source. Adapted from Maglione et al. 2011.

Study type	Study	Subjects/Method/Design/Location	N	Duration	Outcomes/Results	Rating of quality of evidence
3A	Barnett et al. 2007	Subjects over 65 years of age with a diagnosis of dementia Subjects identified via Veterans Administration and Medicare databases Design: longitudinal cohort study Location: United States	14,029 subjects	2002–2003, followed for 18 months	In comparisons with individuals who did not receive an antipsychotic, the risk of a cerebrovascular event (defined as an inpatient admission with a primary or principal diagnosis of cerebrovascular event by ICD-10-CM codes) was comparable for individuals treated with an FGA (HR = 1.29; 95% CI: 0.48, 3.47) or an SGA (HR = 1.20; 95% CI: 0.83, 1.74).	0
3	Chan et al. 2010	Subjects age 65 years or older who were diagnosed with Alzheimer’s disease, vascular dementia, or mixed dementia, with behavioral/psychological symptoms and had an initial visit during the study period Design: retrospective cohort study Location: Hong Kong	1,089 subjects; 654 of the subjects had been treated with an FGA, 72 with an SGA, and 363 with no antipsychotic	January 1, 2000– June 30, 2007	Risk of cerebrovascular adverse events (calculated by Cox regression analysis) did not differ among those treated with an FGA (adjusted HR = 0.964; 95% CI: 0.584, 1.591) or SGA (adjusted HR = 1.036 (95% CI: 0.350, 3.066) as compared with those not treated with an antipsychotic. Incidence rates for cerebrovascular adverse events were 44.6/1,000, 32.7/1,000, and 49.6/1,000 person years, respectively.	0
3	Chatterjee et al. 2012	Community-dwelling elderly subjects, age 50 years or older Risperidone, olanzapine, or quetiapine was initiated anytime during study period. Data were obtained from IMS LifeLink Health Plan claims database. Design: observational-retrospective cohort. Authors used propensity-score adjustments. Location: United States	12,145 subjects; 5,083 of the subjects were treated with risperidone, 4,377 with olanzapine, and 2,685 with quetiapine	Recruitment occurred from July 1, 2000–June 30, 2008. Patients were followed until hospitalization or an emergency room visit for a cerebrovascular event, or until the end of the study period, whichever occurred earlier.	2,458 total cerebrovascular events were identified in the study cohort: 1,081 of 5,083 (21%) risperidone users, 816 of 4,377 (19%) olanzapine users, and 561 of 2,685 (21%) quetiapine users. As compared with use of olanzapine, there was a decreased risk of cerebrovascular adverse events associated with use of quetiapine (HR = 0.88; 95% CI: 0.78, 0.99) but not risperidone (HR = 1.05: 95% CI: 0.95, 1.16) as derived from Cox proportional hazard analysis, which adjusted for multiple propensity scores and other medication exposures.	0
3	Finkel et al. 2005	Subjects with evidence of treatment for dementia who were aged 60 or older and first prescribed an antipsychotic Subjects were identified via a Medicaid database. Design: retrospective cohort Location: United States Funding: Ortho McNeil Janssen	18,987 subjects, with 1,260 of the subjects starting haloperidol, 4,137 risperidone, 2,928 olanzapine, and 710 on quetiapine	1999–2002	Using logistic regression, the study authors found that in comparison to risperidone, the odds ratios for an acute admission for a cerebrovascular event in the initial 90 days of treatment were 1.91 (95% CI: 1.02, 3.60) for haloperidol, 1.05 (95% CI: 0.63, 1.73) for olanzapine, and 0.66 (95% CI: 0.23, 1.87) for quetiapine.	0
