Supplement to: Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized Controlled Trials Wei Zheng, MD

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Supplement to:

Efficacy and Safety of Adjunctive Aripiprazole in Schizophrenia: Meta-Analysis of Randomized Controlled Trials

Wei Zheng, MDâ, Ying-Jun Zheng, MDâ, Xian-Bin Li, MD^bc, Yi-Lang Tang, MD, PhD^b,d, Chuan-Yue Wang, MD, PhD^bc, Ying-Qiang Xiang, MD, PhD^b, Jose de Leon, MDê,f,g

aThe Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China

bBeijing Key Laboratory of Mental Disorders, Department of Psychiatry, Beijing Anding Hospital, Capital Medical University, Beijing 100088, China

cCenter of Schizophrenia, Beijing Institute for Brain Disorders, Laboratory of Brain Disorders (Capital Medical University), Ministry of Science and Technology, Beijing 100088, China

dDepartment of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

eUniversity of Kentucky, Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA^.

fPsychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain,

gBiomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain

Address for reprints after publication: Wei Zheng, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou 510370, China

E-mail: [email protected], Fax: +86-020-81891391, Telephone: +86-18510808443

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TABLE OF CONTENTS

SUPPLEMENTARY TABLE S1. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Description...3

SUPPLEMENTARY TABLE S2. Description of Sensitivity Analyses and Meta-Regressions………...6

SUPPLEMENTARY TABLE S3. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: GRADE Analyses:...7

SUPPLEMENTARY TABLE S4. Subgroup and Sensitivity Analysis of the Effect of Variables on the Total Psychopathology Scale Scores...9

SUPPLEMENTARY TABLE S5. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Secondary Outcomes...11

SUPPLEMENTARY TABLE S6. Subgroup Analysis and Sensitivity Analysis of the Effect of Variables on BMI…...12

SUPPLEMENTARY TABLE S7. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: RCTs Published in Chinese…..14

SUPPLEMENTARY FIGURE S1. Legend……..………..………...27

SUPPLEMENTARY FIGURE S1. Computerized database search………...………...28

SUPPLEMENTARY FIGURE S2. Legend ………..………...29

SUPPLEMENTARY FIGURE S2. Risk of bias of individual randomized controlled trials………....………...30

SUPPLEMENTARY FIGURE S3. Legend ………..………...31

SUPPLEMENTARY FIGURE S3. Representation of risk of bias assessment in all randomized controlled trials grouped together..………..32

SUPPLEMENTARY FIGURE S4. Legend ………...………33

SUPPLEMENTARY FIGURE S4. Funnel plot for total psychopathology...…………...………...……….………….34

SUPPLEMENTARY FIGURE S5. Funnel plot for weight.………...…………...…………...………..36

SUPPLEMENTARY FIGURE S6. Funnel plot for BMI.………...…………...…………...………..……38

SUPPLEMENTARY FIGURE S7. Meta-analyses of discontinuations due to intolerability and inefficacy………..……….40

SUPPLEMENTARY FIGURE S8. Legend ………..………..41

SUPPLEMENTARY FIGURE S8. Meta-analyses of adverse drug reactions ..……….………..……….…………..42

SUPPLEMENTARY FIGURE S9. Legend ……….…………...………….………43

SUPPLEMENTARY FIGURE S9. Meta-analyses of adverse drug reactions (continuation 1).………..……….…………..44

SUPPLEMENTARY FIGURE S10. Legend ……….…………...………….……….45

SUPPLEMENTARY FIGURE S10. Meta-analyses of adverse drug reactions (continuation 2)….…………..……….…………46

SUPPLEMENTARY FIGURE S11. Legend ……….…………...………….……….47

SUPPLEMENTARY FIGURE S11. Meta-analyses of adverse drug reactions (continuation 3).………..………..…….………….48

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SUPPLEMENTARY TABLE S1. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: Description Design Schizophrenia patients Interventions^h

Duration/ Age/ Male Illness Jadadⁱ Author Country N^a weeks Blinding Co-treatment^b Dose^c Setting^d years %^e Criteria^f Phase^g Duration AP (dose mg/day) N score ARIPRAZOLE ADDED TO CLOZAPINE Patients N=1690 (RCT N=21)

Chang¹⁰ Korea 62 8 Double Augmentation Standard Both 32.4 79 DSM-IV Refractory NR 1.CLO (304) N=32 4

2. CLO (291) + ARI (16) N=30

Chi¹¹ China 40 12 Open-label Simultaneous Reduced Inpatients 36.7 NR CCMD-3 Refractory 10.6 1. CLO (332) N=20

2. CLO (101) + ARI (17) N=20 2

Deng¹² China 68 12 Open-label Simultaneous Reduced NR 30.2 60 NR Chronic 7.6 1. CLO (NR) N=34 3 2. CLO (NR) +ARI (NR) N=34

Ding¹³ China 66 8 Open-label Simultaneous Reduced Outpatients 33.6 56 CCMD-3 Refractory 15.9 1. CLO (NR) N=33 2 2. CLO (NR) + ARI (NR) N=33

Fan¹⁴ USA 38^j 8 Double Augmentation Standard Inpatients 44.2 73 DSM-IV Chronic NR 1. CLO (400) N=18 3

2. CLO (397) + ARI (15) N=20

Fleischhacker¹⁵ Europe 207 16 Double Augmentation Standard Outpatients 39.0 64 DSM-IV Refractory 13.5 1. CLO (363) N=108 4

and South 2. CLO (384) + ARI (11) N=99

Africa

Guan¹⁶ China 60 16 Open-label Augmentation Reduced Inpatients NR 50 ICD-10 Refractory NR 1. CLO (NR) N=30 2 2. CLO(NR) +ARI (NR) N=30

