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Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in Adults: A Systematic Review and Meta-analysis
Abstract
CONTEXT: Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder. OBJECTIVE: To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration. DATA SOURCES AND STUDY SELECTION: Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events. DATA EXTRACTION: Independent article review and study quality assessment by 2 investigators. DATA SYNTHESIS: Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms. CONCLUSIONS: Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.
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“Three RCTs, all in care homes, evaluated music therapy by trained therapists using a specific protocol - typically involving warming up with a well-known song, listening to and then joining in with the music. 28-30”
From Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials (2014) · cites this paper as [28]
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“The largest study, which included participants irrespective of agitation level, found music therapy twice a week for 6 weeks was effective compared with the usual care group. 28”
From Non-pharmacological interventions for agitation in dementia: systematic review of randomised controlled trials (2014) · cites this paper as [28]
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Off-Label Use of Atypical Antipsychotics
McKean, A., & Monasterio, E. (2012) · CNS Drugs · doi:10.2165/11632030-000000000-00000 · Cited by 67
Antipsychotic Use Among Nursing Home Residents
Briesacher, B. A., Tjia, J., Field, T. S., Peterson, D., & Gurwitz, J. H. (2013) · JAMA · doi:10.1001/jama.2012.211266 · Cited by 65
“To the Editor: The prescribing of antipsychotic medications persists at high levels in US nursing homes (NHs) despite extensive data demonstrating marginal clinical benefits and serious adverse effects, including death.(1,2) However, imprecise and outdated data have limited the understanding of the current state of an…”
BackgroundChiu, Y., Bero, L. A., Hessol, N. A., Lexchin, J., & Harrington, C. A. (2015) · Health Policy · doi:10.1016/j.healthpol.2015.02.014 · Cited by 68
More action needed: Psychotropic prescribing in Australian residential aged care
Westbury, J. L., Gee, P. R., Ling, T. R., Kitsos, A. R., & Peterson, G. M. (2018) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867418758919 · Cited by 65
Caregiver perspectives about using antipsychotics and other medications for symptoms of dementia
Kerns, J. W., Winter, J. D., Winter, K. M., Kerns, C. C., & Etz, R. S. (2018) · The Gerontologist · doi:10.1093/geront/gnx042 · Cited by 62
“Of medications, antipsychotics have the best evidence for management of agitated and psychotic symptoms in dementia, though the reported benefit is modest: between one in four and one in three patients show improvement (Maher et al., 2011; Sink et al., 2005).”
BackgroundAripiprazole in the treatment of Alzheimer's disease
Deyn, P. P. D., Drenth, A. F. J., Kremer, B. P. H., Voshaar, R. C. O., & Dam, D. V. (2013) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2013.764989 · Cited by 63
“has led to off-label uses as well, including treatment of schizophrenia in children, treatment of dementia-related psychosis in geriatric patients and treatment of other behavior problems [10,11].”
BackgroundHoward, R. J., Cort, E., Bradley, R., Harper, E., Kelly, L. J., Bentham, P., Ritchie, C. W., Reeves, S., Fawzi, W., Livingston, G., et al. (2018) · The Lancet Psychiatry · doi:10.1016/s2215-0366(18)30141-x · Cited by 66
Ruths, S., Sørensen, P. H., Kirkevold, Ø., Husebo, B. S., Krüger, K., Halvorsen, K. H., & Selbæk, G. (2012) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.3902 · Cited by 63
“Conventional and atypical agents provide only small benefits for neuropsychiatric symptoms but appear to equally increase the risk of death (Maher et al., 2011).”
BackgroundPlasencia-García, B. O., Rodríguez-Menéndez, G., Rico-Rangel, M. I., Rubio-García, A., Torelló-Iserte, J., & Crespo‐Facorro, B. (2021) · Psychopharmacology · doi:10.1007/s00213-020-05716-4 · Cited by 61
Chow, R. T. S., Whiting, D., Favril, L., Ostinelli, E. G., Cipriani, A., & Fazel, S. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105454 · Cited by 59
O’Dwyer, M., Peklar, J., Mulryan, N., McCallion, P., McCarron, M., & Henman, M. C. (2017) · Journal of Intellectual Disability Research · doi:10.1111/jir.12391 · Cited by 60
Evaluation and Management of the Elderly Patient Presenting with Cognitive Complaints
Hildreth, K. L., & Church, S. D. (2014) · Medical Clinics of North America · doi:10.1016/j.mcna.2014.11.006 · Cited by 66
Psychopharmacology of chronic pain: a focus on antidepressants and atypical antipsychotics
Khouzam, H. R. (2016) · Postgraduate Medicine · doi:10.1080/00325481.2016.1147925 · Cited by 59
“approved indications, it is recommended for clinicians not to prescribe the atypical antipsychotics as first line treatment for chronic pain [79] as weight gain in particular could also”
BackgroundAlbert, U., Carmassi, C., Cosci, F., De Cori, D., Di Nicola, M., Ferrari, S., Poloni, N., Tarricone, I., & Fiorillo, A. (2016) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000127 · Cited by 58
“Olanzapine is possibly effective in PTSD both as monotherapy and as adjunctive treatment in resistant patients.”
BackgroundInfluentialAljuhani, A., Ahmed, H. E. A., Ihmaid, S. K., Omar, A. M., Althagfan, S. S., Alahmadi, Y. M., Ahmad, I., Patel, H., Ahmed, S., Almikhlafi, M. A., et al. (2022) · RSC Advances · doi:10.1039/d2ra04015h · Cited by 58
Role of Atypical Antipsychotics in the Treatment of Generalized Anxiety Disorder
Hershenberg, R., Grös, D. F., & Brawman‐Mintzer, O. (2014) · CNS Drugs · doi:10.1007/s40263-014-0162-6 · Cited by 63
The Psychoactive Effects of Psychiatric Medication: The Elephant in the Room
Moncrieff, J., Cohen, D., & Porter, S. (2013) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2013.845328 · Cited by 63
“The ability to flatten emotions may explain why neuroleptics are distinguished from placebo in trials of depression (Robertson & Trimble 1982), and this, combined with their sedative effects, would also explain why many people find them helpful in anxiety (Maher et al. 2011).”
BackgroundDennis, M., Shine, L., John, A. M., Marchant, A. L., McGregor, J., Lyons, R. A., & Brophy, S. T. (2017) · Neurology and Therapy · doi:10.1007/s40120-016-0060-6 · Cited by 60
Mueller, C., John, C., Perera, G., Aarsland, D., Ballard, C. G., & Stewart, R. J. (2020) · European Journal of Epidemiology · doi:10.1007/s10654-020-00643-2 · Cited by 58
Jin, H., Shih, P.-A. B., Golshan, S., Mudaliar, S. R. D., Henry, R. R., Glorioso, D., Arndt, S. V., KRAEMER, H. C., & Jeste, D. V. (2012) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.12m08001 · Cited by 56
Emerging drugs for schizophrenia: an update
Köster, L.-S., Carbon, M., & Correll, C. U. (2014) · Expert Opinion on Emerging Drugs · doi:10.1517/14728214.2014.958148 · Cited by 55
“Additionally, off-label prescribing for aggression associated with disruptive behavior disorders or dementia, obsessive compulsive disorder, anxiety disorders, post-traumatic stress disorder and insomnia [80] further increased sales of agents developed originally as antipsychotics for schizophrenia.”
BackgroundSerotonin in antipsychotic drugs action
Amato, D. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.025 · Cited by 52
Use of Antipsychotics Among Older Residents in VA Nursing Homes
Gellad, W. F., Aspinall, S. L., Handler, S. M., Stone, R. A., Castle, N. G., Semla, T. P., Good, C. B., Fine, M. J., Dysken, M. W., & Hanlon, J. T. (2012) · Medical Care · doi:10.1097/mlr.0b013e31825fb21d · Cited by 53
Buckley, P. F. (2012) · Yearbook of Psychiatry and Applied Mental Health · doi:10.1016/j.ypsy.2012.07.016 · Cited by 52
Gordon, S. E., Dufour, A. B., Monti, S. M., Mattison, M. L. P., Catic, A., Thomas, C. P., & Lipsitz, L. A. (2016) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2016.03.002 · Cited by 52
Yasue, I., Matsunaga, S., Kishi, T., Fujita, K., & Iwata, N. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150818 · Cited by 50
“Therefore, the potential benefits must be evaluated against these risks [9, 10].”
A Systematic Review of Atypical Antipsychotics in Chronic Pain Management
Jimenez, X. F., Sundararajan, T., & Covington, E. C. (2017) · Clinical Journal of Pain · doi:10.1097/ajp.0000000000000567 · Cited by 52
Valproate preparations for agitation in dementia
Baillon, S. F., Narayana, U., Luxenberg, J. S., & Clifton, A. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003945.pub4 · Cited by 54
Metadata
- Authors
- Maher, A. R., Maglione, M., Bagley, S., Suttorp, M., Hu, J.-H., Ewing, B., Wang, Z., Timmer, M., Sultzer, D., & Shekelle, P. G.
- Affiliations
- RAND Corporation (US)
- United States Department of Veterans Affairs (US)
- University of California, Los Angeles (US)
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2011-09-28
- Volume
- 306
- Issue
- 12
- Pages
- 1359
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2072303299
- Cited by
- 558
- References
- 80
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 22 · 2023: 24 · 2022: 63 · 2021: 39 · 2020: 31 · 2019: 29 · 2018: 33 · 2017: 35 · 2016: 52 · 2015: 50 · 2014: 55 · 2013: 52 · 2012: 45
- FWCI
- 33.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (HHSA2902007100621)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- atypical antipsychotics, off-label drug use, generalized anxiety disorder, obsessive-compulsive disorder, risperidone, olanzapine, quetiapine, aripiprazole, extrapyramidal symptoms, stroke risk, adverse drug reactions, comparative effectiveness, elderly patients, treatment efficacy and safety, number needed to harm
- MeSH terms
- Adult, Aged, Anxiety Disorders, Dementia, Humans, Middle Aged, Obsessive-Compulsive Disorder, Antipsychotic Agents, United States, United States Food and Drug Administration, Treatment Outcome, Off-Label Use
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