Maintenance treatment with antipsychotic drugs for schizophrenia

Stefan Leucht; Magdolna Tardy; Katja Komossa; Stephan Heres; Werner Kissling; John M Davis

doi:10.1002/14651858.CD008016.pub2

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Topics

Figure 1

Study flow diagram.

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Figure 2

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Figure 3

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Figure 4

Summary of pooled results

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Figure 5

Funnel plot of comparison: 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, outcome: 1.1 Relapse.

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Figure 6

Summary of subgroup analysis

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Figure 7

Meta‐regression study duration

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Analysis 1.1

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 1 Relapse: up to 3 months.

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Analysis 1.2

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 2 Relapse: 4 to 6 months.

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Analysis 1.3

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 3 Relapse: 7 to 12 months.

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Analysis 1.4

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 4 Relapse: > 12 months.

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Analysis 1.5

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 5 Relapse: independent of duration.

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Analysis 1.6

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 6 Leaving the study early: due to any reason.

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Analysis 1.7

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 7 Leaving the study early: due to adverse events.

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Analysis 1.8

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 8 Leaving the study early: due to inefficacy.

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Analysis 1.9

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 9 Global state: number of participants improved.

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Analysis 1.10

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 10 Service use: number of participants hospitalised.

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Analysis 1.11

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 11 Service use: number of participants discharged.

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Analysis 1.12

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 12 Death: any.

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Analysis 1.13

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 13 Death: due to natural causes.

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Analysis 1.14

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 14 Suicide.

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Analysis 1.15

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 15 Suicide attempts.

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Analysis 1.16

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 16 Suicide ideation.

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Analysis 1.17

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 17 Violent/aggressive behaviour.

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Analysis 1.18

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 18 Adverse effects: at least one adverse event.

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Analysis 1.19

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 19 Adverse effects: movement disorders: at least one movement disorder.

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Analysis 1.20

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 20 Adverse effects: movement disorders: akathisia.

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Analysis 1.21

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 21 Adverse effects: movement disorders: akinesia.

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Analysis 1.22

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 22 Adverse effects: movement disorders: dyskinesia.

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Analysis 1.23

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 23 Adverse effects: movement disorders: dystonia.

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Analysis 1.24

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 24 Adverse effects: movement disorders: rigor.

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Analysis 1.25

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 25 Adverse effects: movement disorders: tremor.

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Analysis 1.26

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 26 Adverse effects: movement disorders: use of antiparkinson medication.

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Analysis 1.27

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 27 Adverse effects: sedation.

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Analysis 1.28

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 28 Adverse effects: weight gain.

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Analysis 1.29

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 29 Quality of life.

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Analysis 1.30

Comparison 1 Maintenance treatment with antipsychotic drugs versus placebo/no treatment, Outcome 30 Number of participants employed: 7 to 12 months.

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Analysis 2.1

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 1 Subgroup analysis: participants with a first episode.

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Analysis 2.2

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 2 Subgroup analysis: participants in remission.

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Analysis 2.3

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 3 Subgroup analysis: various durations of stability before entering the study.

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Analysis 2.4

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 4 Subgroup analysis: abrupt withdrawal versus tapering.

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Analysis 2.5

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 5 Subgroup analysis: single antipsychotic drugs.

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Analysis 2.6

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 6 Subgroup analysis: depot versus oral drugs.

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Analysis 2.7

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 7 Subgroup analysis: first‐ versus second‐generation antipsychotic drugs.

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Analysis 2.8

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 8 Subgroup analysis: appropriate versus unclear allocation concealment.

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Analysis 2.9

Comparison 2 Subgroup analysis (relapse at 12 months), Outcome 9 Subgroup analysis: blinded versus open trials.

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Analysis 3.1

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 1 Exclusion of studies that were not explicitly described as randomised.

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Analysis 3.2

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 2 Exclusion of non‐double‐blind studies.

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Analysis 3.3

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 3 Fixed‐effects model.

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Analysis 3.4

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 4 Original authors' assumptions on dropouts.

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Analysis 3.5

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 5 Inclusion of only large studies (> 200 participants).

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Analysis 3.6

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 6 Exclusion of studies with clinical diagnosis.

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Analysis 3.7

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 7 Three months stable.

