Cochrane Database of Systematic Reviews (Reviews) || Aripiprazole versus other atypical...

Aripiprazole versus other atypical antipsychotics for

schizophrenia (Review)

Khanna P, Suo T, Komossa K, Ma H, Rummel-Kluge C, El-Sayeh HG, Leucht S, Xia J

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2014, Issue 1

http://www.thecochranelibrary.com

Aripiprazole versus other atypical antipsychotics for schizophrenia (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .7BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

17RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

46ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .60DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

304DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Analysis 1.1. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 1 Global state: 1. No

clinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . . 329Analysis 1.2. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 2 Mental state: 1.

Specific - binary outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331Analysis 1.3. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 3 Mental state: 2.

Average endpoint scores of various scales (short term, up to 12 weeks, high=poor). . . . . . . . . . . 332Analysis 1.4. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 4 Mental state: 3.

Average endpoint scores of various scales (medium term, 12 to 26 weeks, high=poor). . . . . . . . . . 334Analysis 1.6. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 6 Mental state: 5.

Specific - average endpoint positive score (PANSS, high=poor). . . . . . . . . . . . . . . . . . 335Analysis 1.7. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 7 Mental state: 6.

Specific - average endpoint negative score (PANSS, high=poor). . . . . . . . . . . . . . . . . 337Analysis 1.8. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 8 Mental state: 7.

Specific - average endpoint general psychopathological score (PANSS, high=poor ). . . . . . . . . . . 338Analysis 1.9. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 9 Mental state: 8.

Specific - average total score decreased rate (PANSS, low=poor). . . . . . . . . . . . . . . . . 340Analysis 1.10. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 10 Mental state: 9.

Specific - average positive score decreased rate (PANSS, low=poor). . . . . . . . . . . . . . . . 340Analysis 1.11. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 11 Leaving the study

early. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341Analysis 1.12. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 12 Quality of life: 1a.

Average scores (short term, up to 12 weeks, WHO-QOL-100, low=poor). . . . . . . . . . . . . . 342Analysis 1.13. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 13 Quality of life: 1b.

Average scores (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor). . . . . . . . . . . . . 343Analysis 1.14. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 14 Quality of life: 2.

Average endpoint general quality of life score (GQOLI - 74, low=poor). . . . . . . . . . . . . . . 345

iAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


Analysis 1.15. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 15 Adverse effects: 1.At least one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

Analysis 1.16. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 16 Adverse effects: 2.Cardiac effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

Analysis 1.17. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 17 Adverse effects: 3.Central / peripheral nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . . 351

Analysis 1.18. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 18 Adverse effects: 4.Extrapyramidal effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

Analysis 1.19. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 19 Adverse effects: 6.Haematological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

Analysis 1.20. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 20 Adverse effects: 5.Gastrointestinal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Analysis 1.21. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 21 Adverse effects: 7.Hormonal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Analysis 1.22. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 22 Adverse effects: 8a.Metabolic - binary measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

Analysis 1.23. Comparison 1 COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE, Outcome 23 Adverse effects: 8b.Metabolic - continuous measures (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . 368

Analysis 2.1. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 1 Global state: 1.Noclinically significant response (as defined by original studies). . . . . . . . . . . . . . . . . . 370

Analysis 2.2. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 2 Global state: 2a.Average endpoint total score (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . . 371

Analysis 2.3. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 3 Global state: 2b.Average endpoint scale score (medium term, 12 to 24 weeks, high=poor). . . . . . . . . . . . . . 372

Analysis 2.4. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 4 Global state: 3.Average endpoint SI score (CGI, high=poor). . . . . . . . . . . . . . . . . . . . . . . . 372

Analysis 2.5. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 5 Mental state: 2a.Specific - binary outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

Analysis 2.6. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 6 Mental state: 3.Specific - average endpoint positive score (PANSS, high=poor). . . . . . . . . . . . . . . . . . 374

Analysis 2.7. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 7 Mental state: 4.Specific - average endpoint negative score (PANSS, high=poor). . . . . . . . . . . . . . . . . 375

Analysis 2.8. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 8 Mental state: 5.Specific - average endpoint general pathological score (PANSS, high=poor ). . . . . . . . . . . . . 376

Analysis 2.10. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 10 Leaving the studyearly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378

Analysis 2.11. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 11 Quality of life:Average score (medium term, 12 to 24 weeks, WHO-QOL-100, low=poor). . . . . . . . . . . . . 380

Analysis 2.12. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 12 Adverse effects:1.At least one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381

Analysis 2.13. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 13 Adverse effects: 2.Cardiac effects (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . . . . . . . 383

Analysis 2.14. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 14 Adverse effects: 3.Central / peripheral nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Analysis 2.15. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 15 Adverse effects: 4.Extrapyramidal symptoms - various (short term, up to 12 weeks). . . . . . . . . . . . . . . . . 388

Analysis 2.16. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 16 Adverse effects: 5.Gastrointestinal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389

Analysis 2.17. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 17 Adverse effects: 6.Haematological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Analysis 2.18. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 18 Adverse events: 7.Hormonal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

iiAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


Analysis 2.19. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 19 Adverse effects:8a. Metabolic - binary measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 393

Analysis 2.20. Comparison 2 COMPARISON 2. ARIPIPRAZOLE versus QUETIAPINE, Outcome 20 Adverse effects:8b. Metabolic - continuous measure. . . . . . . . . . . . . . . . . . . . . . . . . . . 395

Analysis 3.1. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 1 Global state: 1. Noclinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . . 396

Analysis 3.2. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 2 Global state: 2.Average endpoint total score(short term, up to 12 weeks, CGI, high=poor). . . . . . . . . . . . . 399

Analysis 3.3. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 3 Global state: 3.Average CGI subscale scores (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . . 400

Analysis 3.5. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 5 Mental state: 1.Specific - binary outcomes (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . . . 401

Analysis 3.6. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 6 Mental state: 2.Average endpoint scale score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

Analysis 3.7. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 7 Mental state: 3.Specific - average endpoint positive score (PANSS, high=poor). . . . . . . . . . . . . . . . . . 407

Analysis 3.8. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 8 Mental state: 4.Specific - average endpoint negative score (PANSS, high=poor). . . . . . . . . . . . . . . . . 409

Analysis 3.9. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 9 Mental state: 5.Specific - average endpoint general psychopathological score (PANSS, high=poor ). . . . . . . . . . . 411

Analysis 3.10. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 10 Mental state: 6.PANSS average score decreased rate (short term, up to 12 weeks, low=poor). . . . . . . . . . . . . 414

Analysis 3.11. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 11 Mental state: 7.BPRS total score decreased rate (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . 415

Analysis 3.12. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 12 Mental state: 8.General - average total score (PANSS, high=poor). . . . . . . . . . . . . . . . . . . . . . 415

Analysis 3.14. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 14 Leaving thestudy early. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

Analysis 3.15. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 15 Adverse effects:1. At least one adverse effect, non-specific. . . . . . . . . . . . . . . . . . . . . . . . . 424

Analysis 3.16. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 16 Adverse effects:2a.Cardiac effects (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . . . . . . 428

Analysis 3.17. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 17 Adverse effects:2b. Cardiac - QTc change from baseline (in ms). . . . . . . . . . . . . . . . . . . . . . . 432

Analysis 3.18. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 18 Adverse effects:3. Central / peripheral nervous system (short term, up to 12 weeks). . . . . . . . . . . . . . . . 433

Analysis 3.19. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 19 Adverse effects:3a. Endocrine - Prolactin - average change (ng/ml). . . . . . . . . . . . . . . . . . . . . . 441

Analysis 3.20. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 20 Adverse effects:3b. Endocrine - Prolactin-associated. . . . . . . . . . . . . . . . . . . . . . . . . . . 442

Analysis 3.21. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 21 Adverse effects:4. Various extrapyramidal symptoms (short term, up to 12 weeks). . . . . . . . . . . . . . . . 443

Analysis 3.22. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 22 Adverse effects:4b. Extrapyramidal - average score. . . . . . . . . . . . . . . . . . . . . . . . . . . 449

Analysis 3.23. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 23 Adverse effects:5. Gastrointestinal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

Analysis 3.24. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 24 Adverse effects:6. Haematological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

Analysis 3.25. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 25 Adverse effects:7a. Metabolic - binary measures (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . 455

Analysis 3.26. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 26 Adverse effects:7b. Metabolic - continuous measures (high=poor ). . . . . . . . . . . . . . . . . . . . . . 461

iiiAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


Analysis 3.27. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 27 Adverse effect :7c. Metabolic - continuous measures. . . . . . . . . . . . . . . . . . . . . . . . . . . 463

Analysis 3.28. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 28 Adverse effect:8. required additional drug combination. . . . . . . . . . . . . . . . . . . . . . . . . 465

Analysis 3.29. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 29 Adverse effects:9. TESS score (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . . . . . . . 466

Analysis 3.32. Comparison 3 COMPARISON 3. ARIPIPRAZOLE versus RISPERIDONE, Outcome 32 Cognitivefunctioning: 1. Specific - average endpoint total score. . . . . . . . . . . . . . . . . . . . . 468

Analysis 4.1. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 1 Global state: 1. Noclinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . . 469

Analysis 4.2. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 2 Global state: 2.Average endpoint CGI-GI score (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . 470

Analysis 4.3. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 3 Global state: 3.Average change score (CGI-S, decline=good). . . . . . . . . . . . . . . . . . . . . . . . 470

Analysis 4.4. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 4 Mental state: 1.Average endpoint total score (short term, up to 12 weeks, high=poor). . . . . . . . . . . . . . . 471

Analysis 4.5. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 5 Mental state: 2.Specific - binary outcomes (up to 12 weeks - short term). . . . . . . . . . . . . . . . . . . . 472

Analysis 4.6. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 6 Mental state: 3.Specific - average endpoint PANSS subscale scores (short term, high=poor). . . . . . . . . . . . . 473

Analysis 4.8. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 8 Leaving the studyearly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

Analysis 4.9. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 9 Adverse effects: 1.At least one adverse effect, non-specific. . . . . . . . . . . . . . . . . . . . . . . . . . 476

Analysis 4.10. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 10 Adverse effects:2. Cardiac effects (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . . . . . . 478

Analysis 4.11. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 11 Adverse effects:3. Central / peripheral nervous system (short term, up to 12 weeks). . . . . . . . . . . . . . . . 479

Analysis 4.12. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 12 Adverse effects:4. Various extrapyramidal symptoms (short term, up to 12 weeks). . . . . . . . . . . . . . . . 481

Analysis 4.13. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 13 Adverse effects:5. Gastrointestinal (short term, up to 12 weeks). . . . . . . . . . . . . . . . . . . . . . . 483

Analysis 4.14. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 14 Adverse effects:6. Haematological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

Analysis 4.15. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 15 Adverse effects:7. Hormonal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485

Analysis 4.16. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 16 Adverse effects:8a. Metabolic - binary measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

Analysis 4.17. Comparison 4 COMPARISON 4. ARIPIPRAZOLE versus ZIPRASIDONE, Outcome 17 Adverse effects:8b. Metabolic - continuous measures. . . . . . . . . . . . . . . . . . . . . . . . . . 487

Analysis 5.1. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 1 Global state: 1.Noclinically significant response (as defined by the original studies). . . . . . . . . . . . . . . . . 488

Analysis 5.2. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 2 Global state: 2. Notresponded (decline in PANSS of 30% or more). . . . . . . . . . . . . . . . . . . . . . . 489

Analysis 5.3. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 3 Global state: 3.Remission not achieved (as defined in the study). . . . . . . . . . . . . . . . . . . . . . 490

Analysis 5.4. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 4 Global state: 4.Average endpoint EI score (CGI, high=poor). . . . . . . . . . . . . . . . . . . . . . . . 491

Analysis 5.5. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 5 Global state: 5.Average endpoint CGI score decreased rate (short term, low=poor). . . . . . . . . . . . . . . . 491

Analysis 5.6. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 6 Global state: 6.Average change score (CGI-S, decline=best). . . . . . . . . . . . . . . . . . . . . . . . 492

ivAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


Analysis 5.7. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 7 Global state: 7.Improvement (CGI-I, high=poor). . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Analysis 5.8. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 8 Mental state: 1.Average endpoint scale score (PANSS, high=poor). . . . . . . . . . . . . . . . . . . . . . 493

Analysis 5.9. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 9 Mental state: 2.Average endpoint scale score (SANS, high=poor). . . . . . . . . . . . . . . . . . . . . . 494

Analysis 5.11. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 11 Mental state: 4.Specific - average endpoint positive score (PANSS, high=poor). . . . . . . . . . . . . . . . . . 495

Analysis 5.12. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 12 Mental state: 5.Specific - average endpoint negative subscale score (PANSS, high=poor). . . . . . . . . . . . . . 496

Analysis 5.13. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 13 Mental state: 6.Specific - average endpoint general pathological score (PANSS, high=poor ). . . . . . . . . . . . . 497

Analysis 5.14. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 14 Mental state: 7.Specific - binary outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498

Analysis 5.16. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 16 Adverse effects:1. At least one adverse effect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499

Analysis 5.17. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 17 Adverse effects:2. Cardiac effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501

Analysis 5.18. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 18 Adverse effects:3a. Cardiac - QTc change from baseline (in ms). . . . . . . . . . . . . . . . . . . . . . . 502

Analysis 5.19. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 19 Adverse effects:3b. Central / peripheral nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . 503

Analysis 5.20. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 20 Adverse effects:4. Endocrine - Prolactin - average increase. . . . . . . . . . . . . . . . . . . . . . . . . 505

Analysis 5.21. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 21 Adverse effects:5. Extrapyramidal - various. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

Analysis 5.22. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 22 Adverse effects:6. Gastrointestinal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

Analysis 5.23. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 23 Adverse effects:7. Hormonal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

Analysis 5.24. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 24 Adverse effects:8a. Metabolic - binary measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

Analysis 5.25. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 25 Adverse effects:8b. Metabolic - continuous measures (high=poor). . . . . . . . . . . . . . . . . . . . . . 512

Analysis 5.27. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 27 Leaving thestudy early. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514

Analysis 5.28. Comparison 5 COMPARISON 5. ARIPIPRAZOLE versus OLANZAPINE, Outcome 28 Quality of life: 1.Average endpoint general quality of life score (GQOLI-74, low=poor). . . . . . . . . . . . . . . 517

Analysis 6.1. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 1 Global state: Average improvement (BPRS, high=good). . . . . . . . . . . . 518

Analysis 6.2. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 2 Mental state: Specific - binary outcomes. . . . . . . . . . . . . . . . . 518

Analysis 6.3. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 3 Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . 519

Analysis 6.4. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 4 Adverse effects: 1. Central nervous system. . . . . . . . . . . . . . . . . 520

Analysis 6.5. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 5 Adverse effects: 2. Endocrine - Prolactin - average increase. . . . . . . . . . . 521

Analysis 6.6. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 6 Adverse effects: 3a. Extrapyramidal - various. . . . . . . . . . . . . . . . 522

Analysis 6.7. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 7 Adverse effects: 3b. Extrapyramidal - average score. . . . . . . . . . . . . . 523

vAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


Analysis 6.8. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 8 Adverse effects: 4. