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長期服用抗精神病藥物治療行為和心理症狀的失智症長者是否應停藥或繼續服藥

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Referencias

References to studies included in this review

Ballard 2004 {published data only}

Ballard C, Thomas A, Fossey J, Lee L, Jacoby R, Lana MM, et al.A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the Neuropsychiatric Inventory median cut-off is a predictor of clinical outcome. Journal of Clinical Psychiatry 2004;65(1):114-9. CENTRAL

Ballard 2008 {published data only}

Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, et al.The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurology 2009;8(2):151-7. CENTRAL
Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, Jacoby R, et al.A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Medicine 2008;5(4):e76. CENTRAL
ISRCTN33368770.A randomised, double blind, placebo-controlled clinical trial to compare the progression of cognitive impairment in dementia patients continuing to take, or discontinued from, treatment with neuroleptics. www.isrctn.com/ISRCTN33368770 (First received 30 September 2005). CENTRAL [DOI: 10.1186/ISRCTN33368770]

Bergh 2011 {unpublished data only}NCT00594269

NCT00594269.Dementia antipsychotics and antidepressants discontinuation study (DESEP) [Discontinuation of antipsychotics and antidepressants among patients with dementia and BPSD living in nursing homes - a 24 weeks double blind RCT]. clinicaltrials.gov/ct2/show/NCT00594269 (First received 15 January 2008). CENTRAL

Bridges‐Parlet 1997 {published data only}

Bridges-Parlet S, Knopman D, Steffes S.Withdrawal of neuroleptic medications from institutionalized dementia patients: results of a double-blind, baseline-treatment-controlled pilot study. Journal of Geriatric Psychiatry and Neurology 1997;10(3):119-26. CENTRAL
Bridges-Parlet S, Lyn S.The effect of neuroleptic withdrawal on physically aggressive behaviour in dementia [Dissertation]. Minnesota (USA): University of Minnesota, 1996. CENTRAL

Cohen‐Mansfield 1999 {published data only}

Cohen-Mansfield J, Lipson S, Werner P, Billig N, Taylor L, Woosley R.Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home. Archives of Internal Medicine 1999;159(15):1733-40. CENTRAL

Devanand 2011 {published data only}

Devanand D, Pelton G, Cunqueiro K, Sackeim HA, Marder K.A 6-month, randomized, double-blind, placebo-controlled pilot discontinuation trial following response to haloperidol treatment of psychosis and agitation in Alzheimer's disease. International Journal of Geriatric Psychiatry 2011;26(9):937-43. CENTRAL

Devanand 2012 {published data only}

Devanand DP, Mintzer J, Schultz SK, Andrews HF, Sultzer DL, de la Pena D, et al.Relapse risk after discontinuation of risperidone in Alzheimer's disease. New England Journal of Medicine 2012;367(16):1497-507. CENTRAL

Findlay 1989 {published data only}

Findlay DJ, Sharma J, McEwen J, Ballinger BR, MacLennan WJ, McHarg AM.Double-blind controlled withdrawal of thioridazine treatments in elderly female inpatients with senile dementia. International Journal of Geriatric Psychiatry 1989;4(2):115-20. CENTRAL

Ruths 2008 {published data only}

Ruths S, Straand J, Nygaard H, Aarsland D.Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study - the Bergen District Nursing Home Study (BEDNURS). International Journal of Geriatric Psychiatry 2008;23(9):889-95. CENTRAL
Ruths S, Straand J, Nygaard H, Bjorvatn B, Pallesen S.Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen district nursing home study. Journal of American Geriatric Society 2004;52(10):1737-43. CENTRAL [Ruths 2004, JAGS]

van Reekum 2002 {published data only}

van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T, et al.A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. International Psychogeriatrics 2002;14(2):197-210. CENTRAL

References to studies excluded from this review

Azermai 2013 {published data only}

Azermai M, Petrovic M, Engelborghs S, Elseviers M, Van der Mussele S, Debruyne H, et al.The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: a pilot study. Aging & Mental Health 2013;17(1):125-32. CENTRAL [DOI: 10.1080/13607863.2012.717255]

Ballard 2015 {published data only}

Ballard C, Thomas A, Gerry S, Yu L, Aarsland D, Merritt C, et al.A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer's disease (MAIN-AD). Journal of the American Medical Association 2015;16(4):316-22. CENTRAL [DOI: 10.1016/j.jamda.2014.11.002]

Bergh 2012 {published data only}

Bergh S, Selbaek GF, Engedal K.Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP study): double blind, randomised, parallel group, placebo controlled trial. British Medical Journal 2012;344:e1566. CENTRAL [DOI: 10.1136/bmj.e1566]

Devanand 2013 {published data only}

Devanand DF, Schultz SK, Sultzer DL.Discontinuation of risperidone in Alzheimer's disease. New England Journal of Medecine 2013;368(2):187-88. CENTRAL [DOI: 10.1056/NEJMc1214030]

Garner 2015 {published data only}

Arkansas Foundation for Medical Care.Reducing Antipsychotics for Dementia Patients in Nursing Homes [pdfs.semanticscholar.org/ef0e/a1c3000fbd8897c206fd7b219e15e3d38c21.pdf]. accessed prior to 24 Mars 2018. CENTRAL

Gill 2013 {published data only}

Gill SS, Seitz DP.Antipsychotics can be withdrawn from many older people with dementia, though caution is needed for people with more severe neuropsychiatric symptoms. Evidence Based Mental Health2013;16(3):81. CENTRAL

Gnjidic 2013 {published data only}

Gnjidic DF, Hilmer SN.Discontinuation of risperidone in Alzheimer's disease. New England Journal of Medecine 2013;368(2):186. CENTRAL [DOI: 10.1056/NEJMc1214030]

Horwitz 1995 {published data only}

Horwitz G, Tariot P, Mead K, Cox C.Discontinuation of antipsychotics in nursing home patients with dementia. American Journal of Geriatric Psychiatry 1995;3(4):290-9. CENTRAL

Ling 2013 {published data only}

Ling SM, Bonner AF, McMullen TL, McMullen TL.Discontinuation of risperidone in Alzheimer's disease. New England Journal of Medecine 2013;368(2):187. CENTRAL [DOI: 10.1056/NEJMc1214030#SA3]

Lolk 2014 {published data only}

Lolk A.Withdrawal versus continuation of antipsychotic drugs in people with dementia. Ugeskrift for Laeger2014;176(31):1871-3. CENTRAL

McLennan 1992 {published data only}

McLennan J, Findlay D, Sharma J, McEwen J, Ballinger BR, Maclennan WJ, et al.Prolactin response to withdrawal of thioridazine in dementia. International Journal of Geriatric Psychiatry 1992;7(10):739-42. CENTRAL

Patel 2017 {published data only}

Patel AN, Lee S, Andrews HF, Pelton G, Schultz S, Sultzer D, et al.Prediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations. The American Journal of Psychiatry 2017;174(4):362-369. CENTRAL [DOI: 10.1176/appi.ajp.2016.16020226]

Power 2013 {published data only}

Power GA.Discontinuation of risperidone in Alzheimer's disease. New England Journal of Medecine2013;368(2):186-7. CENTRAL [DOI: 10.1056/NEJMc1214030#SA2]

Renard 2014 {published data only}

Renard D, de Pelichy E, von Elm E.Long-term antipsychotics for patients with dementia - discontinue or continue treatment?Praxis2014;103(2):109-10. CENTRAL

Rule 2003 {unpublished data only}

Rule 2003.A randomised double blind placebo controlled clinical trial to compare the progression of cognitive impairment in dementia patients continuing to take or discontinued from treatment with typical neuroleptics. National Research Register2003. CENTRAL

Wessels 2010 {published data only}

Wessels A, Pollock B, Anyama N, Schneider LS, Lieberman JA, Marder SR, et al.Association of 9-hydroxy risperidone concentrations with risk of switching or discontinuation in the Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease trial. Journal of Clinical Psychopharmacology 2010;30(6):683-7. CENTRAL

Westbury 2011 {published data only}

Westbury J, Tichelaar L, Peterson G, Gee P, Jackson S.A 12-month follow-up study of "REDuse": a trial aimed at reducing antipsychotic and benzodiazepine use in nursing homes. International Psychogeriatrics 2011;23(8):1260-9. CENTRAL

Ballard 2011

Ballard C, Creese BF, Corbett A, Aarsland D.Atypical antipsychotics for the treatment of behavioral and psychological symptoms in dementia, with a particular focus on longer term outcomes and mortality. Expert Opinion on Drug Safety2011;10(1):35-43.

Ballard 2016

Ballard C, Orrell M, YongZhong S, Moniz-Cook E, Stafford J, Whittaker R, et al.Impact of Antipsychotic Review and Nonpharmacological Intervention on Antipsychotic Use, Neuropsychiatric Symptoms, and Mortality in People With Dementia Living in Nursing Homes: A Factorial Cluster-Randomized Controlled Trial by the Well-Being and Health for People With Dementia (WHELD) Program. American Journal of Psychiatry2016;173(3):252-62. [DOI: 10.1176/appi.ajp.2015.15010130]

Banerjee 2009

Banerjee S.The use of antipsychotic medication for people with dementia: time for action. A Report for the Minister of State for Care Services by Professor Sube Banerjee. www.rcpsych.ac.uk/pdf/Antipsychotic%20Bannerjee%20Report.pdf (accessed 1 July 2017).

CADTH 2010

Canadian Agency for Drugs and Technologies in Health.Short-acting benzodiazepines versus other strategies for the management of agitation in older patients: clinical effectiveness and guidelines, 2010. www.cadth.ca/media/pdf/k0209_managing_agitation_older_patients_htis_1-5.pdf (accessed 4 February 2013).