Li¹⁷ China 64 12 Open-label Simultaneous Reduced Inpatients 39.0 0 CCMD-3 Refractory 10.2 1. CLO (NR) N=32 3 2. CLO (NR) + ARI (NR) N=32

Liang¹⁸ China 48 12 Open-label Simultaneous Reduced Both 30.0 47 CCMD-3 Chronic 4.8 1. CLO (NR) N=24 3 2. CLO (NR) + ARI (NR) N=24

Luo¹⁹ China 86 12 Open-label Simultaneous Reduced Inpatients 40.0 50 ICD-10 Chronic 10.7 1. CLO (NR) N=43 2

2. CLO (100) + ARI (NR) N=43

Ma²⁰ China 96 12 Open-label Augmentation Reduced NR 35.2 62 ICD-10 Refractory 12.1 1. CLO (NR) N=48 2

2. CLO (118) + ARI (20) N=48

Muscatello²¹ Italy 40 24 Double Augmentation Standard Outpatients 31.3 57 DSM-IV Chronic NR 1. CLO (314) N=20 4

2. CLO (310) + ARI (11) N=20

Ren²² China 60 8 Open-label Simultaneous Reduced Inpatients 36.0 41 CCMD-3 Refractory 7.0 1. CLO (NR) N=30 3 2. CLO (NR) + ARI (NR) N=30

Sun²³ China 64 8 Open-label Simultaneous Standard Inpatients 37.0 100 CCMD-3 Refractory 8.0 1. CLO (250) N=32 2

2. CLO (250) + ARI (12) N=32

Sun²⁴ China 62 12 Open-label Augmentation Reduced Inpatients 32.0 58 CCMD-3 Chronic 16.5 1. CLO (368) N=30 2

2. CLO (168) + ARI (21) N=32

Wang²⁵ China 92 8 Open-label Simultaneous Reduced NR 36.1 48 CCMD-3 Chronic 5.7 1. CLO (NR) N=46 2 2. CLO (NR) + ARI (30) N=46

Wang²⁶ China 90 12 Open-label Simultaneous Reduced Inpatients 50.2 47 CCMD-3 Chronic 27.5 1. CLO (227) N=45 2

2. CLO (182) + ARI (12) N=45

Xu²⁷ China 97 8 Open-label Simultaneous Reduced Inpatients 32.0 53 CCMD-3 Chronic NR 1. CLO (350) N=48 2

2. CLO (155) + ARI (26) N=49

Xu²⁸ China 92 8 Open label Simultaneous Reduced Inpatients 31.0 59 NR Chronic 0.9 1. CLO (NR) N=46 2

2. CLO (NR) + ARI (30) N=46

Yin²⁹ China 90 12 Open-label Simultaneous Reduced Inpatients 39.2 63 CCMD-3 Refractory 12.4 1. ARI (25) N=30 2

2 .CLO (375) N=30

3. CLO 106) + ARI (15) N=30

Zhang³⁰ China 168 24 Open-label Augmentation Standard Inpatients 38.2 64 CCMD-3 Refractory >10 1. CLO (NR) N=84 2 2. CLO (NR) + ARI (10) N=84

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ARIPRAZOLE ADDED TO ANOTHER ANTIPSYCHOTIC Patients N=2747 (RCT N=34)

Chen³¹ China 86 8 Open-label Simultaneous Standard Inpatients NR 0 CCMD-3 Acute NR 1. OLA (NR) N=46 2 2. OLA (NR) + ARI (10) N=40 Chen³² China 100 8 Open-label Simultaneous Reduced Outpatients 33.0 58 ICD-10 Chronic 3.4 1. RIS (NR) N=50 2

2. RIS (NR) + ARI (16) N=50 Chen³³ China 116 8 Double Augmentation Standard NR 34.1 46 ICD-10 Chronic 8.6 1. RIS (5) N=57 5

2. RIS (5) + ARI (20) N=59 Henderson³⁴ USA 14 4 Double Augmentation Standard Outpatients 49.0 57 DSM-IV Chronic NR 1. OLA (22) N=7 3

2. OLA (22) + ARI (15) N=7

Jin³⁵ China 80 6 Double Augmentation Standard Both 27.6 55 CCMD-3 Chronic 8.6 1. CPZ (238) N=40 4

2. CPZ (258) + ARI (5) N=40

Kane³⁶ USA 323^k 16 Double Simultaneous Standard Outpatients 44.2 61 DSM-IV Chronic NR 1. QUE (516) + RIS (5) N=155 3

2. QUE (513) + RIS (5) +

ARI (10) N=168

Lai³⁷ China 40 8 Open-label Simultaneous Reduced Inpatients NR NR ICD-10 Acute NR 1. OLA (25) N=20 2 2. OLA (12) +ARI (16) N=20 Lee³⁸ Korea 35 12 Double Augmentation Standard NR 50.7 74 DSM-IV Chronic 20.0 1. RIS (3) N=18 4

2. RIS (3) + ARI (10) N=17

Li³⁹ China 110 4 Open-label Simultaneous Standard NR 34.7 49 ICD-10 Chronic 4.4 1. RIS (NR) N=55 2 2. RIS (NR) + ARI (NR) N=55 Li⁴⁰ China 80 8 Open-label Simultaneous Standard Inpatients 33.5 55 CCMD-3 Acute 0.2 1. SUL (NR) N=40 2

2. SUL (NR) + ARI (NR) N=40 Li⁴¹ China 70 6 Open-label Simultaneous Standard Both 30.8 38 ICD-10 Chronic 1.6 1. OLA (17) N=35 2

2. OLA (17) + ARI (10) N=35 Li⁴² China 60 4 Open-label Augmentation Standard Inpatients 28.5 45 CCMD-3 Chronic 2.4 1. OLA (4) N=27 4

2. OLA (4) + ARI (20) N=32 Liang⁴³ China 41 4 Double Simultaneous Reduced Both 30.0 37 DSM-IV Chronic 1.5 1. PAL (10) N=21 5

2. PAL (6) + ARI (10) N=20

Liu⁴⁴ China 70 6 Open-label Simultaneous Standard Both 31.0 38 ICD-10 Chronic 1.6 1. RIS (5) N=35 2 2. RIS (5) + ARI (10) N=35

Ou⁴⁵ China 70 8 Open-label Augmentation Standard Inpatients 29.5 50 CCMD-3 Chronic 1.0 1. OLA (18) N=35 3 Pan⁴⁶ China 58 6 Rater Augmentation Standard NR NR 0 CCMD-3 Chronic 1.1 1.APs (NR) N=29 3

masked 2. APs (NR) + ARI (10) N=29

2. OLA (18) + ARI (10) N=35 Pan⁴⁷ China 80 6 Open-label Simultaneous Standard Inpatients 25.0 62 CCMD-3 Acute 0.6 1.OLA (17) N=29 3

2. OLA (40) + ARI (10) N=40 Ren⁴⁸ China 72 8 Rater Simultaneous Standard Outpatients NR NR ICD-10 Acute NR 1. SUL (NR) N=36 3

masked 2. SUL (NR) + ARI (NR) N=36

Shim⁴⁹ Korea 54 8 Double Augmentation Standard NR 39.4 40 DSM-IV Chronic 15.3 1. HAL (25) N=28 4 2. HAL (21) + ARI (NR) N=26

Shu⁵⁰ China 60 12 Open-label Simultaneous Standard Outpatients 32.9 0 CCMD-3 Acute ≤3 1. RIS (4) N=30 2

2. RIS (4) + ARI (7) N=30 Sun⁵¹ China 56 12 Open-label Augmentation Standard Inpatients 37.0 0 ICD-10 Chronic NR 1. OLA (15) N=28 2

2. OLA (15) + ARI (10) N=28 Sun⁵² China 34 6 Open-label Augmentation Standard Inpatients 34.9 0 CCMD-3 Chronic NR 1. RIS (4) N=17 2

2. RIS (3) + ARI (5) N=17

Wang⁵³China 70 8 Open-label Simultaneous Standard Inpatients 33.5 0 CCMD-3 Chronic 5.6 1. RIS (5) N=35 2 2. RIS (5) + ARI (5) N=35

Wang⁵⁴ China 80 12 Open-label Simultaneous Reduced Inpatients 32.3 50 ICD-10 Chronic 3.7 1. AMI (NR) N=40 2 2. AMI (NR) + ARI (NR) N=40 Xiong⁵⁵ China 68 8 Open-label Simultaneous Standard NR 25.2 59 CCMD-3 Chronic 2.4 1. RIS (4) N=34 2

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Xu⁵⁶ China 68 6 Open-label Simultaneous Standard Both 29.0 40 ICD-10 Chronic 1.8 2. RIS (4) +ARI (10) N=34

1. QUE (624) N=32 2 Xue⁵⁷ China 68 6 Rater Augmentation Standard Inpatients 42.4 NR CCMD-3 Chronic NR

2. QUE (604) + ARI (10) N=31 1. RIS (5) N=34 3 Yang⁵⁸ China 180 8 masked

Double Same time Standard NR 24.6 52 CCMD-3 Acute 2.0 2. RIS (5) + ARI (5) N=34

1. RIS (5) N=60 2 2. ARI (5) N=60

Yang⁵⁹ China 212 8 Open-label Same time Reduced Both 33.9 50 CCMD-3 Chronic 22.5

3. RIS (5) + ARI (10) N=60

1. RIS (NR) N=107 2 Yasui- Furukori⁶⁰ Japan 36 12 Double Augmentation Standard Outpatients 35.3 33 DSM-IV Chronic 9.4 2. RIS (NR) + ARI (NR) N=105

1. RIS (5) + OLA (13) N=18

2. RIS (6) + OLA (12) + Zhao⁶¹ China 56 12 Open-label Augmentation Standard Both NR 0 CCMD-3 Chronic NR

ARI (15) N=18

1. RIS (NR) N=28 3 Zhou⁶² China 60 24 Rater Augmentation Standard Both 28.6 42 ICD-10 Chronic 0.6 2. RIS (NR) + ARI (10) N=28

1. RIS (4) N=30 3 Zhou⁶³ China 100 24 masked

Open-label Augmentation Standard Both NR 0 CCMD-3 Chronic NR

2. RIS (4) + ARI (10) N=30

1. RIS (NR) N=50 3 Zhuo⁶⁴ China 60 12 Double Augmentation Standard NR 38.9 0 NR Chronic 1.0

2. RIS (NR) + ARI (5) N=50

1. APs (NR) N=30 4

2. APs (NR) + ARI (23) N=30

55 RCTs 4457 ^l10.1 ^l34.9 ^l44.2 ^l7.0 ^l2.6

46 Chinese ±4.9 14 Double- 33Augmentation 35 Standard 10 NR ±6.0 ±24.6 2 NR 7 Acute ±6.3 21 CLO ±0.8 blind

9 Non-Chinese 4 Rater 22 Same time 20 Reduced 9 Outpatients 9 CCMD-3 37 Chronic 14 RIS masked

37 Open- 26 Inpatients 14 ICD-10 11 Refractory 9 OLA^m

label NR, not reported; RCT, randomized clinical trial.

aThis number reflects the total sample size recruited, including patients on aripiprazole and placebo.

10 Both 10 DSM-IV

bCo-treatment with aripiprazole was started simultaneously with the other antipsychotic or added as an augmentation strategy.

cThe dose of the other antipsychotic was the standard dose or was reduced when aripiprazole was added.

dThe setting was classified as inpatient, outpatient or both.

ePercentage of males who completed the study.

fDiagnostic criteria used to diagnose schizophrenia. CCMD-3, China's mental disorder classification and diagnosis, standard 3^rdedition; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4^thedition;

ICD-10, International Classification of Diseases, 10^thedition.

gPhase was classified as acute, chronic or refractory. All acute phase studies were completed in first-episode patients. Refractory-phase studies included chronic patients who also were considered refractory to treatment.

hIn 53 RCTs the two comparison interventions are listed as 1 and 2. In two trials there were 3 interventions listed as 1, 2 and 3. In each intervention the mean daily dose prescribed was included in parentheses when it was described, followed by the number of patients, N, taking this treatment. AP, antipsychotic; AMI, amisulpiride; ARI, aripiprazole; CLO, clozapine; CPZ, chlorpromazine; HAL, haloperidol; OLA, olanzapine; PAL, paliperidone; QUE, quetiapine; RIS, risperidone; SUL, sulpiride.

iThe Jadad scale focused on five criteria: “randomization,” “double blinding,” “description withdrawals and dropouts,” “generation of random numbers,” and “allocation concealment” for assessing the quality of RCTs. One point was given for each area addressed in the study. The total Jadad score ranged from a minimum of 0 to a maximum of 5 points. RCTs were classified as high quality if their Jadad score was ≥4 and low quality if their Jadad score was <4.

jOnly 30 of 38 patients completed the study, including 20 patients with schizophrenia and 10 with schizoaffective disorder.

kThe 323 patients were diagnosed with schizophrenia (n=252) or schizoaffective disorder (n=71).

lMean ± standard deviation calculated used available data. In some columns there were studies with NR data.

mOther less frequent trials included 4 APs, 2 SUL, 1 CPZ, 1 AMI, 1 HAL, 1 QUE, and 1 PAL.

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SUPPLEMENTARY TABLE S2. Description of Sensitivity Analyses and Meta-Regressions Sensitivity analyses

We conducted 14 subgroup analyses in order to identify potential moderators or mediators of the effect on total psychopathology and BMI. These subgroup analyses included:

(1) Chinese vs. non-Chinese studies

(2) Studies describing vs. those not describing randomization details (3) Double blind/rater-masked vs. non-blinded studies

(4) Illness phase classified into 3 groups: acute (all were first-episode trials), chronic, or refractory (5) Standard vs. reduced antipsychotic doses in the co-treatment arm

(6) Simultaneous augmentation vs. delayed augmentation after nonresponse (7) Treatment duration <12 weeks vs. ≥ 12 weeks

(8) Added to clozapine vs. another antipsychotic

(9) Aripiprazole co-treatment with first-generation antipsychotic compared with first-generation antipsychotic vs. aripiprazole co-treatment with second-generation antipsychotic

(10) Male predominance (≥ 60%), female predominance (≥ 60%), and no sex predominance (11) Jadad score ≥ (high quality) vs. Jadad score < 4 (low quality)

(12) Inpatients, outpatients, and in-outpatients

(13) Last observation carried forward vs. observed cases (14) Placebo vs. comparison antipsychotic

(15) Studies with blinding and ≥12 weeks vs. other studies Meta-regression analyses

Meta-regression analyses including available data were conducted in order to examine the potentially moderating and mediating effect on outcomes of:

(1) RCT duration

(2) Mean age of study participants (3) Percentage of males

(4) Illness duration

(5) Chinese vs. non-Chinese (6) Blinded vs. non-blinded (7) Illness phase

Outcomes included:

(1) PANSS/BPRS total score change/endpoint difference (2) Body weight

(3) BMI change difference

BMI, body mass index; BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Symptoms Scale; RCT, randomized clinical trial.

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SUPPLEMENTARY TABLE S3. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: GRADE Analyses

Primary/secondary outcomes^a N^b (studies)

Risk of bias^c

Inconsistency^d Indirectness Imprecision Publication bias

Large effect^e

Is it plausible that confounding factors would change the effect?

Dose response gradient

Overall quality of evidence^f

PANSS/BPRS total score 3351 (43) Serious Serious No No Undetected No No No +/+/-/-/; Low

PANSS Positive Symptom Sub-Score

2223 (29) Serious Serious No No Undetected No No No +/+/-/-/; Low

PANSS Negative Symptom Sub-Score

PANSS General Symptom Sub-Score

Body weight (kg) 505 (9) Serious No No No Undetected No No No +/+/+/; Moderate

Body mass index 809 (14) Serious No No No Undetected No No No +/+/+/; Moderate

Waist circumference (cm) 218 (5) Serious No No No Undetected No No No +/+/+/; Moderate

Serum triglycerides (mg/dL) 631 (9) Serious Serious No No Undetected No No No +/+/-/-/; Low

Serum total cholesterol (mg/dL)

HDL cholesterol (mg/dL) 544 (8) Serious Serious No No Undetected No No No +/+/-/-/; Low

LDL cholesterol (mg/dL) 540 (8) Serious Serious No No Undetected No No No +/+/-/-/; Low

Fasting glucose (mg/dL) 710 (10) Serious No No No Undetected No No No +/+/+/; Moderate

Prolactin (ng/mL) 1038 (15) Serious Serious No No Undetected No No No +/+/-/-/; Low

TESS total score 559 (9) Serious Serious No No Undetected No No No +/+/-/-/; Low

Anxiety 348 (3) No Serious No No Undetected No No No +/+/+/; Moderate

Weight gain 1079 (13) Serious No No No Undetected Large No No +/+/+/+/; High

Drowsiness 983 (10) Serious Serious No No Undetected No No No +/+/-/-/; Low

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aThis row describes all studies reporting that primary (in bold) or secondary (in bold and italic) measure. Subgroups of studies from the same measure may be described in succeeding rows. HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TESS, treatment emergent symptom scale; EKG = electrocardiogram.

bN=total number of individuals after adding all studies providing that outcome. The number of studies is described in parentheses.

cAll studies reported as having a serious bias used a single-blind method and only mentioned random allocation without describing the method.

dAll studies reported as having a serious inconsistency had I²> 50%.

eStudies with large effects (or even more with very large) provided increased quality of evidence. Large effects= 2<RR<0.5. Very large effects= 5<RR<0.2. RR, risk ratios.

fGRADE 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. GRADE, grading of recommendations, assessment, development, and evaluation.

Constipation 920 (13) Serious No No No Undetected Large No No +/+/+/+/; High

Extrapyramidal symptoms 506 (5) Serious No No No Undetected No No No +/+/+/; Moderate

Drooling/hypersalivation 679 (10) Serious No No No Undetected No No No +/+/+/; Moderate

Tachycardia 807 (11) Serious No No No Undetected No No No +/+/+/; Moderate

Electrocardiographic abnormality

557 (7) Serious No No No Undetected Large No No +/+/+/+/; High

All cause-discontinuation 1953 (22) Serious No No No Undetected No No No +/+/+/; Moderate

Discontinuation due to intolerability

729 (6) No No No No Undetected No No No +/+/+/+/; High

Discontinuation due to inefficacy

730 (5) No No No No Undetected No No No +/+/+/+/; High

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SUPPLEMENTARY TABLE S4. Subgroup and Sensitivity Analysis of the Effect of Variables on the Total Psychopathology Scale Scores^a N

Variable Patients (RCTs) SMD (95% CI) I² (%) p^c

1. Origin: Chinese 2931 (37) -0.52 (-0.75, -0.30) 88 <0.00001 Non-Chinese 420 (6) -0.13 (-0.41, 0.14) 40 0.04 2. Description of randomization details: Yes 1182 (14) -0.51 (-0.91, -0.10) 91 0.01

No 2169 (29) -0.47 (-0.70, -0.23) 86 <0.0001

3. Blinded studies: Yes^b 916 (12) -0.19 (-0.50, 0.13) 81 0.24 No^b 2435 (31) -0.59 (-0.83, -0.34) 88 <0.00001 4. Phase: Acute 455 (6) -0.52 (-0.93, -0.10)^$ 78 0.01

Chronic 2154 (27) -0.34 (-0.60, -0.08)^$ 89 0.01 Refractory 742 (10) -0.84 (-1.22, -0.46)^$ 83 <0.0001 5. Dose: Standard 1996 (26) -0.34 (-0.57, -0.10) 85 0.005

Reduced 1355 (17) -0.70 (-1.05, -0.35) 89 0.0001

6. Co-treatment: Simultaneous 2207 (29) -0.54 (-0.79, -0.28) 88 <0.0001 Augmentation 1144 (14) -0.36 (-0.67, -0.04) 85 0.03 7. Trial duration: < 12 weeks 2025 (26) -0.45 (-0.73, -0.17) 89 0.002

≥ 12 weeks 1326 (17) -0.51 (-0.80, -0.22) 84 0.0005 8. Added to clozapine: Yes 1453 (18) -0.58 (-0.88, -0.28) 87 0.0002 No 1898 (25) -0.40 (-0.68, -0.12) 88 0.005 9. ARI + FGA vs. FGA 374 (4) -0.53 (-1.00, -0.05) 79 0.03

ARI + SGA vs. SGA 2977 (39) -0.47 (-0.69, -0.25) 88 <0.0001 10. Predominance: Males (≥ 60%) 732 (8) -0.70 (-1.19, -0.20) 90 0.006

Females (≥ 60%) 617 (10) -0.00 (-0.20, 0.19) 32 0.98 None 1762 (21) -0.68 (-0.99, -0.37) 90 <0.0001 11. Jadad score: ≥ 4 (high quality) 639 (8) -0.18 (-0.39, 0.03) 37 0.09

< 4 (low quality) 2712 (35) -0.53 (-0.77, -0.29) 89 <0.0001 12. Setting: Inpatients 1454 (20) -0.43 (-0.66, -0.20) 78 0.0002

Outpatients 570 (7) -0.47 (-0.92, -0.02) 84 0.04

Both 723 (9) -0.23 (-0.79, 0.33) 92 0.42

13. Last observation carried forward 2890 (36) -0.51 (-0.75, -0.28) 89 <0.0001 Observed cases 461 (7) -0.30 (-0.60, -0.00) 61 0.05 14. Control: Placebo^b 916 (12) -0.19 (-0.50, 0.13) 81 0.24

Other comparison: an antipsychotic^b 2435 (31) -0.59 (-0.83, -0.34) 88 <0.00001 15. Studies with blinding and ≥12 weeks 307 (4) -0.17 (-0.64, 0.29) 64 0.47

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Other studies 3044 (39) -0.50 (-0.72, -0.29) 88 <0.00001

ARI, aripiprazole; CI, 95% confidence interval; FGA, first-generation antipsychotics; RCT, randomized clinical trials; SGA, second-generation antipsychotics; SMD, standardized mean difference.

aOutcome is measured by change or endpoint of the total scores on the PANSS, Positive and Negative Symptoms Scale, or the BPRS, Brief Psychiatric Rating Scale.

bThe same 12 RCTs were blinded and used placebo. Therefore, the subgroup analysis variables Number 3 “blinded yes vs. no” and Number 14

“control placebo vs. comparison antipsychotic” provided the same results.

cp-values <0.05 are bolded.

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SUPPLEMENTARY TABLE S5. Adjunctive Aripiprazole for Schizophrenia-Spectrum Disorders: Secondary Outcomes N^a SMD or I²

Secondary outcomes Patients (RCTs) WMD^b(CI) (%) p^c PANSS/BPRS Positive symptom sub-score 2223 (29) -0.01 (-0.26, 0.25) 88 0.95 PANSS/BPRS Negative symptom sub-score 2294 (30) -0.61 (-0.91, -0.31) 91 <0.0001 PANSS General symptom sub-score 1138 (13) -4.02 (-7.23,-0.81) 99 0.01 Waist circumference (cm) 174 (3) -2.71 (-6.89, 1.48) 54 0.20 Prolactin (ng/mL) 1038 (15) -46.48 (-62.64, -30.33) 100 <0.00001 Fasting glucose (mg/dL) 710 (10) -3.97 (-6.48,-1.46) 54 0.02 Serum triglycerides (mg/dL) 631 (9) -20.18 (-35.50, -4.87) 86 0.010 Serum total cholesterol (mg/dL) 692 (10) -9.78 (-34.83, 15.27) 98 0.44 HDL cholesterol (mg/dL) 544 (8) -0.21 (-4.65, 4.23) 82 0.93 LDL cholesterol (mg/dL) 540 (8) -5.70 (-9.39, -2.01) 35 0.002 TESS total score 559 (9) -0.64 (-1.26, -0.02) 88 0.04

BPRS, Brief Psychiatric Rating Scale; CI, 95% confidence interval; HDL, High Density Lipoprotein; LDL, Low Density Lipoprotein; PANSS, Positive and Negative Symptoms Scale; RCT, randomized clinical trial; SMD, standardized mean difference;TESS: Treatment Emergent Symptom Scale; WMD, weighted mean difference.

aPatients refers to the total number of individuals included in the statistical analysis. In parentheses, the number of RCTs from which these patients come.

bWMDs were calculated in these analyses.

cP-values <0.05 are bolded.

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SUPPLEMENTARY TABLE S6. Subgroup Analysis and Sensitivity Analysis of the Effect of Variables on BMI N

Variable

1. Origin: Chinese Non-Chinese

Patients (RCTs) 704 (11) 105 (3)

WMD (95% CI)

-1.77 (-2.17, -1.36) -1.83 (-5.86, 2.19)

I²(%) 43 81

p^a

<0.00001 0.37 2. Description of randomization details: Yes 369 (6) -1.75 (-2.38, -1.12) 55 <0.00001

No 440 (8) -1.88 (-2.62, -1.13) 55 <0.00001

3. Blinded studies: Yes^b 283 (6) -1.82 (-2.82, -0.83) 70 0.0003

No^b 526 (8) -1.66 (-2.15, -1.18) 32 <0.00001

4. Phase: Acute 80 (1) -1.40 (-2.23, -0.57) N/A 0.0009

Chronic 628 (11) -1.89 (-2.41, -1.36) 54 <0.00001

Refractory 101 (2) -1.12 (-4.15, 1.90) 84 0.47

5. Dose: Standard 628 (12) -1.94 (-2.48, -1.41) 53 <0.00001

Reduced 181 (2) -1.17 (-1.65, -0.68) 0 <0.00001

6. Co-treatment: Simultaneous 324 (4) -1.30 (-1.73, -0.87) 3 <0.00001

Augmentation 485 (10) -1.98 (-2.61, -1.35) 57 <0.00001

7. Trial duration: < 12 weeks 547 (9) -1.55 (-2.15, -0.94) 53 <0.00001

≥ 12 weeks 262 (5) -2.15 (-2.90, -1.41) 50 <0.00001

8. Added to clozapine: Yes 312 (5) -1.59 (-2.88, -0.30) 72 0.02

No 497 (9) -1.85 (-2.29, -1.42) 29 <0.00001

9. ARI + FGA vs. FGA 63 (1) -2.90 (-4.90, -0.90) N/A 0.005

ARI + SGA vs. SGA 746 (13) -1.73 (-2.21, -1.26) 55 <0.00001

10. Predominance: Males (≥ 60%) 225 (5) -1.82 (-3.30, -0.34) 68 0.02

Females (≥ 60%) 283 (5) -2.44 (-2.97, -1.92) 0 <0.00001

None 301 (4) -1.21 (-1.57, -0.85) 0 <0.00001

11. Jadad score: ≥ 4 (high quality) 121 (2) -1.10 (-3.95, 1.75) 86 0.45

< 4 (low quality) 688 (12) -1.78 (-2.24, -1.31) 45 <0.00001 12. Setting^c: Inpatients 354 (6) -1.96 (-2.79, -1.13) 54 <0.00001

Outpatients 14 (1) -0.70 (-5.52, -4.12) N/A 0.78

Both 234 (4) -1.52 (-2.80, -0.25) 64 0.02

13. Last observation carried forward 554 (9) -1.55 (-2.05, -1.05) 52 <0.00001

Observed cases 255 (5) -2.61 (-3.74, -1.49) 55 <0.00001

14. Control: Placebo^b 283 (6) -1.82 (-2.82, -0.83) 70 0.0003

Other comparison antipsychotic^b 526 (8) -1.66 (-2.15, -1.18) 32 <0.00001 15. Studies with blinding and ≥12 weeks 120 (2) -1.77 (-3.01, -0.54) 79 0.005

¹²

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Other studies 689 (12) -1.80 (-2.35, -1.25) 53 <0.00001 ARI, aripiprazole; BMI, body mass index; CI, 95% confidence interval; FGA, first-generation antipsychotics; N/A, not applicable. RCTs, randomized clinical trials; SGA, second-generation antipsychotics; WMD, weighted mean difference.

aP-values <0.05 are bolded.

bThe same 6 RCTs were blinded and used placebo. Therefore, the subgroup analysis variables Number 3 “blinded yes vs. no” and Number 14

“control placebo vs. comparison antipsychotic” provided the same results.

cOnly 11 RCTs reported the setting.

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Supplementary Table 7. Adjunctive Aripiprazole Randomized Controlled Trials in Schizophrenia: RCTs Published in Chinese^a First Author: Chi¹¹

Illness Stage: Refractory patients

Trial Design: A 12-week randomized, open-label trial

Sample: All 40 inpatients meeting inclusion criteria: 1) both sexes, 2) PANSS ≥60, 3) the CCMD-3 diagnostic criteria for refractory schizophrenia, and 4) failure of treatment with ≥2 different classes for ≥4 weeks (≥600 mg/day CPZE). Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (101 mg/day) + ARI (17 mg/day) (N=20) Comparisons: CLO (332 mg/day) (N=20)

Outcomes: PANSS, TESS and discontinuation rate First Author: Deng¹²

Illness Stage: Chronic patients

Sample: All 68 patients meeting inclusion criteria: 1) failure of treatment with APs and 2) failure to tolerate AP-induced ADRs. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females.

Treatment: CLO (NR) +ARI (NR) (N=34) Comparison: CLO (NR) (N=34)

Outcomes: PANSS, TESS and discontinuation rate First Author: Ding¹³

Illness Stage: Refractory patients

Trial Design: An 8-week randomized, open-label trial

Sample: All 66 outpatients meeting inclusion criteria: 1) refractory schizophrenia, 2) both sexes and 3) PANSS ≥60. Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (NR) + ARI (NR) (N=33) Comparison: CLO (NR) (N=33)

Outcomes: PANSS, TESS and discontinuation rate First Author: Guan¹⁶

Sample: All 60 inpatients meeting inclusion criteria: 1) ICD-10 diagnostic criteria for schizophrenia, 2) both sexes, 3) PANSS ≥80s and 4) failure of treatment with ≥2 different AP classes for ≥8 weeks and CLO-resistant (>500 mg/day). Exclusion criteria were relevant medical

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conditions, drug or alcohol abuse.

Treatment: CLO (NR) +ARI (NR) (N=30) Comparison: CLO (NR) (N=30)

Outcomes: PANSS and TESS First Author: Li¹⁷

Sample: 64 female inpatientsmeeting inclusion criteria: 1) failure of treatment with ≥3 different AP classes for ≥12 weeks. Exclusion criteria were relevant medical conditions or drug or alcohol abuse.

Treatment: CLO (NR) + ARI (NR) (N=32) Comparison: CLO (NR) (N=32)

Outcomes: PANSS, TESS, and discontinuation rate First Author: Liang¹⁸

Sample: All 48 in/outpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS ≥60.

Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females.

Treatment: CLO (NR) + ARI (NR) (N=24) Comparison: CLO (NR) (N=24)

Outcomes: PANSS, WCST, CPT, TESS, and discontinuation rate First Author: Luo¹⁹

Sample: All 86 inpatients with schizophrenia meeting inclusion criteria: 1) ICD-10 diagnostic criteria, 2) both sexes and 3) PANSS≥70.

Treatment: CLO (100 mg/day) + ARI (NR) (N=43) Comparison: CLO (NR) (N=43)

Outcomes: PANSS, TESS, and discontinuation rate First Author: Ma²⁰

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Sample: All 96 patients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) failure of treatment with ≥4 APs from ≥3 different classes for ≥6 weeks and 5) CLO-resistant (>500 mg/day). Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (118 mg/day) + ARI (20 mg/day) (N=48) Comparisons: CLO (NR) monotherapy (N=48)

Outcomes: BPRS, TESS, and discontinuation rate First Author: Ren²²

Sample: All 60 inpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS >60 and 4) failure of treatment with ≥3 APs from ≥2 different classes for ≥6 weeks. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females, or other mental diseases.

Treatment: CLO (NR) + ARI (NR)( N=30) Comparisons: CLO (NR) (N=30)

Outcomes: PANSS, TESS and discontinuation rate First Author: Sun²³

Sample: All 64 male inpatients meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria for refractory schizophrenia, 2) PANSS ≥60 and 3) failure of treatment with at ≥3 different AP classes for ≥6 weeks with CPZE (≥600 mg/day). Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (250 mg/day) + ARI (12 mg/day) ( N=32) Comparison: CLO (250 mg/day) (N=32)

Outcomes: PANSS, TESS and discontinuation rate First Author: Sun²⁴

Sample: All 62 inpatients with schizophrenia meeting inclusion criteria: 1) CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS ≥70.

Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (168 mg/day) + ARI (21 mg/day) (N=32) Comparison: CLO (368 mg/day) (N=30)

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Outcomes: PANSS, TESS and discontinuation rate First Author: Wang²⁵

Sample: All 92 patients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) WBC >6,500/mm.³ Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (NR) + ARI (30 mg/day) (N=46) Comparison: CLO (NR) (N=46)

Outcomes: PANSS, TESS and discontinuation rate First Author: Wang²⁶

Sample: All 90 inpatients meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria for schizophrenia, 2) both sexes and 3) PANSS ≥60.

Treatment: CLO (NR) + ARI (30 mg/day) (N=45) Comparisons: CLO (NR) (N=45)

Outcomes: PANSS and TESS and discontinuation rate First Author: Xu²⁷

Sample: All 97 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS >60.

Treatment: CLO (155 mg/day) + ARI (26 mg/day) ( N=49) Comparisons: CLO (350 mg/day) (N=48)

Outcomes: PANSS and TESS First Author: Xu²⁸

Sample: All 92 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: CLO (NR) + ARI (30 mg/day) (N=46)

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Comparison: CLO (NR) (N=46)

Outcomes: PANSS, TC, TGs, HDL-C, LDL-C, BMI, FG and discontinuation rate First Author: Yin²⁹

Sample: All 90 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS ≥60 and 4) failure of treatment with APs with ≥3 different classes for ≥12 weeks (600-800 mg/day of CPZE). Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females.

Treatment: CLO (106 mg/day) + ARI (15 mg/day) (N=30)

Comparison:ARI (25 mg/day) (N=30), CLO (375 mg/day) (N=30) Outcomes: PANSS, GAF, TESS and discontinuation rate

First Author: Zhang³⁰

Sample: All 168 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) ages 20-60 years and 4) failure of treatment with ≥2 APs for 6 to 8 weeks.Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females.

Treatment: CLO (NR) + ARI (10 mg/day) (N=84) Comparison: CLO (NR) (N=84)

Outcomes: BRPS, TESS, and discontinuation rate First Author: Chen³¹

Illness Stage: Acute patients

Sample: 86 female inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) ages from 18 to 55 years.

Exclusion criteria were treatment with any AP before the trial.

Treatment: OLA (NR) + ARI (10 mg/day) ( N=40) Comparisons: OLA (NR) (N=46)

Outcomes: PANSS, BMI and PRL First Author: Chen³²

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Sample: All 100 outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) both sexes.

Treatment: RIS (NR) + ARI (16 mg/day) ( N=50) Comparison: RIS (NR) (N=50)

Outcomes: PANSS, TESS and discontinuation rate First Author: Chen³³

Trial Design: An 8-week randomized, double-blind, placebo-controlled trial

Sample: All 116 female patients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria and 2) ages from 18 to 45 years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse.

Treatment: RIS (5 mg/day) + ARI (20 mg/day) (N=59) Comparison: RIS (5 mg/day) (N=57)

Outcomes: PANSS, CGI, PRL and discontinuation rate First Author: Jin³⁵

Trial Design: A 6-week randomized, double-blind, placebo-controlled trial

Sample: 80 in-outpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria and 2) both sexes. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females.

Treatment: CPZ (258 mg/day) + ARI (5 mg/day) (N=40) Comparisons: CPZ (238 mg/day) (N=40)

Outcomes: BPRS, TESS, PRL and discontinuation rate First Author: Lai³⁷

Sample: 40 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, and 3) ages 18-65 years.

Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females.

Treatment: OLA (12 mg/day) +ARI (16 mg/day) (N=20)

Comparison: OLA (25 mg/day) (N=10), ARI (28 mg/day) (N=10)

Outcomes: PANSS, BMI, FG, TGs, TC, HDL, LDL and discontinuation rate First Author: Li³⁹

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Sample: All 110 patients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes and 3) PANSS ≥60.

Treatment: RIS (NR) + ARI (NR) (N=55) Comparison: RIS (NR) (N=55)

Outcomes: PRL, PANSS, TESS and discontinuation rate First Author: Li⁴⁰

Sample: All 80 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes, 3) PANSS ≥60, and 4) ages from 18 to 65 years. Exclusion criteria were relevant medical conditions, drug or alcohol abuse, pregnancy or breastfeeding in females.

Treatment: SUL (NR) + ARI (NR) (N=40) Comparison: SUL (NR) (N=40)

Outcomes: PANSS, TESS and discontinuation rate First Author: Li⁴¹

Sample: 70 in/outpatients with schizophrenia meeting inclusion criteria: 1) the ICD-10 diagnostic criteria, 2) both sexes, 3) PANSS ≥60, and 4) ages 18-65 years. Exclusion criteria were relevant medical conditions, pregnancy or breastfeeding in females, allergic constitution or disease.

Treatment: OLA (17 mg/day) + ARI (10 mg/day) (N=35) Comparison: OLA (17mg/day) (N=35)

Outcomes: PANSS, TESS and discontinuation rate First Author: Li⁴²

Sample: All 60 inpatients with schizophrenia meeting inclusion criteria: 1) the CCMD-3 diagnostic criteria, 2) both sexes and 3) PANSS ≥60.

Exclusion criteria were relevant medical conditions, drug abuse, pregnancy or breastfeeding in females.

Treatment: OLA (4 mg/day) + ARI (20 mg/day) (N=32) Comparisons: OLA (4 mg/day) (N=27)

Outcomes: PANSS, TESS and discontinuation rate First Author: Liang⁴³