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Analysis 3.8

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 8 Six months stable.

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Analysis 3.9

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 9 Nine months stable.

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Analysis 3.10

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 10 Exclusion of studies with unclear randomisation method.

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Analysis 3.11

Comparison 3 Sensitivity analysis (relapse at 12 months), Outcome 11 Exclusion of studies with unclear allocation concealment method.

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Table 1. Design of a future study

Methods	Allocation: randomised ‐ clearly described generation of sequence and concealment of allocation. Blinding: double ‐ described and tested. Duration: 3 years.
Participants	People with schizophrenia or schizophrenia like disorder in remission for at least one month. N=500. Age: any. Sex: both. History: any.
Interventions	1. Any antipsychotic drug (flexible dose within appropriate range). 2. Placebo (after gradual withdrawal of the previous antipsychotic drug).
Outcomes	Relapse (primary outcome) Rehospitalisation for psychosis Time ill Global state (number of participants improved) Leaving the study early (including specific causes) Death (natural and unnatural causes) Violence Quality of life Satisfaction with care Side‐effects Employment and other measures of functioning

Table 1. Design of a future study

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Summary of findings for the main comparison. Maintenance treatment with antipsychotic drugs versus placebo/no treatment for schizophrenia

Maintenance treatment with antipsychotic drugs versus placebo/no treatment for schizophrenia
Patient or population: patients with schizophrenia Settings: Inpatients and Outpatients Intervention: Maintenance treatment with antipsychotic drugs versus placebo/no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Maintenance treatment with antipsychotic drugs versus placebo/no treatment
Relapse: 7 to 12 months Follow‐up: 7‐12 months	642 per 1000	263 per 1000 (218 to 315)	RR 0.41 (0.34 to 0.49)	2669 (24 studies)	⊕⊕⊕⊕ high^1,2,3,4
Leaving the study early: due to any reason Follow‐up: 1‐36 months	544 per 1000	288 per 1000 (250 to 332)	RR 0.53 (0.46 to 0.61)	4718 (47 studies)	⊕⊕⊕⊕ high^1,2,5
Service use: Number of participants hospitalised Follow‐up: 1‐24 months	256 per 1000	97 per 1000 (69 to 141)	RR 0.38 (0.27 to 0.55)	2090 (16 studies)	⊕⊕⊕⊕ high^1,5,6
Suicide Follow‐up: 3‐12 months	2 per 1000	1 per 1000 (0 to 7)	RR 0.34 (0.04 to 3.28)	1941 (8 studies)	⊕⊕⊝⊝ low^5,7,8
Quality of life Follow‐up: 7‐18 months		The mean quality of life in the intervention groups was 0.62 standard deviations lower (1.15 to 0.09 lower)		527 (3 studies)	⊕⊕⊝⊝ low^2,5,9,10,11	SMD ‐0.62 (‐1.15 to ‐0.09)
Number of participants employed: 7 to 12 months	504 per 1000	484 per 1000 (378 to 620)	RR 0.96 (0.75 to 1.23)	259 (2 studies)	⊕⊕⊝⊝ low^5,12,13,14
The basis for the assumed risk* (e.g. the median control group risk across 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;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Risk of bias: rated 'no' ‐ many studies did not report the methods for sequence generation and/or allocation concealment. However, the ones that did, showed a similar effect size in subgroup and sensitivity analyses. ² Inconsistency: rated 'no' ‐ although the p value for heterogeneity was statistically significant and the I‐square higher than 50%, the direction of the effect of almost all studies was the same. Therefore, this inconsistency does not challenge the overall results. ³ Publication bias: rated 'undetected' ‐ although the funnel plot was asymmetrical, the trim and fill test did not change the point estimate and the point estimate was also similar when only large studies were included. ⁴ Large effect: statistically significant RR that was lower than 0.5 (the actual value was 0.41). ⁵ Publication bias: The possibility of publication bias was only examined concerning the primary outcome (relapse at 12 months). ⁶ Large effect: statistically significant RR that was lower than 0.50 (the actual value was 0.38). ⁷ Almost all studies contributing to this outcome used adequate randomisation and allocation methods. ⁸ Imprecision: rated 'very serious' ‐ only few studies contribute data to this rare event an the CI was quite wide. ⁹ Risk of bias: rated 'no' ‐ the two large studies (out of three) that drove the effect used appropriate randomisation and allocation methods. ¹⁰ Indirectness: rated 'serious' ‐ the rating scales in the studies have been criticized for eventually not measuring what people understand by quality of life. ¹¹ Imprecise data ‐ only a few studies contributed to this rare event and the confidence interval was large. ¹² Risk of bias: rated 'no' ‐ the two studies used appropriate randomisation and allocation methods. ¹³ Indirectness: rated 'serious' ‐ the only two studies included mixed groups of employed and non‐employed participants at baseline, and it is unclear whether employment was supported or competitive employment. ¹⁴ Imprecision: rated 'serious' ‐ only two studies contributed to this event which is difficult to measure because it depends on various factors (e.g. the existence of supported employment, rural versus service economy etc).

Summary of findings for the main comparison. Maintenance treatment with antipsychotic drugs versus placebo/no treatment for schizophrenia

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Comparison 1. Maintenance treatment with antipsychotic drugs versus placebo/no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse: up to 3 months Show forest plot	34	3942	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.24, 0.38]

2 Relapse: 4 to 6 months Show forest plot	40	5285	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.30, 0.42]

3 Relapse: 7 to 12 months Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

4 Relapse: > 12 months Show forest plot	6	811	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.42, 0.82]

5 Relapse: independent of duration Show forest plot	62	6392	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.29, 0.41]

6 Leaving the study early: due to any reason Show forest plot	47	4718	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.46, 0.61]

6.1 up to 3 months	8	245	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.07, 0.72]
6.2 4 to 6 months	17	1646	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.35, 0.66]
6.3 7 to 12 months	18	2420	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.46, 0.66]
6.4 > 12 months	4	407	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.36, 1.26]
7 Leaving the study early: due to adverse events Show forest plot	43	4333	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.70, 1.91]

7.1 up to 3 months	8	245	Risk Ratio (M‐H, Random, 95% CI)	2.84 [0.12, 65.34]
7.2 4 to 6 months	14	1549	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.57, 1.74]
7.3 7 to 12 months	17	2339	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.59, 2.60]
7.4 > 12 months	4	200	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Leaving the study early: due to inefficacy Show forest plot	46	4546	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.31, 0.44]

8.1 up to 3 months	9	295	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.07, 0.79]
8.2 4 to 6 months	16	1661	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.31, 0.54]
8.3 7 to 12 months	18	2420	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.28, 0.45]
8.4 > 12 months	3	170	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.08, 0.95]
9 Global state: number of participants improved Show forest plot	14	1524	Risk Ratio (M‐H, Random, 95% CI)	2.34 [1.68, 3.26]

9.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	4.61 [1.22, 17.40]
9.2 4 to 6 months	8	1037	Risk Ratio (M‐H, Random, 95% CI)	2.33 [1.69, 3.21]
9.3 7 to 12 months	5	438	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.91, 4.18]
10 Service use: number of participants hospitalised Show forest plot	16	2090	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.27, 0.55]

10.1 up to 3 months	2	55	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.04, 4.06]
10.2 4 to 6 months	3	109	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.01, 0.42]
10.3 7 to 12 months	8	1295	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.18, 0.57]
10.4 > 12 months	3	631	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.44, 0.70]
11 Service use: number of participants discharged Show forest plot	3	404	Risk Ratio (M‐H, Random, 95% CI)	2.76 [0.69, 11.06]

11.1 4 to 6 months	3	404	Risk Ratio (M‐H, Random, 95% CI)	2.76 [0.69, 11.06]
12 Death: any Show forest plot	14	2356	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.28, 2.11]

12.1 up to 3 months	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
12.2 4 to 6 months	5	856	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.48, 9.81]
12.3 7 to 12 months	8	1464	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.08, 1.27]
13 Death: due to natural causes Show forest plot	14	2401	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.39, 3.97]

13.1 4 to 6 months	5	856	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.48, 9.81]
13.2 7 to 12 months	9	1545	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.09, 3.36]
14 Suicide Show forest plot	8	1941	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.04, 3.28]

14.1 up to 3 months	1	36	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14.2 4 to 6 months	2	730	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14.3 7 to 12 months	5	1175	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.04, 3.28]
15 Suicide attempts Show forest plot	5	1177	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.10, 2.33]

15.1 4 to 6 months	2	466	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 71.51]
15.2 7 to 12 months	3	711	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.04, 1.61]
16 Suicide ideation Show forest plot	3	556	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.04, 10.56]

16.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.01, 3.88]
16.2 4 to 6 months	1	386	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.3 7 to 12 months	1	121	Risk Ratio (M‐H, Random, 95% CI)	2.77 [0.11, 66.57]
17 Violent/aggressive behaviour Show forest plot	5	680	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.15, 0.52]

17.1 up to 3 months	1	26	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.50]
17.2 4 to 6 months	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 3.92]
17.3 7 to 12 months	3	614	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.14, 0.53]
18 Adverse effects: at least one adverse event Show forest plot	10	2184	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.87, 1.18]

18.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.30, 0.93]
18.2 4 to 6 months	3	776	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.80, 1.15]
18.3 7 to 12 months	6	1359	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.88, 1.38]
19 Adverse effects: movement disorders: at least one movement disorder Show forest plot	22	3411	Risk Ratio (M‐H, Random, 95% CI)	1.55 [1.25, 1.93]

19.1 up to 3 months	4	158	Risk Ratio (M‐H, Random, 95% CI)	2.42 [0.70, 8.33]
19.2 4 to 6 months	8	1658	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.06, 1.99]
19.3 7 to 12 months	10	1595	Risk Ratio (M‐H, Random, 95% CI)	1.52 [1.11, 2.07]
20 Adverse effects: movement disorders: akathisia Show forest plot	12	2026	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.87, 3.51]

20.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.24, 15.97]
20.2 4 to 6 months	6	1009	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.41, 6.80]
20.3 7 to 12 months	5	968	Risk Ratio (M‐H, Random, 95% CI)	1.74 [0.88, 3.45]
21 Adverse effects: movement disorders: akinesia Show forest plot	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.09, 9.92]

21.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.09, 9.92]
22 Adverse effects: movement disorders: dyskinesia Show forest plot	13	1820	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.28, 0.97]

22.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.06, 34.91]
22.2 4 to 6 months	3	418	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.11, 0.84]
22.3 7 to 12 months	9	1353	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.30, 1.58]
23 Adverse effects: movement disorders: dystonia Show forest plot	6	824	Risk Ratio (M‐H, Random, 95% CI)	1.89 [1.05, 3.41]

23.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	2.5 [0.13, 49.22]
23.2 4 to 6 months	2	382	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.94, 3.29]
23.3 7 to 12 months	3	393	Risk Ratio (M‐H, Random, 95% CI)	3.97 [0.44, 35.54]
24 Adverse effects: movement disorders: rigor Show forest plot	5	249	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.54, 2.88]

24.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.24, 2.22]
24.2 4 to 6 months	3	160	Risk Ratio (M‐H, Random, 95% CI)	1.98 [0.67, 5.85]
24.3 7 to 12 months	1	40	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
25 Adverse effects: movement disorders: tremor Show forest plot	10	1468	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.81, 1.93]

25.1 up to 3 months	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.40, 3.01]
25.2 4 to 6 months	3	160	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.33, 2.61]
25.3 7 to 12 months	6	1259	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.82, 2.43]
26 Adverse effects: movement disorders: use of antiparkinson medication Show forest plot	7	1317	Risk Ratio (M‐H, Random, 95% CI)	1.40 [1.03, 1.89]

26.1 4 to 6 months	3	841	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.90, 2.61]
26.2 7 to 12 months	4	476	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.86, 2.05]
27 Adverse effects: sedation Show forest plot	10	2146	Risk Ratio (M‐H, Random, 95% CI)	1.50 [1.22, 1.84]

27.1 4 to 6 months	6	1577	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.86, 2.07]
27.2 7 to 12 months	4	569	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.90, 3.31]
28 Adverse effects: weight gain Show forest plot	10	2321	Risk Ratio (M‐H, Random, 95% CI)	2.07 [1.31, 3.25]

28.1 4 to 6 months	3	736	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.92, 3.37]
28.2 7 to 12 months	7	1585	Risk Ratio (M‐H, Random, 95% CI)	2.57 [1.30, 5.07]
29 Quality of life Show forest plot	3	527	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐1.15, ‐0.09]

29.1 (7 to 12) months	2	509	Std. Mean Difference (IV, Random, 95% CI)	‐0.62 [‐1.26, 0.01]
29.2 (> 12 ) months	1	18	Std. Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.66, 0.45]
30 Number of participants employed: 7 to 12 months Show forest plot	2	259	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.75, 1.23]

Comparison 1. Maintenance treatment with antipsychotic drugs versus placebo/no treatment

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Comparison 2. Subgroup analysis (relapse at 12 months)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Subgroup analysis: participants with a first episode Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.48]

1.1 first episode	8	528	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.38, 0.58]
1.2 not first episode	19	2141	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.31, 0.49]
2 Subgroup analysis: participants in remission Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

2.1 in remission	8	516	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.24, 0.61]
2.2 not in remission	16	2153	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]
3 Subgroup analysis: various durations of stability before entering the study Show forest plot	18		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 stable at least 1 month	5	428	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.15, 0.46]
3.2 stable at least 3 months	5	806	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.21, 0.44]
3.3 stable at least 6 months	1	20	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.69]
3.4 stable at least 12 months	5	326	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.57]
3.5 stable at least 3 to 6 years	2	54	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.18, 0.78]
4 Subgroup analysis: abrupt withdrawal versus tapering Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Abrupt withdrawal	16	1946	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.34, 0.54]
4.2 Taper	8	723	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.23, 0.50]
5 Subgroup analysis: single antipsychotic drugs Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Chlorpromazine	2	406	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.36, 0.55]
5.2 Fluphenazine depot	6	296	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.14, 0.39]
5.3 Haloperidol depot	1	43	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.04, 0.55]
5.4 Quetiapine	1	178	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.34, 0.69]
5.5 Paliperidone	2	617	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.30, 0.45]
5.6 Various, mixed groups of antipsychotic drugs	10	705	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.27, 0.65]
5.7 Ziprasidone	2	424	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.43, 0.64]
6 Subgroup analysis: depot versus oral drugs Show forest plot	21		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 depot	7	663	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.23, 0.41]
6.2 oral	14	1785	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.37, 0.57]
7 Subgroup analysis: first‐ versus second‐generation antipsychotic drugs Show forest plot	24		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 First‐generation antipsychotic drugs	18	1430	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.25, 0.48]
7.2 Second‐generation antipsychotic drugs	6	1239	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.37, 0.53]
8 Subgroup analysis: appropriate versus unclear allocation concealment Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

8.1 appropriate allocation concealment	9	1410	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.33, 0.52]
8.2 unclear allocation concealment	15	1259	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.28, 0.53]
9 Subgroup analysis: blinded versus open trials Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

9.1 blinded trials	22	2412	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.35, 0.51]
9.2 unblinded trials	2	257	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.17, 0.39]

Comparison 2. Subgroup analysis (relapse at 12 months)

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Comparison 3. Sensitivity analysis (relapse at 12 months)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Exclusion of studies that were not explicitly described as randomised Show forest plot	23	2654	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

2 Exclusion of non‐double‐blind studies Show forest plot	22	2412	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.35, 0.51]

3 Fixed‐effects model Show forest plot	24	2669	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.36, 0.44]

4 Original authors' assumptions on dropouts Show forest plot	24	2669	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.33, 0.49]

5 Inclusion of only large studies (> 200 participants) Show forest plot	5	1506	Risk Ratio (M‐H, Random, 95% CI)	0.39 [0.32, 0.48]

6 Exclusion of studies with clinical diagnosis Show forest plot	16	2325	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.36, 0.49]

7 Three months stable Show forest plot	20	2942	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.30, 0.55]

8 Six months stable Show forest plot	13	1382	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.26, 0.61]

9 Nine months stable Show forest plot	10	831	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.29, 0.73]

10 Exclusion of studies with unclear randomisation method Show forest plot	8	1546	Risk Ratio (IV, Random, 95% CI)	0.41 [0.34, 0.50]

11 Exclusion of studies with unclear allocation concealment method Show forest plot	9	1410	Risk Ratio (IV, Random, 95% CI)	0.41 [0.33, 0.52]

Comparison 3. Sensitivity analysis (relapse at 12 months)

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