Declerck 2009a [pers comm]

Declerck T.Results RCT [personal communication]. Email to: J. Cohen-Mansfield 21 April 2009.

Declerck 2009b [pers comm]

Declerck T.Results RCT [personal communication]. Email to: J. Cohen-Mansfield 1 July 2009.

Declerck 2009c [pers comm]

Declerck T.Clarification for a Cochrane review [personal communication]. Email to: C. Ballard 7 September 2012.

Devanand 2012a

Devanand D, Mintzer J, Schultz S, Sultzer D, de la Pena D, Gupta S, et al.The antipsychotic discontinuation in Alzheimer disease trial: clinical rationale and study design. American Journal of Geriatric Psychiatry 2012;20(4):362-73.

DSM‐III

American Psychiatric Association.Diagnostic and statistical manual of mental disorders. 3th edition. Washington, DC: American Psychiatric Press, 1987.

DSM‐IV

American Psychiatric Association.Diagnostic and statistical manual of mental disorders. 4th edition. Washington, DC: Amarican Psychiatric Press, 1994.

Elbourne 2002

Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV.Meta-analysis involving cross-over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140-9.

FDA 2005

USA Food and Drug Administration Public Health Advisory.Deaths with antipsychotics in elderly patients with behavioral disturbances. psychrights.org/drugs/FDAantipsychotics4elderlywarning.htm (accessed 1 May 2017).

Ferri 2005

Ferri C, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al.Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366(9503):2112-17.

Gilley 2000

Gilley DW.Are behavioral and psychological symptoms of dementia associated with mortality in Alzheimer's disease? International Psychogeriatrics 2000;12(1):63-6.

GRADEpro GDT [Computer program]

GRADEpro GDT.Version accessed 1 July 2017. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015. Available at gradepro.org.

Herrmann 2006

Herrmann N, Lanctôt K, Sambrook R, Lesnikova N, Hébert R, McCracken P, et al.The contribution of neuropsychiatric symptoms to the cost of dementia care. International Journal of Geriatric Psychiatry 2006;21(10):972-6.

Higgins 2011

Higgins JP, Green S, editor(s).Cochrane Handbook for Systematic Reviews of Interventions Version 5.2.0 [updated June 2017]. The Cochrane Collaboration, 2017. Available from www.cochrane-handbook.org.

Higgins 2016

Higgins JPT, Lasserson T, Chandler J, Tovey D, Churchill R.Methodological expectations of Cochrane intervention reviews. Available from community.cochrane.org/mecir-manual2016.

ICD‐10

World Health Organization.International statistical classification of diseases and related health problems 10th revision. apps.who.int/classifications/icd10/browse/2016/en (accessed prior to 24 mars 2018).

ICD‐9

World Health Organization.International classification of diseases, ninth revision. www.cdc.gov/nchs/icd/icd9.htm (accessed prior to 24 Mars 2018).

Livingston 2017

Livingston G, Sommerlad A, Orgeta V, Costafreda S, Huntley J, Ames D et al.Dementia prevention, intervention, and care. The Lancet2017;390(10113):2673-2734. [DOI: 10.1016/ S0140-6736(17)31363-6]

McCleery 2012

McCleery J, Fox R.Antipsychotic prescribing in nursing homes. British Medical Journal 2012;344:e1093.

Meador 1997

Meador K, Taylor J, Thaba P, Fought R, Ray W.Predictors of antipsychotic withdrawal or dose reduction in a randomized controlled trial of provider education. Journal of the American Geriatric Society 1997;45(2):207-10.

NICE 2016

National Institute for Health and Clinical Excellence.Dementia: supporting people with dementia and their carers in health and social care. guidance.nice.org.uk/CG42 (accessed 8 September 2017).

Pan 2014

Pan Y, Wu C, Gau S, Chan HY, Banerjee S.Antipsychotic discontinuation in patients with dementia: a systematic review and meta-analysis of published randomised controlled studies. Dementia Geriatric and Cognitive Disorder2014;37(3-4):125-40.

Petrovic 2007

Petrovic M, Hurt C, Collins D, Burns A, Camus V, Liperoti R, et al.Clustering of behavioural and psychological symptoms in dementia (BPSD): a European Alzheimer's Disease in Consortium (EADC) Study. Acta Clinica Belgica 2007;62(6):426-32.

Porsteinsson 2014

Porsteinsson A, Drye L, Pollock B, Devanand D, Frangakis C, Ismail Z, et al.Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. Journal of the American Medical Association2014;311(7):682-91. [DOI: 10.1001/jama.2014.93]

Prince 2016

Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M.World Alzheimer report 2016: improving healthcare for people living with dementia: coverage, quality and costs now and in the future. www.alz.co.uk/research/WorldAlzheimerReport2016.pdf (accessed 1 September 2017).

Review Manager 2014 [Computer program]

Review Manager 5 (RevMan 5).Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Schneider 2005

Schneider L, Dagerman K, Insel P.Risk of death with atypical antipsychotic drug treatment for dementia. Journal of the American Medical Association 2005;294(15):1934-43.

Schneider 2006

Schneider L, Dagerman K, Insel P.Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomised, placebo-controlled trials. American Journal of Geriatric Psychiatry 2006;14:191-210.

Seitz 2011

Seitz DP, Adunuri N, Gill SS, Gruneir A, Herrmann N, Rochon P.Antidepressants for agitation and psychosis in dementia. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No: CD008191. [DOI: 10.1002/14651858.CD008191.pub2]

Smith 2011

Smith T.Antipsychotics in dementia - mortality risks and strategies to reduce prescribing. Evidence Based Mental Health 2011;14(2):35-6.

Van Leeuwen 2017 [pers comm]

Van Leeuwen E.Discontinuation study [personal communication]. Email to: S Bergh 9 June 2017.

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Zuidema 2007

Zuidema S, Koopmans R, Verhey F.Prevalence and predictors of neuropsychiatric symptoms in cognitively impaired nursing home patients. Journal of Geriatric Psychiatry and Neurology 2007;20(1):41-9.

References to other published versions of this review

Declerck 2009

Declercq T, Petrovic M, Vander Stichele R, De Sutter AIM, van Driel ML, Christiaens T.Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and neuropsychiatric symptoms in elderly patients with dementia. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No: CD007726. [DOI: 10.1002/14651858.CD007726]

Declercq 2013

Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AIM, van Driel ML et al.Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No: CD007726. [DOI: 10.1002/14651858.CD007726.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ballard 2004

Study characteristics

Methods

Design: double‐blind, placebo‐controlled study

Duration: 3 months

Participants

Country: UK

Centres: 2

Setting: residents of 2 long‐term care facilities

Total number of participants: 100 (46 intervention, 54 control)

Analysis: completed at least 1 follow‐up randomisation

Gender distribution (F%): 76 % intervention = 76%, control = 87%

Mean age (years): intervention = 83.1 (SD 7.1), control = 83.6 (SD 9.3)

Cognitive function (Mean MMSE): intervention = 5.5 (SD 6.8), control = 5.5 (SD 6.5)

Total NPI: intervention = 13.3 (SD 9.3), control = 15.7 (SD 8.3)

Inclusion criteria: older participants (aged > 65 years) care facility residents, probable or possible Alzheimer's disease by the NINCDS‐ADRDA criteria (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association Criteria), a Clinical Dementia Rating Scale stage 1 or greater and no severe behavioural symptoms (no individual scores above 7) on the NPI at time of evaluation, taking neuroleptics (thioridazine, chlorpromazine, haloperidol, trifluoperazine or risperidone) for more than 3 months (median prescription time longer than 1 year)

Exclusion criteria: no severe behavioural disturbances, taking neuroleptics for longer than 3 months, having severe behavioural symptoms (individual scores above 1) and no severe behavioural symptoms (individual scores above 7 on 1 of the 12 items of the NPI‐scale)

Interventions

Intervention 1: abrupt discontinuation of antipsychotics (intervention group)

Intervention 2: continuing antipsychotics (control group)

No dose reduction of tapering

Outcomes

Duration of follow‐up: 3 months (0, 1 and 3 months)

Outcomes measured: behavioural and psychiatric symptoms (NPI), quality of life (DCM)

Notes

Funding provided by Research into Aging (London, UK) and Age Concern (London, UK).

Conflicts of interests were not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: method of sequence generation is not reported

Quote: "Subjects were then randomised to neuroleptic (N = 54) or placebo (N = 46)"

Allocation concealment (selection bias)

Unclear risk

Comment: method of allocation concealment is not described

Quote: "...Dispensing was coordinated by the pharmacy departments at the 2 centres. Prescriptions were written prior to randomisation in a twice daily regimen, allocating to each participant the closest dose..."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken. Encapsulation of the administered drugs ensured blinding of participants and doctors/nurses.

Quote: "The study was conducted using a double‐blind design. All study neuroleptics were encapsulated by an independent company to maintain blind, and dispensing was coordinated by the pharmacy departments at the 2 centres. Prescriptions were written prior to randomisation in a twice‐daily regimen, allocating to each participant the closest dose to their pre‐existing prescription from the doses encapsulated"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken. Blinding of the outcome raters is not described.