3	Gill et al. 2005	Subjects with dementia age 65 or older who were first prescribed an antipsychotic during the observation period Design: retrospective population-based cohort Location: Ontario, Canada Funding: Canadian Institute of Health Research	32,710 subjects; 14,865 of the subjects were started on an FGA, and 17,845 on an SGA	April 1, 1997–March 31, 2002	Crude incidence rates of hospitalization for ischemic stroke were comparable for FGAs and SGAs (1.5% and 1.6%, respectively). Cox proportional hazards model, including covariates for sociodemographic factors, comorbid conditions, and concomitant medication use, also showed no differences between FGAs and SGAs (adjusted hazard ratio = 1.01 [95% CI: 0.81, 1.26]).	0
3	Herrmann et al. 2004	Subjects over 66 years of age who were first prescribed an antipsychotic during the observation period Subjects identified from approximately 1.4 million potential subjects in administrative health care databases in Ontario, Canada. Design: retrospective population-based cohort Location: Ontario, Canada Funding: no pharmaceutical funding received	11,400 subjects; 1,015 of the subjects were first prescribed an FGA, 6,964 risperidone, and 3,421 olanzapine	April 1, 1997–March 31, 2002	In comparisons with treatment with an FGA, covariate adjusted relative risk estimates for stroke were 1.1 (95% CI: 0.5, 2.3) for olanzapine and 1.4 (95% CI: 0.7, 2.8) for risperidone, suggesting no statistically significant increase in the risk of stroke. Inclusion of individuals who did not have a diagnosis of dementia limits generalizability.	0
3	Imfeld et al. 2013	Subjects age 65 years or older with an incident diagnosis of Alzheimer’s or vascular dementia, compared with a group of dementia-free patients. Subjects were identified from the United Kingdom–based General Practice Research Database. Design: nested case-control follow-up study Location: United Kingdom Funding source: unconditional pharmaceutical company grant	18,729 subjects; 6,443 case subjects had Alzheimer’s dementia, 2,302 had vascular dementia, and 9,984 had no dementia diagnosis	1998 and 2008	During the follow-up, there were 281 case subjects with incident ischemic stroke, 139 with hemorrhagic stroke, and 379 with a transient ischemic attack. The incidence rates of ischemic stroke for patients with Alzheimer’s dementia, vascular dementia, or no dementia were 4.7/1,000 person-years (95% CI: 3.8, 5.9), 12.8/1,000 person-years (95% CI: 9.8, 16.8), and 5.1/1,000 person-years (95% CI: 4.3, 5.9), respectively. In comparison with dementia-free patients, the odds ratio of developing a transient ischemic attack when treated with SGAs was increased for patients with Alzheimer’s dementia (OR = 4.5; 95% CI: 2.1, 9.2) but not those with vascular dementia.	0
3	Kleijer et al. 2009	Community-dwelling patients age 50 years or older who were prescribed at least one antipsychotic medication during the study period without having received an antipsychotic prescription for at least the preceding year Subjects were identified through Dutch community pharmacies and hospital discharge records. Design: nested case-control study Location: Netherlands Funding: no external funding	26,157 individuals (mean age = 76 ± 9.7 years) met inclusion criteria; 518 of these individuals had a hospital admission for a cerebrovascular event and were matched by sex and age to four randomly selected individuals from the cohort	1986–2003	Current exposure and recent exposure to antipsychotics were associated with an increased risk of a cerebrovascular event compared with non-users (OR = 1.7; 95% CI: 1.4, 2.2). A strong temporal relationship was found; the OR for a history of use less than a week is 9.9 (5.7–17.2). Risk decreases in time and is comparable to that for non-users after 3 months of use (OR = 1.0; 95% CI: 0.7, 1.3). Inclusion of individuals who did not have a diagnosis of dementia limits generalizability.	0
3	Laredo et al. 2011	Subjects age 65 years or older with a diagnosis of dementia who were prescribed an FGA or SGA Subjects were identified via electronic primary care records in the General Practice Research Database. Design: observational–case control Location: United Kingdom Funding: Foundation	26,885 subjects; 3,149 of the subjects were eligible for the study and were matched to 15,613 control subjects	January 1, 1995– June 22, 2007	After adjustment for confounding variables, the OR of a CVA associated with use of only FGAs versus no antipsychotic use in individuals with dementia age 65 or older was 1.16 (95% CI: 1.07, 1.27), and the OR for use of only SGAs versus no antipsychotics was 0.62 (95% CI: 0.53, 0.72). In the comparison of FGAs and SGAs, the OR was 1.83 (95% CI: 1.57, 2.14). FGAs appear to be associated with a higher risk of CVA, although the risk disappears with medication discontinuation.	0
3	Liperoti et al. 2005	Subjects 65 years or older, residing in nursing facilities, with a diagnosis of dementia. Subjects were identified via Medicare data and the Systematic Assessment of Geriatric drug use via Epidemiology database. Design: retrospective, case-control Location: United States Funding: National Institutes of Health	4,788 subjects; 1,130 of the subjects had been hospitalized for a stroke or transient ischemic attack; 3,658 control case subjects from the same facility had been hospitalized for septicemia or a urinary tract infection	June 30, 1998–December 27, 1999	Using conditional logistic regression, the study authors found that users of antipsychotic medication did not have a significant difference in the odds ratio of being hospitalized for a cerebrovascular event as compared with non-users of antipsychotic medication. Odds ratio of a cerebrovascular event was 0.87 (95% CI: 0.67, 1.12) for risperidone, 1.32 (95% CI: 0.83, 2.11) for olanzapine, 1.57 (95% CI: 0.65, 3.82) for other SGAs, and 1.24 (95% CI: 0.95, 1.63) for FGAs.	0
3	Liu et al. 2013	Subjects age 65 years or older who either had dementia with at least one inpatient service claim or at least two ambulatory care claims or were randomly chosen from the population as a sex-, age-, and index year–matched comparison subject All subjects were identified using the Taiwanese Longitudinal Health Insurance Database for 2005. Design: case-control Location: Taiwan	2,243 subjects with dementia; 1,450 of the subjects were treated with antipsychotic; 6,714 matched comparison subjects	5 years of follow-up	Using Cox proportional-hazard regression, the study authors found that dementia patients had a twofold greater risk of developing stroke within 5 years of diagnosis compared with matched nonsubjects, after adjustment for other risk factors (95% CI: 2.58, 3.08; P < 0.001). Antipsychotic usage among patients with dementia increases risk of stroke 1.17-fold compared with patients without antipsychotic treatment (95% CI: 1.01, 1.40; P < 0.05).	0
3	Percudani et al. 2005	Subjects age 65 or older who had an inpatient admission for a cerebrovascular-related event Subjects were identified via a national database of outpatient prescriptions with record linkage. Design: retrospective population-based cohort Location: Lombardy, Italy Funding: not specified	1,645,978 subjects; 36,075 of the subjects were exposed to an antipsychotic, with 9,265 exposed to an SGA	2001	Using logistic regression analysis, the study authors found that the odds ratio of a CVA in subjects receiving an antipsychotic was 1.24 (95% CI: 1.16, 1.32) relative to those not receiving an antipsychotic. Adjusted odds ratios were 1.42 (95% CI: 1.24, 1.69) for those receiving an SGA as compared with an FGA and 1.57 (95% CI: 1.08, 2.30) for those receiving risperidone as compared with haloperidol. No significant difference was noted in the odds ratio for CVA in those receiving clozapine, olanzapine, or quetiapine as compared with haloperidol. Inclusion of individuals who did not have a diagnosis of dementia limits generalizability.	0
3A	Pratt et al. 2010	Subjects over 65 years of age who were identified via an Australian Government Department of Veterans’ Affairs database Design: observational, self-controlled case series Location: Australia	10,638 subjects, with 514 receiving treatment that included initiation of an FGA and 564 receiving treatment that included initiation of an SGA	January 1, 2003– December 31, 2006	In the first week after initiation of an FGA, there was an increased risk of hospital admission for stroke (IRR = 2.3; 95% CI: 1.3, 3.8), whereas no such risk was seen after initiation of an SGA. Inclusion of individuals who did not have a diagnosis of dementia limits generalizability.	0
3	Sacchetti et al. 2008	Subjects over 65 years of age identified via data from a health search database of primary care patients in Italy Design: observational-retrospective cohort Location: Italy Funding: Health Authority of the Lombardia Region	69,939 identified as non-users of antipsychotic medication; 4,223 had received an initial antipsychotic prescription during the study period (599 with atypicals, 749 with butyrophenones, 907 with phenothiazines, and 1,968 with substituted benzamides)	January 2000– June 2003	Crude incidence of stroke was 12.0/1,000 person-years for subjects not exposed to antipsychotic as compared with 47.1, 72.7, 25.0, and 47.4 per 1,000 person-years for those prescribed butyrophenones, phenothiazines, substituted benzamides, and SGAs, respectively. Using multivariate Cox proportional regression analysis, the study authors found that the adjusted risk ratio for stroke as compared with subjects without antipsychotic exposure was 5.79 (95% CI: 3.07, 10.9), 3.55 (95% CI: 1.56, 8.07), and 2.46 (95% CI: 1.07, 5.65) for butyrophenones, phenothiazines, and SGAs, respectively. As compared with SGAs, the adjusted risk ratio for stroke was 1.44 (95% CI: 0.55, 3.76) for butyrophenones and 2.34 (95% CI: 1.01, 5.41) for phenothiazines.Inclusion of individuals who did not have a diagnosis of dementia limits generalizability.. .	0
3A	Sacchetti et al. 2010	Subjects identified as being over 50 years of age based on data from a Health Search database of primary care patients in Italy Design: observational-retrospective cohort Location: Italy	128,308 subjects (total who were identified as meeting inclusion criteria)	Not stated	Risk of stroke at the end of the first month of treatment was 12.4 times higher in individuals treated with antipsychotic as compared with those without antipsychotic exposure. However, absolute differences were small in terms of the cumulative proportion surviving (0.9921 [95% CI: 0.9899, 0.9943] with antipsychotic vs. 0.9995 [95% CI: 0.9979, 0.9983] without antipsychotic at 1 month; 0.9819 [95% CI: 0.9761, 0.9879] with antipsychotic vs. 0.9964 [95% CI: 0.9960, 0.9968] without antipsychotic at 6 months).	0
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; CVA = cardiovascular accident; FGA = first-generation antipsychotic; HR = hazard ratio; IRR = incidence rate ratio; OR = odds ratio; SGA = second-generation antipsychotic.

Adverse effect	Drug	Number of studies	Drug (adverse events/sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
Cardiovascular	Aripiprazole	1	42/366	12/121	1.18	(0.58 , 2.55)	NC
Cardiovascular	Olanzapine	5	40/778	9/440	2.33	(1.08, 5.61)	48
Cardiovascular	Quetiapine	3	29/355	15/254	1.08	(0.53 , 2.30)	NC
Cardiovascular	Risperidone	6	119/1,757	34/1,010	2.08	(1.38 , 3.22)	34
Note. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; NC = not calculated; NNH = number needed to harm; OR = odds ratio. Source. Adapted from Maglione et al. 2011.

Adverse effect	Drug	Number of studies	Drug (adverse events/sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
Pulmonary	Aripiprazole	1	6/106	3/102	1.97	(0.41 , 12.54)	NC
Pulmonary	Olanzapine	1	0/204	3/94	0.00	(0.00 , 1.10)	NC
Pulmonary	Risperidone	1	6/196	3/94	0.96	(0.20 , 6.05)	NC
Note. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; NC = not calculated; NNH = number needed to harm; OR = odds ratio. Source. Adapted from Maglione et al. 2011.

Study type	Study	Subject/Method/Design/Location	N	Duration	Outcomes/Results	Rating of quality of evidence
3A	Huybrechts et al. 2011*	Nursing home residents age 65 years or older who had treatment with psychotropics initiated after admission Design: retrospective population-based cohort Location: British Columbia	10,900 individuals; 1,942 of the subjects started taking an SGA, 1,902 started taking an FGA, 2,169 started taking an antidepressant, and 4,887 started taking a benzodiazepine	1996–2006	There was no difference observed in the risk of heart failure or pneumonia in individuals receiving FGAs, as compared with SGAs, with RR of 1.03 (95% CI: 0.62, 1.69) and 0.91 (95% CI: 0.41, 2.01), respectively. Inclusion of individuals who did not have a diagnosis of dementia may limit generalizability.	0
3	Knol et al. 2008	Community-dwelling subjects, age 65 or older, who had been exposed to antipsychotic medication Subjects identified via a national pharmacy database. Design: observational-retrospective nested case control study Location: Netherlands Funding: no industry funding	22,944 subjects received an antipsychotic during the study period; 543 of these subjects had a hospitalization for pneumonia, and 2,163 randomly selected individuals served as controls	April 1985–December 2003	Using multivariate logistic regression, the study authors found that current use of an antipsychotic as compared with no prior antipsychotic use was associated with an increased likelihood of hospitalization for pneumonia (adjusted odds ratio = 1.6; 95% CI: 1.3, 2.1), whereas past use of an antipsychotic did not show an effect. Lack of information about dementia diagnosis may limit generalizability.	0
3*	Pratt et al. 2011	Subjects over 65 years of age who were exposed to antipsychotic medication Subjects identified via the Australian Department of Veterans’ Affairs Health Care Claims Database. Design: observational-retrospective cohort Location: Australia Funding: Australian Government	8,235 subjects had at least one hospitalization for hip fracture, and of these 494 had begun receiving an FGA and 1,091 had begun receiving an SGA; 13,324 had at least one hospitalization for pneumonia, and of these 807 had begun receiving an FGA and 1,107 had begun receiving an SGA during the study period	2005–2008; median follow-up: 3.3–4.0 years	Using a self-controlled case-series design, the study authors found that the risk of hospitalization for pneumonia was increased during all postexposure periods for both FGA and SGA and remained significantly increased with more than 12 weeks of continuous exposure (IRR = 1.43; 95% CI: 1.23, 1.66). Risk of pneumonia was elevated for up to 12 weeks prior to the initiation of FGAs or SGAs.	0
3	Schmedt and Garbe 2013	Subjects age 65 years or older with dementia Subjects were identified via the German Pharmacoepidemiological Research Database. Design: nested case-control study Location: Germany Funding: no pharmaceutical funding	72,591 individuals in total cohort, from which there were 1,028 VTE cases and 4,109 controls matched to each case according to age, sex, health insurance, and calendar time of the VTE	2004–2007	Using multivariate conditional logistic regression, the study authors found an increased risk of VTE for current users of antipsychotic medication (OR = 1.23; 95% CI: 1.01–1.50) and for users of a combination of an FGA and an SGA (OR = 1.62; 95% CI: 1.15, 2.27). In current users, only new use was associated with an increased risk (OR = 1.63; 95% CI: 1.10, 2.40).	0
3A	Schneeweiss et al. 2007; Setoguchi et al. 2008*	Subjects over 65 years of age who were being treated with an antipsychotic (risperidone, quetiapine, olanzapine, clozapine, or FGA) Subjects were identified via data from a British Columbia Ministry of Health Pharmanet database. Design: observational-retrospective cohort Location: British Columbia, Canada Funding: government funded	37,241 subjects identified as meeting inclusion criteria; 12,882 of the identified subjects initiated treatment with an FGA, and 24,359 initiated treatment with an SGA	January 1, 1996 to December 31, 2004	Using multivariable and propensity score–adjusted modeling, the study authors found that the adjusted hazard ratio for mortality within 180 days of FGA initiation relative to SGA initiation was 1.71 (95% CI: 1.35, 2.17) for respiratory mortality other than that due to pneumonia. Inclusion of individuals who did not have a diagnosis of dementia may limit generalizability.	0
3	Trifirò et al. 2007, 2010	Subjects age 65 years or older who were taking an antipsychotic drug Subjects were identified via the Dutch Integrated Primary Care Information database as having incident community-acquired pneumonia. Design: population-based, nested case-control study Location: Netherlands Funding: none	258 case subjects with incident pneumonia were matched to 1,686 control subjects on the basis of age, sex, and date of onset	1996–2006	Sixty-five (25%) of the case subjects died in 30 days with death attributable to pneumonia. Using conditional logistic regression, the study authors found that current use of either an FGA (OR = 1.76; CI: 1.22, 2.53) or SGA (OR = 2.61; 95% CI: 1.48, 4.61) was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Current use of SGAs was not associated with an increase in odds ratio of pneumonia relative to FGAs (1.48; 95% CI: 0.84, 2.60). Only SGAs were associated with an increase in the risk for fatal pneumonia (OR = 5.97; CI: 1.49, 23.98).	0
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. *Cited with other outcome. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; FGA = first-generation antipsychotic; IRR = incidence rate ratio; MI = myocardial infarction; RR = rate ratio; SGA = second-generation antipsychotic; VTE = venous thromboembolism.

Study type	Study	Subject/Method/ Design/Location	N	Duration	Outcomes/Results	Rating of quality of evidence
3	Dutcher et al. 2014	Older nursing home residents with newly diagnosed Alzheimer’s disease or related dementias Subjects were identified based on Medicare enrollment and claims data linked to the Minimum Dataset 2.0. Design: prospective cohort study Location: United States	18,950 subjects with a mean age of 83.6 years; 76% of the sample subjects were female. At baseline, 15% were taking antidementia medications, 40% antidepressants, 13% antipsychotics, and 3% mood stabilizers.	2007–2008	Using marginal structural models to account for time-dependent confounding, the study authors found that antipsychotic use was associated with a slower decline in cognition (slope difference: − 0.11 points/year on the CPS, 99% CI: − 0.17, − 0.06), with more rapid declines observed in females. However, the magnitude of these changes was not noted to be clinically significant, although it was statistically significant.	0
3	Rosenberg et al. 2012	Community-ascertained case patients from the Cache County Dementia Progression Study who had incident Alzheimer’s disease Design: prospective cohort Location: United States	230 case subjects	Mean follow-up 3.7 years	At baseline, psychotropic medication use was associated with greater severity of dementia, and poorer medical status was associated with use of psychotropic medications (e.g., antidepressants, antipsychotics, benzodiazepines). Mixed-effects models showed that a higher proportion of observed time of medication exposure was associated with a more rapid decline in MMSE for all medication classes, including antipsychotic agents. In terms of FGAs, a higher proportion of observed time of medication exposure was associated with a more rapid increase in CDR Sum of Boxes and NPI total score.	0
1	Vigen et al. 2011	Ambulatory outpatients living at home or in an assisted-living facility whose symptoms met DSM-IV criteria for dementia of the Alzheimer’s type or NINCDS/ADRDA criteria for probable Alzheimer’s disease and who had delusions, hallucinations, agitation, or aggression nearly every day over the previous week or intermittently over 4 weeks Design: multiphase, multisite double-blind, randomized study. After initial treatment phase, subsequent phases and randomization were dependent on response to initial treatment assignment. Patients could be taking cholinesterase inhibitor medication but not antidepressants or anticonvulsants for mood disorder. Location: United States	421 patients were randomly assigned in a double-blind fashion to receive olanzapine, quetiapine, risperidone, or placebo (randomized allocation 2:2:2:3). 342 subjects had at least one follow-up cognitive measure at 12 weeks, 320 at 24 weeks, and 307 at 36 weeks. Sample patients were 46% male, with a mean age of 77.6 years and a mean of 12.3 years of education ; 64% were taking cholinesterase inhibitors.	36 weeks	Significant declines occurred in multiple cognitive measures, including the MMSE (P = 0.004), BPRS Cognitive subscale (P = 0.05), and a cognitive summary score summarizing change on 18 cognitive tests (P = 0.004). Declines were linear and significant over time (e.g., 2.4-point decrease in MMSE and a 4.4-point decrease in ADAS-Cog over 36 weeks) without effects of baseline MMSE, baseline BPRS score, or size of the study site. Patients taking an SGA for at least 2 weeks showed a greater rate of decline in cognitive function than those receiving placebo, although these declines were not statistically significant for all measures.	1
Note. 1 = randomized controlled trial; 2 = systematic review/meta-analysis; 3 = observational; A = from AHRQ review. ADAS-Cog = Alzheimer’s Disease Assessment Scale—Cognitive Behavior; AHRQ = Agency for Healthcare Research and Quality; BPRS = Brief Psychiatric Rating Scale; CATIE-AD = Clinical Antipsychotic Trials of Intervention Effectiveness for Alzheimer’s Disease; CDR = Clinical Dementia Rating; CI = confidence interval; CPS = Cognitive Performance Scale; FGA = first-generation antipsychotic; MMSE = Mini-Mental State Exam; NINCDS/ADRDA = National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association ; NPI = Neuropsychiatric Inventory; SGA = second-generation antipsychotic.

Adverse effect	Drug	Number of studies	Drug (adverse events/sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
Fatigue	Aripiprazole	3	47/600	11/272	2.44	(1.19 , 5.43)	22
Fatigue	Olanzapine	3	36/482	9/326	2.37	(1.08 , 5.75)	34
Fatigue	Quetiapine	2	25/335	5/234	2.92	(1.03 , 10.26)	34
Fatigue	Risperidone	2	20/281	4/236	3.56	(1.13 , 14.96)	34
Sedation	Aripiprazole	4	116/706	22/374	2.62	(1.57 , 4.54)	16
Sedation	Olanzapine	5	158/778	25/440	4.58	(2.87 , 7.55)	9
Sedation	Quetiapine	4	84/446	18/353	5.16	(2.93 , 9.51)	8
Sedation	Risperidone	6	265/1,260	102/922	2.33	(1.79 , 3.05)	10
Note. AHRQ = Agency for Healthcare Research and Quality; CI = confidence interval; NNH = number needed to harm; OR = odds ratio. Source. Adapted from Maglione et al. 2011.

Adverse effect	Drug	Number of studies	Drug (adverse events/sample size)	Placebo (adverse events/sample size)	OR	(95% CI)	NNH
EPS	Aripiprazole	4	39/706	16/374	1.29	(0.68 , 2.57)	NC
EPS	Olanzapine	1	18/100	2/142	15.21	(3.50 , 138.55)	10
EPS	Quetiapine	3	18/355	9/254	1.15	(0.46 , 3.08)	NC
EPS	Risperidone	5	130/1,561	31/916	3.00	(1.96 , 4.70)	20
Akathisia	Olanzapine	1	1/100	0/142	inf+	(0.04, inf+)	NC
Akathisia	Quetiapine	2	1/114	1/162	1.23	(0.02 , 98.52)	NC
Akathisia	Risperidone	1	0/85	0/142	NC	NC	NC
TD	Olanzapine	1	3/100	4/142	1.07	(0.15 , 6.46)	NC
TD	Quetiapine	1	2/94	4/142	0.75	(0.07 , 5.36)	NC
TD	Risperidone	4	4/949	14/713	0.31	(0.07 , 1.03)	NC
Note. CI = confidence interval; EPS = extrapyramidal symptoms; inf+ = infinity; NC = not calculated; NNH = number needed to harm; OR = odds ratio; TD = tardive dyskinesia. Source. Adapted from Maglione et al. 2011.

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