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Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia

Ellen Van Leeuwen (UGent) , Mirko Petrovic (UGent) , Marie van Driel (UGent) , An De Sutter (UGent) , Robert Vander Stichele (UGent) , Tom Declercq (UGent) and Thierry Christiaens (UGent)
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Abstract
Background : Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in people with dementia although there is uncertainty about the effectiveness of their long-term use for this indication and concern that they may cause harm, including higher mortality. When behavioural strategies have failed and treatment with antipsychotic drugs is instituted, regular attempts to withdraw them have been recommended in guidelines. Physicians, nurses and families of older people with dementia may be reluctant to stop antipsychotics, fearing deterioration of NPS. This is an update of a Cochrane Review published in 2013. Objectives : To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia and NPS in primary care or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older participants with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on participants' behaviour and assess safety. Search methods : We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources up to 11 January 2018. Selection criteria : We included all randomised, controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia who had been treated with an antipsychotic drug for at least three months. Data collection and analysis : We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence for each outcome using the GRADE approach. Main results : We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update. One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias. We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence). Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse. We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline. None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants). There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). Authors' conclusions : There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality. People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS. The overall conclusions of the review have not changed since 2013 and the number of available trials remains low.
Keywords
NURSING-HOME PATIENTS, RANDOMIZED CONTROLLED-TRIAL, PLACEBO-CONTROLLED TRIALS, ALZHEIMERS-DISEASE, NEUROPSYCHIATRIC SYMPTOMS, DOUBLE-BLIND, ATYPICAL ANTIPSYCHOTICS, DISCONTINUATION, RISPERIDONE, THIORIDAZINE

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MLA
Van Leeuwen, Ellen et al. “Withdrawal Versus Continuation of Long-term Antipsychotic Drug Use for Behavioural and Psychological Symptoms in Older People with Dementia.” COCHRANE DATABASE OF SYSTEMATIC REVIEWS 3 (2018): n. pag. Print.
APA
Van Leeuwen, Ellen, Petrovic, M., van Driel, M., De Sutter, A., Vander Stichele, R., Declercq, T., & Christiaens, T. (2018). Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. COCHRANE DATABASE OF SYSTEMATIC REVIEWS, (3).
Chicago author-date
Van Leeuwen, Ellen, Mirko Petrovic, Marie van Driel, An De Sutter, Robert Vander Stichele, Tom Declercq, and Thierry Christiaens. 2018. “Withdrawal Versus Continuation of Long-term Antipsychotic Drug Use for Behavioural and Psychological Symptoms in Older People with Dementia.” Cochrane Database of Systematic Reviews (3).
Chicago author-date (all authors)
Van Leeuwen, Ellen, Mirko Petrovic, Marie van Driel, An De Sutter, Robert Vander Stichele, Tom Declercq, and Thierry Christiaens. 2018. “Withdrawal Versus Continuation of Long-term Antipsychotic Drug Use for Behavioural and Psychological Symptoms in Older People with Dementia.” Cochrane Database of Systematic Reviews (3).
Vancouver
1.
Van Leeuwen E, Petrovic M, van Driel M, De Sutter A, Vander Stichele R, Declercq T, et al. Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. COCHRANE DATABASE OF SYSTEMATIC REVIEWS. 2018;(3).
IEEE
[1]
E. Van Leeuwen et al., “Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia,” COCHRANE DATABASE OF SYSTEMATIC REVIEWS, no. 3, 2018.
@article{8557873,
  abstract     = {Background : Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in people with dementia although there is uncertainty about the effectiveness of their long-term use for this indication and concern that they may cause harm, including higher mortality. When behavioural strategies have failed and treatment with antipsychotic drugs is instituted, regular attempts to withdraw them have been recommended in guidelines. Physicians, nurses and families of older people with dementia may be reluctant to stop antipsychotics, fearing deterioration of NPS. 
This is an update of a Cochrane Review published in 2013. 
Objectives : To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia and NPS in primary care or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older participants with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on participants' behaviour and assess safety. 
Search methods : We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources up to 11 January 2018. 
Selection criteria : We included all randomised, controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia who had been treated with an antipsychotic drug for at least three months. 
Data collection and analysis : We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence for each outcome using the GRADE approach. 
Main results : We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update. 
One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias. 
We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence). 
Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse. 
We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline. 
None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants). 
There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). 
Authors' conclusions : There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality. 
People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS. 
The overall conclusions of the review have not changed since 2013 and the number of available trials remains low.},
  articleno    = {CD007726},
  author       = {Van Leeuwen, Ellen and Petrovic, Mirko and van Driel, Marie and De Sutter, An and Vander Stichele, Robert and Declercq, Tom and Christiaens, Thierry},
  issn         = {1469-493X},
  journal      = {COCHRANE DATABASE OF SYSTEMATIC REVIEWS},
  keywords     = {NURSING-HOME PATIENTS,RANDOMIZED CONTROLLED-TRIAL,PLACEBO-CONTROLLED TRIALS,ALZHEIMERS-DISEASE,NEUROPSYCHIATRIC SYMPTOMS,DOUBLE-BLIND,ATYPICAL ANTIPSYCHOTICS,DISCONTINUATION,RISPERIDONE,THIORIDAZINE},
  language     = {eng},
  number       = {3},
  pages        = {101},
  title        = {Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia},
  url          = {http://dx.doi.org/10.1002/14651858.CD007726.pub3},
  year         = {2018},
}

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