Quote: "...using a double blind design...the centre coordinator, blinded to neuroleptic status, decided whether the patient needed to be withdrawn from the study to receive "rescue" medication."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: reasons for dropouts reported and similar for both groups

Quote: "All evaluations were undertaken at baseline. The NPI and DCM assessments were also completed at 1 and 3 month follow‐up. Study withdrawals and the proportion of participants developing marked (pronounced or manifest) behavioural symptoms are described and compared between groups using the chi‐square test. Fourteen participants (26% active treatment, 30% placebo) withdrew from the study in each group. There were only 6 withdrawals in the placebo‐treated group (13%) and 5 withdrawals in the active treatment group (9%) because of behavioural deterioration. Other withdrawals were because of physical health problems (active group: 3 (6%), placebo group: 3 (7%)), protocol violation (active group: 2 (4%), placebo group: 1(2%)) or withdrawal of consent (active group: 3 (6%), placebo group: 2 (4%)). Eighty‐two (82%) of the participants completed at least 1 follow‐up evaluation and were included in the primary outcome analysis. For all participants who completed at least 1 follow‐up assessment, the last evaluation was carried forward"

Selective reporting (reporting bias)

Low risk

Comment: behavioural and psychiatric symptoms and well‐being reported on all measured time points, cognition was only assessed at start of the study

Other bias

Low risk

No other bias

Ballard 2008

Study characteristics

Methods

Design: randomised, blinded, placebo‐controlled parallel 2‐group treatment discontinuation study

Duration: 12 months

Participants

Country: UK

Setting: residents of 5 long‐term care facilities

Total number of participants: 165 (82 discontinuation, 83 continuation)

Gender distribution (women %): 75.6 % discontinuation, 77.1% continuation

Mean Age, SD (years): 84.9 (SD 6.1) discontinuation, 84.4 (SD 7.0) continuation

Inclusion criteria: participants lived in a nursing or residential home, patient fulfilled the NINCDS/ADRDA criteria for possible or probable Alzheimer's Disease, patient had either a MMSE score > 6 or a Severe Battery Impairment score > 30, patient was taking at least 10mg chlorpromazine equivalents of a typical neuroleptic or at least 0.5 mg daily of risperidone

Exclusion criteria: participants unable to complete primary outcome measures at baseline assessment, clinician responsible for care or study clinician considered the person with any physical condition that would have made participation in the trial distressing or likely to have more physical problems, patient was currently taking thioridazine and showing a prolonged QTc on electrocardiogram, patient was likely to be unable to take capsules

Interventions

Intervention 1: abrupt discontinuation of neuroleptics and switch to placebo (placebo group)

Intervention 2: continuation of neuroleptics (continuation group)

Three fixed dosages (very low‐low‐high) were chosen for each of the permitted neuroleptic drugs and were maintained during the 12 months

Outcomes

Duration of follow‐up: 12 months

Primary outcome:

Cognitive function: total Severe Impairment Battery (SIB) score (0, 6, 12 months)

Secondary outcomes:

neuropsychiatric symptoms: NPI (0, 6, 12 months)

cognitive function: Standardised Mini‐Mental State Examination (SMME) (0, 6 months)

adverse effects: Modified Unified Parkinson's disease Rating Scale (M‐UPDRS) (0, 6 months)

FAS test (0, 6 months)

Bristol Activities of Daily Living Scale (BADLS) (0, 6 months)

Sheffield Test for Acquired Language Disorders (STALD)(0, 6 months)

Functional Assessment Staging (FAST)(0, 6 months)

Clinician's Global Impression of Change (CGIC) (0, 6 months)

Notes

Clive Ballard, first author, has received honoraria en research grants from different companies.

Study was possible by a grant from the Alzheimer's Research Trust, Cambridge, UK.

There are several factors limiting the generalisability of the interpretation of this trial.

First, recruitment focused on participants living in residential care where moderate and severe dementia usually predominates, and the participants generally are older and frailer than their counterparts in other settings. Thus, the results are not easily extrapolated to individuals who are cared for in other community settings

Second, 89% of the participants were taking haloperidol or risperidone, but pharmacological profiles of neuroleptics differ, so that the study might not adequately represent the effects of discontinuation of other neuroleptics

Furthermore, polypharmacy is common in residential care, and the study did not consider other psychotropic prescriptions

Finally, high participant attrition sharply reduced the statistical power and scope for analysis of outcomes at 12 months. Imputation procedures and sensitivity analyses established robustness of estimates, but they cannot account for type II errors (i.e. false‐negative interpretation)

Individual participant data at three months from was kindly provided by the authors to allow pooling of the data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comments: randomisation was done by computer random number generator

Quote: "Randomisation was performed centrally at the Centre for Statistics in Medicine in Oxford (CSMO), using dedicated computer software (MINIM). The randomisation programme included a minimisation algorithm to ensure balanced allocation of participants across the intervention groups for important prognostic factors"

Allocation concealment (selection bias)

Low risk

Comment: central allocation concealment

Quote: "The statistician carrying out the randomisation had no direct contact with patients and allocation was, therefore, totally independent of patient recruitment. The clinician responsible for randomisation of a patient faxed a randomisation form to the CSMO (or sent e‐mail) in exceptional circumstances) and provided details appropriate and sufficient for establishing eligibility. If a person was eligible and informed consent/assent had been obtained and baseline assessments had been completed, the patient was randomised by the statistician either to continue taking medication or to discontinue (placebo group). The statistician directly communicated the allocation to the relevant trial pharmacy, ensuring concealment."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken

Quote: "The clinicians, those administering the trial medication, the carers, the relatives and the participants themselves, and those assessing the outcomes were all blinded to treatment allocation. Each antipsychotic was over‐encapsulated to maintain the double‐blind design. Placebo capsules were identical to the over‐encapsulated antipsychotics,.."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken.

Quote: "... those assessing the outcomes were blinded to treatment allocation..."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: flow of participants is included. Missing data is balanced across groups and similar reasons.

Quote: "Primary analysis was done performed on patients with complete data at both baseline and week 26, including those who did not adhere tot the protocol. To give a completed data set the imputation method was used "filling in" missing data with plausible values. A sensitivity analysis was used to test the robustness of the SIB result. This analysis was limited to those participants for whom the risk of possible floor and ceiling effects was smallest, i.e. SIB baseline cut‐off values ≥ 40 but ≤ 90."

Selective reporting (reporting bias)

Low risk

Comment: all intended primary and secondary outcomes are reported in the first and the follow‐up study

Other bias

Low risk

No other bias

Bergh 2011

Study characteristics

Methods

Design: randomised double‐blind placebo‐controlled trial with two sub‐studies: the antidepressant discontinuation placebo‐controlled study group (Bergh 2012) and the antipsychotic discontinuation placebo controlled study group (Bergh 2011). The antipsychotic discontinuation study (Bergh 2011) met inclusion criteria and was included in the review.

Duration: 25 weeks

Participants

Country: Norway

Setting: residents of 15 nursing homes

Total number of randomised participants: 19 (9 discontinuation, 10 continuation)

Mean age (years): 81.7 discontinuation, 82.6 continuation

Gender distribution (% women): 37.5 discontinuation, 70 continuation

Median CSDD score (range 0 to 38): 5.5 discontinuation, 6 continuation

Median NPI‐10 (range 0 to 144): 22 discontinuation, 21 continuation

Inclusion criteria: vascular or Alzheimer dementia, or mixed Alzheimer's disease/vascular dementia, nursing homes resident for 3 months or more, given risperidone for 3 months or more, Clinical Dementia rating 1, 2 or 3

Exclusion criteria: dementia of other origin, psychiatric disease (schizophrenia, depression or any severe), life expectancy less than 3 months, acute infection last 10 days, unstable diabetes mellitus, terminal disease

Interventions

Treatment 1: discontinuation risperidone after titrated out over one week

Treatment 2: continuation of risperidone (dose in each patient varied, according to the dose the participants were prescribed at inclusion, mean dose at inclusion was 0.92 mg/d)

Concomitant therapy: all kinds of concomitant therapy were allowed before, during and after the study

Outcomes

Primary outcomes: neuropsychiatric symptoms: changes in Neuropsychiatric Inventory‐10 (0 weeks, 25 weeks; range 0 to 120), depressive symptoms of a patient with dementia: changes in Cornell's Depression Scale (0 week, 25 weeks; range 0 to 38), safety analyses: changes on the Unified Parkinson Disease Rating Scale (UPDRS, six‐item version) (0 weeks, 25 weeks)

Secondary outcomes: Quality of life – Alzheimer's disease (QoL‐AD), the Severe Impairment Battery (SIB), the Lawton & Brody's Physical Self‐Maintenance scale (PSMS), the Clinical Dementia Rating Scale (CDR)

Notes

Sponsor: Innlandet Hospital Trust. There is no conflict of interest of the author reported. It is unclear if the author received grants. Provider of study drugs is not described.

This was an unpublished study. We requested results by email communication with the author on 8 June 2017 (Van Leeuwen 2017 [pers comm]). We received study results on 10 June 2017. The study arm with antidepressants was published in 2012 as a separate paper. The antipsychotics discontinuation arm was never published as paper. The study results were known in 2011 and reported to the Norwegian Medicines Agency. This study was not included in the 2013 review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: participants randomised centrally

Quote: "...using computer generated randomisation (1:1) in block of four..."

Allocation concealment (selection bias)

Low risk

Comment: pharmacist was responsible for allocation

Quote: "... patients were allocated to placebo or active treatment group by centralized allocation in blocks of four (1:1) by Sykehusapotekene Gjøvik, who also kept the randomisation list, computer derived, until the statistical analyses were completed.."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study was described as double‐blinded, probably blinding will be successfully done

Quote: "Study blinding was maintained as no other involved partner of the study knew the randomisation list than Sykehusapoteket Gjøvik. All statistical analyses were performed before the randomisation groups were unblended. The bottles with active medication and placebo were identical labelled...replaced by placebo in a blinded way or replaced by a study drug containing active medication (same kind, same dose) as before..."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: probably blinding of assessment outcomes was successfully done. The study involved 57 study nurses which could have biased the results.

