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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).

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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

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Figure 2

Inclusions of trials of study flow diagram 2018

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

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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.

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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

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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.

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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

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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.

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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.

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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]

Figures and Tables -
Comparison 1. Discontinuation versus continuation of long‐term antipsychotic drug use (continuous data, analysis method mean difference)