Quote: "Data collection was done by research nurses. All statistical analyses were performed before the randomisation groups were unblended. A sealed code envelope was stored in the patient’s medical journal at the nursing homes, and could only be opened in case of medical emergencies as a serious adverse event."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

High risk

Comment: all randomised participants (19) are described in the flowchart. Very high dropout and withdrawal in the discontinuation group (7/9) suggests high risk of bias. Dropouts were more frequent in the ApDG (7/9, 77.8%) than in the ApCG (0/10, 0.0%) (P = 0.001). The analysis was based on modified ITT: participants in efficacy analysis: 16, participants included in safety analysis: 18. Unpublished data and high dropouts suggests high risk of attrition bias.

Selective reporting (reporting bias)

High risk

Comment: protocol was registered in ClinicalTrials.gov, outcome measurements were not all reported as per protocol paper. Study is unpublished, no peer reviewing to valid results suggests high risk of bias.

Quote: " ... The number of primary endpoints were reduced from three to two: Cornell Scale of Depression in Dementia and the Neuropsychiatric Inventory...the changes were made prior to breaking the blind, and have limited implications for study interpretation... no observe case analysis en no interim analyses as planned in the protocol."

Other bias

Low risk

No other bias

Bridges‐Parlet 1997

Study characteristics

Methods

Design: double‐blind, baseline treatment neuroleptic‐controlled pilot study

Duration: 4 weeks

Participants

Country: USA

Setting: residents of long‐term care facilities

Participants: 36 (22 discontinuation, 14 continuation)

Inclusion criteria: participants with diagnosis of possible or probable Alzheimer's dementia (criteria were given), participants receiving a neuroleptic (any traditional neuroleptic was acceptable) and who had been on a stable dose for 3 months prior to the study, a history of physically aggressive behaviour according to the referring nursing supervisor, participants residing in a nursing home, participants on antidepressants were permitted to participate if medication doses had been stable

Exclusion criteria: participants with primary psychiatric diagnoses, mental retardation and terminal illness or other recent acute, changes in health status (e.g. recent broken hip)

Interventions

Intervention 1: withdrawal neuroleptics (discontinuation)

Intervention 2: no withdrawal neuroleptics (continuation)

Abrupt withdrawal or tapering off a neuroleptic when baseline dose exceeded the equivalent of 50 mg of chlorpromazine. The tapering was done by dropping the baseline neuroleptic dose by half during week 1 and then discontinuing the neuroleptic completely at the beginning of week 2

Neuroleptic drugs: haloperidol (21), thioridazine (9), thiothixene (3), trifluoperazine (1), mesoridazine (1), loxapine (1)

Outcomes

Primary outcome: completion of the 4 weeks of study (numbers completing the 4 week study), behavioural symptoms: change in the amount of observed physically aggressive behaviour (mean, mean difference) (0, 1, 2, 4 weeks)

Secondary outcomes: use of physical restraint, verbally aggressive behaviour, walking, amount of time spent sleeping and sitting, verbal aggressiveness, physically aggressive acts observed by experienced study personnel and by using a portable barcode reader capable of storing several hours of observation (0, 1, 2, 4 weeks)

Notes

Research grant from the Alzheimer's Association.

There may have been selective recruitment limiting the generalisation of the results.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: randomisation was done by random number table

Quote: "Assignment was based on a predetermined sequence such that three patients were assigned to withdrawal for every two not withdrawn. At the end of week 1, subjects were randomly assigned to either withdrawal or no withdrawal."

Allocation concealment (selection bias)

Unclear risk

Comment: method of allocation concealment is not described, and may not have been blinded. Participant groups were well matched for age, chlorpromazine‐equivalent neuroleptic dose and physically aggressive behaviour at baseline.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken. Nursing staff was involved in decision to discontinue the programme. They were blinded for the treatment allocated, thus outcome assessment may have been adequately blinded.

Quote: "Patients in both groups received identical‐appearing capsules prepared at the University of Minnesota Hospital Pharmacy. Patients receiving their medication in crushed form, received in the placebo group tablets of vitamin C instead of capsules. The patient receiving intramuscular mesoridazine daily was given intramuscular saline from a nurse not directly involved in the patient's care"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely that blinding could have been broken. Participants were directly observed by study personnel, who were blinded to treatment assignments and recording behaviour was done by using a portable bar‐code reader capable of storing several hours of observation.

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: dropouts were described

Quote: "Of the 22 patients who were withdrawn, 20 (91%) completed the 4‐week double‐blinded withdrawal. Two patients were restarted on medication on the recommendation of the nursing staff; only one went back on a neuroleptic. Of the 14 patients not withdrawn, all completed the 4‐week trial. Of the 576 observation periods there were seven in which the bar‐code reader failed. Handwritten back‐up notes were used for physically aggressive behaviour frequency."

Selective reporting (reporting bias)

Low risk

Comment: all intended outcomes were reported

Other bias

Low risk

No other bias

Cohen‐Mansfield 1999

Study characteristics

Methods

Design: double‐blind cross‐over study

Duration: seven weeks followed by seven weeks cross‐over

Participants

Country: USA

Setting: residents of one nursing home

Diagnosis: the diagnosis of dementia was not mentioned

Number of participants: 58

Inclusion criteria: nursing home residents; aged over 70 years; had received at least four weeks haloperidol, thioridazine or lorazepam for agitation

Exclusion criteria: concomitant administration of other antipsychotic or anti‐anxiety drugs other than low‐dose trazodone hydrochloride for sleep, life expectancy less than three months due to obvious causes as judged by the nursing home staff member responsible for direct care psychiatric diagnosis of a major affective disorder of schizophrenia according to DSM‐III, acute infection within 10 days before entry, expectancy of leaving the nursing home within three months, uncontrolled hyperglycaemia or hypoglycaemia

Interventions

Tapering period: withdrawal of antipsychotic and lorazepam use by tapering to placebo during a three‐week period

Intervention 1: seven weeks of taking placebo followed by seven weeks of taking antipsychotic medication

Intervention 2: seven weeks of taking medication followed by seven weeks of placebo

Antipsychotics: haloperidol, thioridazine

Outcomes

Time of measurements: one week after start of dosage tapering (week 1), phase one tapering (week 3), phase one end point (week 10), phase two tapering (week 13), phase two end point (week 20)

Primary outcomes: behavioural symptoms (BPRS) (mean), agitation (CMAI) (mean)

Secondary outcomes (mean): adverse effects (AIMS), cognitive function (MMSE), global impression scale (GCI‐S), sleep and activity level ratings

Time of assessment: one week after start of dosage tapering (week 1), phase one tapering (week 3), phase one end point (week 10), phase two tapering (week 13), phase two end point (week 20)

Notes

Several different analyses were used to assess the robustness of the result. However, it was not clear if an intention‐to‐treat analysis was used. We were unable to use any data from this study. Cohen‐Mansfield 1999 did not report outcome data separately for the different medications discontinued in the trial (which included the benzodiazepine lorazepam as well as the antipsychotics haloperidol and thioridazine).

This study was supported by grants AG00547 and AG10172 from the National Institute on Aging, Bethesda, MD, USA.

No conflicts of interest reported.

Because diagnosis of dementia was not mentioned in the paper, we emailed the first author (Declerck 2009a [pers comm] on 21 april 2009 to ask her whether the participants included had dementia and her answer was positive (referring to the MMSE scores).

We have asked the author by email for more results (SDs of the means…) on 1 July 2009, but we have not received any response on our last e‐mail (Declerck 2009b [pers comm]).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: method of sequence generation is not described

Quote "...half the residents were randomly assigned to have their medication dose tapered during a 3‐week period, followed by receipt of a placebo (the other half continued their usual medication dosage). Residents were randomly assigned to the placebo versus medication group and stratified both by level of cognitive function and by psychotropic medication."

Allocation concealment (selection bias)

Unclear risk

Comment: allocation is not described

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as blinded, unlikely that blinding was broken

Quote: "Study medications (usual medication and placebo) were administered as identical liquids to ensure blindness by the care team. Only the dispensing pharmacist, who was not an employee of the nursing home, knew which medication was administered. The care team, residents, family caregivers, and research team were blinded to which group a participant was assigned."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: study is described as blinded, unlikely that blinding was broken

Quote: "The care team, ... and research team were blinded to which group a participant was assigned. Primary outcome data BPRS was assessed by daytime and evening nursing staff. "

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Unclear risk

Comment: rates and reason for dropout were described. However we were uncertain how many participants discontinued in the discontinuation or continuation group in the first part of the study.

Quote: "Twenty‐three participants discontinued participation in the study before completion for the following reasons: death or dying (3), hospitalisation (1), not eating or weight loss (3), increased agitation (9), lethargy (2), withdrawal of consent (4), facial asymmetry (1) and fall (3); some had multiple reasons. For 12 participants, discontinuation occurred during the original drug dosage, for 9 while taking placebo, and for 2 during titration from drug to placebo. Most discontinuations (20 of 23) occurred in the first part of the study, before the cross‐over."

Selective reporting (reporting bias)

High risk

Comment: no distinction is made for number of withdrawals in each group during the first part of the trial. it is not clear how they analyse these outcome. By not making difference in outcome reporting between discontinuation of antipsychotics, namely haloperidol and thioridazine, versus discontinuation of lorazepam, a benzodiazepine, it is impossible to retain robust conclusions from this withdrawal study.

Quote: "Participants who discontinued the study were similar in demographic characteristics to those who stayed. Although their levels of agitation at baseline were higher than those who stayed in the study, these differences did not reach statistical significance. Most withdrawals from the study occurred in the first part of the study (no numbers given)."

Other bias

Low risk

No other bias

Devanand 2011

Study characteristics

Methods

Design: a six‐month, randomised, double‐blind, placebo‐controlled discontinuation trial (phase B) following response to haloperidol open treatment during 20 weeks (phase A)

Participants

Country: USA

Setting: participants living in the community who presented to a memory disorders clinic or an affiliated behavioural neurology practice group

Total number of participants: 44 participants included in phase A, 22 responders of phase A were eligible for randomisation in phase B (discontinuation trial), 20 in phase B (10 discontinuation, 10 continuation)

Gender distribution (female): 77%

Mean (years): 75 (SD 8.0)

Inclusion criteria: aged 50 to 95 years, clinical diagnosis of dementia by DSM‐IV criteria and probable Alzheimer's disease by NNCDS‐ADRA criteria, MMSE range between 5 and 26, current symptoms of psychosis, agitation or aggression.

Exclusion criteria: acute unstable medical condition, delirium, alcohol or substance abuse or dependence during the prior year, clinical evidence of stroke, other dementias including vascular or Lewy body or frontotemporal dementia, multiple sclerosis, Parkinson's disease, Huntington's disease, tardive dyskinesia, diagnosis of a psychotic disorder predating the onset of dementia, antipsychotic medication usage during the 4 weeks before study entry, and contra‐indication to the use of haloperidol

Interventions

Phase A: open treatment (20 weeks): 44 participants living in the community with Alzheimer's disease and psychosis, agitation or aggression receiving psychotropic medication had a 1‐week washout before entering phase A. During phase A flexible doses of haloperidol 0.5 to 5 mg daily were individually titrated to maximise therapeutic response and minimise side effects, especially extrapyramidal side effects. Visits occurred at 0, 2, 4, 8, 12, 16 and 20 weeks
Phase B: discontinuation trial (24 weeks): 20 phase A responders were double‐blind randomised to a continuation versus placebo (i.e. discontinuation) group. For participants randomised to placebo, there was a 2‐week double‐blind sequential placebo substitution tapering period to placebo.

Outcomes

Phase A: the 3 most prominent targets of psychosis, agitation or aggression, scored on a 7‐point scale (0 = absent to 6 = extreme) and tracked during the study. Criteria for response (primary outcome) were minimum 50% reduction from baseline in the sum score of these 3 target symptoms, a sum score ≤ 6 on these 3 items (range 0 to 18), and minimal or greater improvement on the CGI‐C score (rated only for symptoms of psychosis, agitation or aggression).

Phase B

Primary outcome: relapse, assessed at any single time point during phase B. Criteria for relapse were minimum 50% worsening from the sum score of the 3 target symptoms at the end of phase A, a sum score ≥ 6 on these 3 items (range 0 to 18), and minimal or greater worsening on the CGI‐C score (rated for psychosis and agitation/aggression).

Secondary outcomes: somatic side effects assessed by the TESS, extrapyramidal signs assessed by the UPDRS and tardive dyskinesia assessed by the Rockland TD scale. Cognition was assessed by change in MMSE and impairment in ADL was assessed by the modified BFAS.

Time points of assessment during phase B: 0 (same as end of phase A), 2, 4, 8, 12, 16, 20 and 24 weeks (i.e. 6 months).

Pretrial: a 1‐week washout prior to entering phase A.

Notes

Disclosures: authors had financial links with several pharmaceutical companies. Study supported by NIH grant.

The discontinuation trial included only participants who responded to haloperidol. Non‐responders after the first 20 weeks (phase A) were excluded from the discontinuation phase (B). This limits the generalisability of the results.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: not described in the study

Allocation concealment (selection bias)

Unclear risk

Comment: no description of the blinding of random allocation

Quote: "Responders by end‐Phase A were eligible for Phase B, a 24‐week, random assignment (1:1 assignment of haloperidol and placebo), double‐blind, trial of continuation haloperidol (same dose as end‐Phase A) versus switch to placebo."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as double‐blinded, unlikely blinding could have been broken

Quote: "Haloperidol and placebo were made up in identical looking opaque white capsules."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: blinding of outcome raters is not described. In these trial, they were several subjective outcomes, so a lack of blinding of outcome assessors could had an influence.

The protocol (Devanand 2012a) for the subsequent study (Devanand 2012) mentions: Quote: "The blind is maintained after study exit to avoid biasing raters. A code‐break is authorized only if needed in cases of overdose or medical emergency... raters remained unaware of the group assignments of all patients during the entire study."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: non‐completers data were described and balanced between the groups

Attrition at end of phase A fully accounted for; quote: "There were 15 Phase A non‐completers (34%), with all early terminations attributed either to lack of efficacy (n = 9) or side effects (n = 6)."

Attrition at end of phase B accounted for and ITT included; quote: "Twenty of the 21 patients randomised in Phase B to continuation haloperidol or placebo had at least one follow‐up visit after randomisation and were included in the Phase B analysis. Among patients who did not relapse, reasons for early study termination prior to 24 weeks in Phase B were side effects (n = 2), moving out of the area (n = 1), medical illness (n = 1) and noncompliance (n = 1). All data from these patients were included in the intent‐to‐treat, last observation carried forward, analyses. "

Selective reporting (reporting bias)

Unclear risk

Comment: several outcomes were measured at baseline of the open haloperidol treatment and at time of the discontinuation period, but no results were reported at later times of assessment

Other bias

Low risk

No other bias

Devanand 2012

Study characteristics

Methods

Phase A: flexible dose risperidone open treatment for 16 weeks

Phase B: six‐month, randomised, double‐blind, placebo‐controlled discontinuation trial, following response to phase A

Duration: 48 weeks

Participants

Country: USA

Setting: outpatients through physician referrals and advertising; and residents of assisted‐living facilities (memory clinics (including Alzheimer’s research centres), geriatric psychiatry clinics and clinics at Veterans' Affairs medical centres) or nursing home

Total number of participants: 253 participants screened

Phase A: 180 received risperidone, participants who had a response in phase A entered phase B.

Phase B: 110 randomised

Group 1: continue risperidone: 32 participants at start, 13 received risperidone at 16 weeks, 10 completed 48 weeks without relapse

Group 2: continue risperidone for 16 weeks and then placebo: 38 participants at start, 27 received placebo at 16 weeks, 14 completed 48 weeks without relapse

Group 3: start placebo in phase B: 40 participants at start, 13 received placebo at week 16, 10 completed 48 weeks without relapse

Gender distribution at baseline: 59%

Mean (years) at baseline: 79.6 (SD 7.6)

Inclusion criteria: outpatients or residents of assisted‐living facilities or nursing homes, aged 50 to 95 years, met the criteria for dementia of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV) and the criteria for probable Alzheimer’s disease of the NINCDS–Alzheimer’s Disease and Related Disorders Association, a score on the Neuropsychiatric Inventory (NPI) of 4 or more at both screening and baseline on the delusions or hallucinations subscale (psychosis score) or the agitation/aggression subscale (agitation score) (with scores on all NPI subscales ranging from 0 to 12 and higher scores indicating more pronounced symptoms), a score of 5 to 26 on the Mini‐Mental State Examination (MMSE, with scores ranging from 0 to 30) in the case of outpatients, a score of 2 to 26 in the case of nursing home residents (with the lower range reflecting the greater severity of dementia in nursing homes)

Exclusion criteria: history of stroke, transient Ischaemic attack, or uncontrolled atrial fibrillation

Interventions

Participants with Alzheimer’s disease and psychosis, agitation or aggression received open‐label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double‐blind fashion, 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)

Phase A: open‐label treatment with flexible dose risperidone for 16 weeks, participants who had a response entered phase B

Phase B: 110 randomised in phase B
Group 1: continue risperidone
Group 2 continue risperidone for 16 weeks and then placebo
Group 3: discontinuation of antipsychotics

Concomitant treatment: quote: "If washout was not feasible ... stable doses of selective serotonin‐reuptake inhibitors or low‐dose trazodone or of sedatives or hypnotic agents were permitted ... Lorazepam, at a dose of 1 mg or less per day, was permitted if needed... cholinesterase inhibitors and memantine at stable dose were permitted"

Outcomes

Primary end point: the time to relapse of psychosis and agitation/aggression during weeks 0 to 16 of phase B, the time to relapse psychosis and agitation/aggression during weeks 17 to 32 of phase B

Phase A: participants were considered to have had a response if they had a reduction of 30% or more from baseline on the NPI

score (the sum of the sub‐scores for agitation–aggression, hallucinations, and delusions) and a score of one (very much improved) or two (much improved) on the Clinical Global Impression of Change (CGI‐C) scale (which ranges from one to seven, with higher scores indicating less improvement) for overall psychosis, agitation or aggression

Phase B: participants were considered to have had a relapse if they had an increase in the NPI core score of 30% or more, or a 5‐point increase from the score at the end of phase A, and a score of six (much worse) or seven (very much worse) on the CGI‐C

Secondary outcomes: assessments of extrapyramidal signs, with the use of the Simpson–Angus scale (which ranges from 0 to 40, with higher scores indicating more extrapyramidal signs), tardive dyskinesia, with the use of the Abnormal Involuntary Movement Scale (AIMS, which ranges from 0 to 35, with higher scores indicating more severe symptoms), general somatic symptoms developing during treatment, as assessed with the use of the Treatment Emergent Symptoms Scale (TESS, which ranges from 0 to 26, with higher scores indicating more somatic symptoms), cognitive status, as assessed with the use of the MMSE and the Alzheimer's Disease Assessment Scale (ADAS)–cognitive score (which ranges from 0 to 70, with higher scores indicating worse cognition), physical function, as assessed with the use of the Physical Self‐Maintenance Scale (PSMS, which ranges from 1 to 30, with higher scores indicating worse functioning) and adverse events

Notes

Outcome symptoms slightly unevenly distributed in randomised groups in phase B: 9% agitation‐aggression in group 1 (continue risperidone) versus 19% in group 2 (switch to placebo after 16 weeks) and 18% in group 3 (placebo throughout phase B).

High rates of discontinuation of risperidone (38% in phase A; 68% in group 1 and 29% in group 2).

Funding sources: quote "...Johnson & Johnson, donated the risperidone tablets and matching placebo but had no role in the conduct of the study or the analysis or reporting of the data... Supported by grants from the National Institutes of Health (R01 AG021488 and R01 AG17761) and the Department of Veterans Affairs."

Conflict of interest: not reported in the paper, but included in the Supplementary Appendix available online (add link). The first author received grants from several pharmaceutical companies (inside and outside the submitted work). The discontinuation trial only included only participants who responded to risperidone. Non‐responders after first 16 weeks (phase A) were excluded from the discontinuation phase (B). This limits the generalisability of the results.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: block randomisation is described

Quote: "The study statistician prepared a randomised permuted‐blocks procedure, with blocks of three or six, to balance the group assignment in each of four (2 × 2) strata, with stratification within each site according to the presence or absence of psychosis at baseline and residence (assisted‐living facility or nursing home vs. home)."

Allocation concealment (selection bias)

Low risk

Comment: central allocation by pharmacist

Quote: "Patients who had a response entered phase B of the study and were randomly assigned...The central pharmacy of the New York State Psychiatric Institute maintained the assignment code, and clinicians and raters remained unaware of the group assignments of all patients during the entire study."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as double‐blinded and unlikely that blinding could have been broken.

Quote: "...double‐blind fashion... clinicians and raters remained unaware of the group assignments of all patients during the entire study ... all tablets identical in appearance ... Immediately before the end of phase A, the pharmacy dispensed pre‐packaged blister packs of risperidone or placebo tablets that were identical in appearance for patients eligible for randomisation in phase B. The number of tablets the patient was receiving daily at the end of phase A was the number he or she received throughout phase B."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Comment: study is described as double‐blinded and unlikely that blinding could have been broken. The blind is maintained after study exit to avoid biasing raters. A code‐break is authorized only if needed in cases of overdose or medical emergency.

Quote: "...raters remained unaware of the group assignments of all patients during the entire study..."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: all randomised participants accounted for in the flowchart

Quote: "The dropout rates did not differ significantly among the randomised groups (Fig. 1)"

Selective reporting (reporting bias)

Unclear risk

Comment: the results for the CGI‐C were not reported in the study, the total NPI scores and the NPI core score were measured at baseline (phase A) and at time of randomisation (phase B), but no results were reported at later times of assessment

Other bias

Low risk

No other bias.

Findlay 1989

Study characteristics

Methods

Design: randomised double‐blind placebo‐controlled trial

Duration: 4 weeks

Participants

Country: UK

Setting: residents from one long stay of psychogeriatric ward of hospital

Total number of participants: 36

Gender distribution: 100% women

Mean age (years): 65 years or older

Inclusion criteria: senile dementia, Alzheimer type, according to ICD‐9, receiving a stable dose of between 10 mg and 100 mg of thioridazine per day for at least 2 months

Exclusion criteria: male, multi‐infarct dementia and antipsychotic agents other than thioridazine

Interventions

Intervention 1: withdrawal of thioridazine

Intervention 2: continuation of thioridazine

Antipsychotic drug: thioridazine

Pre‐trial: tapering to half of the daily dose in the first week and to placebo over the next week

Post‐trial: all participants were restored to half their original dose of thioridazine with any subsequent alterations being made by their regular medical attendant on an empirical base

Concomitant treatment: chlormethiazole

Outcomes

Primary outcomes: cognitive function: CAS (0, 2, 4 weeks), cognitive and behavioural dysfunction: LPRS (0, 2, 4 weeks), functioning: SCAGS (0, 2, 4 weeks)

Secondary outcomes: systolic BP and heart rate (0, 2, 4 weeks)

Results only given as means, ranges and numbers of observations

Notes

Conflict of interest and source of funding were not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Comment: methods of sequence generation were not described

Quote "...matching active and placebo (liquid) formulations of thioridazine were used, each subject being entered separately and allocated by a random code to the active or placebo group in a double‐blind manner"

Allocation concealment (selection bias)

Unclear risk

Comment: study described as 'randomised', the randomisation process was not completely successful

Quote: "...each subject being allocated by a random code to the active or placebo group in a double‐blind manner ... The starting difference in Cognitive Assessment Scale scores between active‐continued and placebo‐substituted groups represents an artefact of the randomisation process."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study described as "double blinded", unlikely that blinding was been broken

Quote: "matching active and placebo (liquid) formulations were used ... During the first week patients in the 'placebo' group received placebo substitution for half of their daily dose of thioridazine and over the next week a total substitution. Similar mock substitutions with thioridazine were given to the 'active' group, so that initial medication was continued but the trial remained double‐blind. After four weeks all patients were restored to half their original dose of thioridazine with any subsequent alterations being made by their regular medical attendant on an empirical basis ... as it was not possible to break the code in the middle of the trial "

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: study is described as double‐blinded, blinding of the outcome assessors is not described. Assessment was done by clinicians and nurses with psychiatric training. In these trial, they were several subjective outcomes, so a lack of blinding of outcome assessors could had an influence.

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Unclear risk

Comment: information of dropouts is not reported in the study

Selective reporting (reporting bias)

Unclear risk

Comment: primary outcome is not described, it is unclear if a selection of measured outcomes was reported

Other bias

Unclear risk

Comment: the randomisation procedure unfortunately resulted in a baseline imbalance in 1 of the 3 cognitive/behavioural rating scales (starting difference in cognitive assessment scale (CAS) between active continued was 4.2 treatment and 9.8 in the placebo‐substituted groups. The author noted: "Difference represents an artefact of the randomisation process." It is unclear if this has had an impact on outcomes.

Ruths 2008

Study characteristics

Methods

Design: randomised, placebo‐controlled, double‐blinded study

Duration: 4 weeks

Participants

Country: Norway

Setting: residents of 13 nursing homes

Diagnosis: dementia diagnosis according to the clinical criteria of ICD‐10

Number of participants: 55 (27 intervention, 28 reference)

Gender distribution (F) (number, %): 20 (74%) intervention, 23 (82%) reference

Mean age (years): 83.6 (SD 8.1) intervention, 84.6 (SD 5.9) reference

Inclusion criteria: older participants, aged 65 years and over, dementia diagnosis according to the clinical criteria of ICD‐10 residence in the facility for at least 3 months before inclusion, taking haloperidol, risperidone or olanzapine for nonpsychotic symptoms for at least 3 months before the study as standing medication in stable doses

Exclusion criteria: participants with antipsychotic use for a primary diagnosis of major psychotic disorder, mental retardation, terminal illness with life expectancy judged to be shorter than 3 months and recent major changes in health status

Interventions

Intervention group: abrupt discontinuation of antipsychotic medication

Reference group: no discontinuation of antipsychotic medication

Note: same dose of initial daily dose of antipsychotic drugs in intervention group: risperidone 1.0 (0.5 to 2.0) mg, haloperidol 1.0 (0.5 to 1.5) mg or olanzapine 5.0 (2.5 to 5.0) mg

Outcomes

Behavioural and psychological symptoms measured by the NPI‐Q (second baseline period, week 1, week 4). The NPI‐Q covers 12 symptoms: delusions, hallucinations, agitation/aggression, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behaviour (restlessness, e.g. purposeless wandering and inappropriate activity), sleep problems and eating disorders. Information on participants' symptoms was obtained by interview with the primary nurse informant. Individual symptoms were scored as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe), providing an NPI‐Q sum score rating from 0 to 36. Three separate ratings were conducted for all the participant. These ratings included symptoms occurring during the 7‐day period before assessment.

Sleep/wake activity was recorded continuously during baseline and intervention (i.e. over 6 weeks) using an Actiwatch portable recorder (second baseline week, week 1, week 4). The Actiwatch is a small wrist‐worn device containing an accelerometer that is optimised for highly effective sleep‐week inference from wrist activity. Actigraphically measured wrist activity is a feasible and reliable method for sleep/wake evaluation in nursing home residents. The following actigraphic parameters were calculated: total sleep time, total wake time, sleep efficiency (proportion of sleep during night window, i.e. 11 pm to 7 am), daytime activity and night‐time activity. The ratio of day‐to‐night‐time activity was calculated and expressed as a light/dark ratio. Mean 24‐hours activity and peak times of activity were calculated. Analyses of sleep/wake activity were based on 3 x 7‐day records.

Notes

Conflict of interests and funding were not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: method of randomisation is done computer random number generator

Quote: "Participants were assigned to antipsychotic drug discontinuation (intervention group) or no discontinuation (reference group) by means of computer generated, random, permuted blocks of 4... "

Allocation concealment (selection bias)

Unclear risk

Comment: allocation concealment was provided central, no further details were reported

Quote: "...an independent researcher ... participants were consecutively assigned to antipsychotic drug discontinuation or no discontinuation..."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: blinding of participants and personnel is described, unlikely that blinding could have been broken.

Quote: "In the intervention group, patients received inert placebo capsules consisting of lactose, whereas reference group patients received identically looking capsules containing continued antipsychotic drug treatment at current dose ... all study medications were provided by an independent pharmacy to maintain blindness ... Sealed envelopes, containing details of study medication for each patient, were available for the nursing home physicians in case of serious health events."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: study is described as double‐blinded. Blinding of the assessment interviewers is not described. In these trial, they were several subjective outcomes, so a lack of blinding of outcome assessors could had an influence.

Quote: "NPI rating was based on interviews with patient' prime nurse on her observations of BPSD the previous week. The interviews were conducted by specially trained medical students... Sealed envelopes... At the completion of the intervention, randomizations codes were broken."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Unclear risk

Comments: all 55 participants completed at least the week one evaluation were included in study analysis. No statistical difference in dropout between intervention and reference group.

Quote: "Seven patients completed the study prematurely, due to unblinding for randomisation code, behavioural deterioration, restless legs or delirium."

Selective reporting (reporting bias)

Low risk

Comment: all intended outcomes reported in accordance with the methods section

Other bias

Unclear risk

Comment: the selection of participants may have been biased. It is not clear if the participating nursing homes participants are different from non‐participating nursing home patients.

van Reekum 2002

Study characteristics

Methods

Design: randomised, double‐blind, placebo‐controlled trial

Duration: 26 weeks

Participants

Country: Canada

Setting: residents of two nursing homes and geriatric chronic care floor of an academic health science centre

Total number of participants: 34 (17 placebo, 17 active)

Gender distribution (male): 47.1% placebo; 56.3% active

Mean (SD) age, years: 84.4 (SD 4;6) placebo, 82.9 (SD 6.9) active

Inclusion criteria: any form of dementia, receiving antipsychotics for 6 months or longer, stable behaviour

Exclusion criteria: history of antipsychotic discontinuation having failed within the past 6 months, a history of schizophrenia, antipsychotic use for nausea, diagnosis of delirium (DSM‐IV criteria), a global rating scale of 3 on the BEHAVE‐AD rating scale at the time of the screening, 1 week prior to the start of the study or within the 2 weeks of the pre‐trial period

Interventions

Placebo group: discontinuation antipsychotics

Active treatment: continuing antipsychotic treatment with the same dose

Antipsychotics: risperidone, thioridazine, loxapine, perphenazine, haloperidol, olanzapine, nozinan

Note: pre‐trial period: 2‐week pre‐trial period and a 2 week dose reduction period by tapering (dose reduction with original medication halved for the first week of the dose reduction period and the remaining dose halved for the second week)

Concomitant medication: lorazepam 0.5 mg to 1 mg every 8 hours on a per need basis for agitation

Outcomes

Behavioural outcome measures: BEHAVE‐AD, the NPI and the ROAS (each visit: 15 times)

Cognitive functioning: MMSE (0, 4, 8, 12, 14, 16, 20, 24 weeks), MDRS (0, 24 weeks)

Functional level: BDS, ADL and motivational behaviour subscale (0, 4, 8, 12, 14, 16, 20, 24 weeks)

Extrapyramidal signs: ESRS (0, 4, 8, 12, 14, 16, 20, 24 weeks)

Clinical impression of severity of behavioural disturbance: CGI (all visits). The CGI quantified the clinical impression of severity of behavioural disturbance on a 7‐point, verbally anchored scale. The degree of change from baseline was also ranked on a similar scale

All outcome data were obtained by a trained research assistant upon interview of the prime nurse or the subject as appropriate for the instrument.

Notes

Funding source and conflict of interests were not reported in study

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Comment: participants randomly assigned to treatment by random number table

Quote: "A random number table was used to allocate subjects to receive either continued antipsychotic treatment at the current dose or to receive identical placebo"

Allocation concealment (selection bias)

Unclear risk

Comment: no reference made to the method in which allocation concealment was ensured

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Comment: study is described as "double blind" and unlikely blinding could have been broken

Quote: "A randomised double blind placebo controlled study design was used ... During all study periods, medications, including placebo, were placed into identical capsules to maintain blindness."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Comment: study is described as double‐blinded, blinding of the research team is not described. In these trial, they were several subjective outcomes, so a lack of blinding of outcome assessors could had an influence.

Quote: "All outcome data were obtained by a trainee research assistant upon interview of the prime nurse or the subject as appropriate for the instrument... if the clinical staff observed significant behavioural worsening that they thought warranted early withdrawal from the study, the ware asked to contact the research team immediately and the outcome measures were repeated at that time."

Incomplete outcome data (attrition bias)
NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)

Low risk

Comment: rates and reasons for dropouts were reported. Analysis is done by intention‐to‐treatment principle.

Quote: "The total number of subjects who were withdrawn from the study early was 10/17 in the placebo group and 6/17 in the active treatment group. The difference in the rate of early study withdrawal was not statistically significant. Subjects were withdrawn due to medical illness (3), death (3), extrapyramidal symptoms (3), and exacerbations of behavioural problems (4 in the placebo and 3 in the active group)."

Selective reporting (reporting bias)

High risk

Comments: some data of the continuation and the discontinuation group for several outcomes is not completely given in numerical results but only in descriptive figures. NPS assessed by NPI, aggression assessed by the ROAS, extrapyramidal signs assessed by the ESRS, cognitive functioning assessed by MMSE and functional outcome assessed by the BDS were not reported in the paper.

Other bias

Low risk

No other bias.

ADL: activities of daily living; BDS: Blessed Dementia Scale; BEHAVE‐AD: Behavioural Pathology in Alzheimer’s disease; BFAS: Blessed Functional Activity Scale; BP: blood pressure; BPRS: Brief Psychiatric Rating Scale; CAS: Cognitive Assessment Scale; CGI: Clinical Global Impression; CGI‐C: Clinical Global Impression‐Change; CMAI: Cohen‐Mansfield Agitation Inventory; DCM: Dementia Care Mapping; DSM‐III: Diagnostic and Statistical Manual of Mental Disorders ‐ 3th Edition; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders ‐ 4th Edition; ESRS: Extrapyramidal Symptom Rating Scale; LPRS: London Psychogeriatric Rating Scale; MDRS: Mattis Dementia Rating Scale; MMSE: Mini‐Mental State Examination; NIH: National Institutes of Health; NPI: Neuropsychiatric Inventory; NPQ‐I: Neuropsychiatric Inventory Questionnaire; NPS: neuropsychiatric symptoms; RCT: randomised controlled trial; SCAGS: Sandoz Clinical Assessment Geriatric Scale; SIB: Severe Impairment Battery; TESS: Treatment Emergent Symptom Scale; ROAS: Retrospective Overt Aggression Scale; UPDRS: Unified Parkinson's Disease Rating Scale.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Azermai 2013

Not an RCT but a clinical trial without a suitable control group

Ballard 2015

Intervention was discontinuation of memantine

Bergh 2012

Intervention was discontinuation of antidepressants

Devanand 2013

Commentary

Garner 2015

Commentary

Gill 2013

Commentary

Gnjidic 2013

Commentary

Horwitz 1995

Not a clinical trial, but a naturalistic study

Ling 2013

Commentary

Lolk 2014

Commentary

McLennan 1992

This trial reports a primary outcome (prolactin response to withdrawal of thioridazine assessed in the Findlay 1989 cohort), which has no relationship with the neuropsychiatric symptom in which we were interested

Patel 2017

Not an RCT; post hoc analysis of Devanand 2012

Power 2013

Commentary

Renard 2014

Commentary

Rule 2003

This reference probably refers to the registration of a discontinuation study which has not been published until now (no more information found on this reference)

Wessels 2010

This trial was not a discontinuation trial

Westbury 2011

This trial was a follow‐up study and not a discontinuation trial

RCT: randomised controlled trial

Data and analyses

Open in table viewer
Comparison 1. Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Behavioural assessment Show forest plot

2

194

Mean Difference (IV, Fixed, 95% CI)

‐1.49 [‐5.39, 2.40]

Analysis 1.1

Comparison 1: Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference), Outcome 1: Behavioural assessment

Comparison 1: Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference), Outcome 1: Behavioural assessment

Forest plot of comparison: 1 Discontinuation versus continuation of long‐term antipsychotic drug use: continuous data, analysis method: mean difference, outcome: 1.1 Behavioural assessment by using Neuropsychiatric Inventory (NPI) measuring neuropsychiatric symptoms (NPS) at 3 months (Ballard 2004 and Ballard DART‐AD) (Analysis 1.1).

Figuras y tablas -
Figure 1

Forest plot of comparison: 1 Discontinuation versus continuation of long‐term antipsychotic drug use: continuous data, analysis method: mean difference, outcome: 1.1 Behavioural assessment by using Neuropsychiatric Inventory (NPI) measuring neuropsychiatric symptoms (NPS) at 3 months (Ballard 2004 and Ballard DART‐AD) (Analysis 1.1).

Inclusions of trials of study flow diagram 2018

Figuras y tablas -
Figure 2

Inclusions of trials of study flow diagram 2018

Risk of bias graph for the 10 included studies in the review.

Figuras y tablas -
Figure 3

Risk of bias graph for the 10 included studies in the review.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study in the review.

Figuras y tablas -
Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study in the review.

Comparison 1: Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference), Outcome 1: Behavioural assessment

Figuras y tablas -
Analysis 1.1

Comparison 1: Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference), Outcome 1: Behavioural assessment

Summary of findings 1. Discontinuation compared to continuation of antipsychotic medication for behavioural and psychological symptoms in older people with dementia

Discontinuation compared to continuation of antipsychotic medication for behavioural and psychological symptoms in older participants with dementia

Patient or population: older people with dementia who had been taking an antipsychotic drug for at least 3 months
Setting: any setting
Intervention: discontinuation of long‐term antipsychotic drug use
Comparison: continuation of long‐term antipsychotic drug use

Outcomes

Illustrative comparative risks (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Continuation antipsychotics

Corresponding risk

Discontinuation antipsychotics

Success of withdrawal from antipsychotics

Measured with a variety of outcomes related to failure to complete the study

Follow‐up: 1 to 8 months

In 7 studies there was no overall difference in the outcomes reported for success of withdrawal.

In two studies of participants with psychosis, aggression or agitation who had responded to antipsychotic treatment, discontinuation accelerated symptomatic relapse without affecting the number of participants experiencing a relapse in one study and was associated with a higher rate of symptomatic relapse in the other study.

In one small study a high proportion of the participants in the discontinuation group failed to complete the study.

575 (9 RCTs)

⊕⊕⊝⊝

LOWab

Our intended primary outcome, success of withdrawal defined as the ability to complete the study in the allocated study group, i.e. no failure due to worsening of NPS or relapse to antipsychotic drug use, was not reported in any study. We used the difference between groups in the number of non‐completers of the study as a proxy for our primary outcome. However, data could not be pooled due to variability in outcome measures.

Behavioural and psychological symptoms

Assessed with various scales.

Follow up: 1 to 8 months

In 2 pooled studies there was no difference in NPI scores between the continuation and discontinuation groups (see Data and analyses and Figure 1).

In five non‐pooled studies, there was no difference in the outcomes on scales measuring overall behaviour and psychological symptoms between groups.

519 (7 RCTs)

⊕⊕⊝⊝
LOW⊝bc

Data could only be pooled for 2 studies due to variability in outcome measures.

The two pooled studies performed subgroup analyses according to baseline NPI‐score (≤ 14 or > 14). In one study, some participants with milder symptoms at baseline were less agitated at three months in the discontinuation group. In both studies, discontinuation led to worsening of NPS in some participants with more severe baseline NPS.

Adverse events

Assessed with various scales.

Follow‐up: 1 to 8 months

In 5 studies, there was no evidence of a difference between groups in adverse events.

381 (5 RCTs)

⊕⊕⊝⊝

LOWab

Data could not be pooled due to variability in outcome measures. Adverse events of antipsychotics were not systematically reported.

Quality of life (QoL)

Assessed with DCM or QoL‐AD.

Follow‐up: 3 months to 25 weeks

In 2 studies, there was no evidence of an effect on quality of life.

119 (2 RCTs)

⊕⊕⊝⊝
LOWbc

Data could not be pooled due to variability in outcome measures.

There was no difference between discontinuation and continuation group in the overall cohort or in subgroups with baseline NPI score above or below the median (14).

Cognitive function

Assessed with various scales.

Follow‐up: 1 to 8 months

In 5 studies, there was no evidence of an impact on scales measuring overall cognitive function.

In one of these trials, discontinuation improved a measure of verbal fluency.

365 (5 RCTs)

⊕⊕⊝⊝
LOWbc

Data could not be pooled due to variability in outcome measures.

Use of physical restraint

Follow‐up: 1 month

In one study there was no effect on the use of physical restraint.

36 (1 RCT)

⊕⊝⊝⊝
VERY LOWcd

Conclusion made by the authors but not supported by data.

Mortality

Assessed with various scales.

Follow‐up: 4 to 12 months

In two studies there was no evidence of an effect on mortality.

275 (2 RCTs)

⊕⊝⊝⊝
VERY LOWcd

Data could not be pooled due to clinical heterogeneity.

In a long‐term follow‐up of 36 months after the 12 months randomised discontinuation trial (Devanand 2012), we were uncertain whether discontinuation decreased mortality.

*The basis for the assumed risk (e.g. the median control group risk across the studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High‐quality evidence: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate‐quality evidence: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low‐quality evidence: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low‐quality evidence: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

a Downgraded one level for indirectness.

b Downgraded one level for risk of bias.

c Downgraded one level for imprecision due to a small number of participants.

d Downgraded two level for risk of bias.

Figuras y tablas -
Summary of findings 1. Discontinuation compared to continuation of antipsychotic medication for behavioural and psychological symptoms in older people with dementia
Table 1. Antipsychotic drug classes

Phenothiazines with aliphatic side chain

Phenothiazines with piperazine structure

Fhenothiazines with piperidine structure

Butyrophenone derivatives

Indole derivatives

Thioxanthene derivatives

Diphenylbutylpiperidine derivatives

Diazepines, Oxazepines and Thiazepines

Benzamides

Other antipsychotics

Figuras y tablas -
Table 1. Antipsychotic drug classes
Table 2. Antipsychotic drugs with defined daily doses

Phenothiazines with aliphatic side‐chain

N05AA01 Chlorpromazine 0.3 g per os

N05AA02 Levomepromazine 0.3 g per os

N05AA03 Promazine 0.3 g per os

N05AA04 Acepromazine 0.1 g per os

N05AA05 Triflupromazine 0.1 g per os

N05AA06 Cyamemazine

N05AA07 Chlorproethazine

Phenothiazines with piperazine structure

N05AB01 Dixyrazine 50 mg per os

N05AB02 Fluphenazine 10 mg per os

N05AB03 Perphenazine 30 mg per os

N05AB04 Prochlorperazine 0.1 g per os

N05AB05 Thiopropazate 60 mg per os

N05AB06 Trifluoperazine 20 mg per os

N05AB07 Acetophenazine 50 mg per os

N05AB08 Thioproperazine 20 mg per os

N05AB09 Butaperazine 10 mg per os

N05AB10 Perazine 0.1 g per os

N05AB20 Homophenazine

Phenothiazines with piperidine structure

N05AC01 Periciazine 50 mg per os

N05AC02 Thioridazine 0.3 g per os

N05AC03 Mesoridazine 0.2 g per os

N05AC04 Pipotiazine 10 mg per os

Butyrophenone derivatives

N05AD01 Haloperidol 8 mg per os

N05AD02 Trifluperidol 2 mg per os

N05AD03 Melperone* 0.3 g per os

N05AD04 Moperon 20 mg per os

N05AD05 Pipamperone 0.2 g per os

N05AD06 Bromperidol 10 mg per os

N05AD07 Benperidol 1.5 mg per os

N05AD08 Droperidol

N05AD09 Fluanisone

N05AE Indole derivatives

N05AE01 Oxypertine 0.12 g per os

N05AE02 Molindone 50 mg per os

N05AE03 Sertindole* 16 mg per os

N05AE04 Ziprasidone* 80 mg per os

Thioxanthene derivatives

N05AF01 Flupentixol 6 mg per os

N05AF02 Clopenthixol 0.1 g per os

N05AF03 Chlorprothixene 0.3 g per os

N05AF04 Tiotixene 30 mg per os

N05AF05 Zuclopenthixol 30 mg per os

Diphenylbutylpiperidine derivatives

N05AG01 Fluspirilene

N05AG02 Pimozide 4 mg per os

N05AG03 Penfluridol 6 mg per os

Diazepines, Oxazepines and Thiazepines

N05AH01 Loxapine 0.1 g per os

N05AH02 Clozapine* 0.3 g per os

N05AH03 Olanzapine* 10 mg per os

N05AH04 Quetiapine* 0.4 g per os

Benzamides

N05AL01 Sulpiride 0.8 g per os

N05AL02 Sultopride 1.2 g per os

N05AL03 Tiapride 0.4 g per os

N05AL04 Remoxipride 0.3 g per os

N05AL05 Amisulpride* 0.4 g per os

N05AL06 Veralipride

N05AL07 Levosulpiride 0.4 g per os

Other antipsychotics

N05AX07 Prothipendyl 0.24 g per os

N05AX08 Risperidone* 5 mg per os

N05AX09 Clotiapine 80 mg per os

N05AX10 Mosapramine*

N05AX11 Zotepine* 0.2 g per os

N05AX12 Aripiprazole* 15 mg per os

N05AX13 Paliperidone*

*atypical antipsychotics

* Atypical antipsychotic agents.

Figuras y tablas -
Table 2. Antipsychotic drugs with defined daily doses
Table 3. Characteristics of included studies

Study IDI

Setting

Duration

Randomised number

Discontinuation group

Continuation group

Discontinuation schedule

Control

Behavioural inclusion criteria

Notes

Ballard 2004

Residents in long‐term care facilities

3 months

100

46

54

Abrupt

Typical APa or risperidone

NPIb not higher than 7

Ballard 2008

Residents in long‐term care facilities

6 months

12 months

165

82

83

Abrupt

Typical and risperidone

NRc

Bergh 2011

Residents in nursing homes

25 weeks

19

9

10

Tapering over 2 week

Risperidone

NRc

Unpublished study

Bridges‐Parlet 1997

Residents in long‐term care facilities

1 month

36

22

14

Abrupt + tapering over 2 weeks

Typical APa

Physically aggressive participants identified by nurse supervisors

Cohen‐Mansfield 1999

Residents in nursing homes

7 weeks followed by 7 weeks cross‐over

58

29

29

Tapering over 3 weeks

Typical APa + lorazepam

NRc

Cross‐over study

Devanand 2011

Residents in the community

6 months (primary analysis)

12 months

20

10

10

Abrupt + tapering over 2 weeks

Haloperidol

Current symptoms of psychosis, agitation or aggression

Participants had a response to haloperidol open treatment for 20 weeks

Devanand 2012

Residents in the community and

nursing homes

4 months

8 months

110

70

40

Abrupt + tapering over 2 week

Risperidone

NPIb score higher than 4 on psychosis or agitation/aggression subscale

Participants had a response to risperidone open treatment for 16 weeks

Findlay 1989

Residents in nursing homes

1 month

36

18

18

Tapering over 1 week

Thioridazine

NRc

Ruths 2008

Residents in nursing homes

1 month

55

27

28

Abrupt

Haloperidol risperidone, olanzapine

All participants regardless individual symptoms

van Reekum 2002

Residents in nursing homes

26 weeks

34

17

17

Tapering over 2 weeks

Typical APa

Stable behaviour

a AP: antipsychotic drug.

b NPI: Neuropsychiatric Inventory.

c NR: not reported.

Figuras y tablas -
Table 3. Characteristics of included studies
Comparison 1. Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Behavioural assessment Show forest plot

2

194

Mean Difference (IV, Fixed, 95% CI)

‐1.49 [‐5.39, 2.40]

Figuras y tablas -
Comparison 1. Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference)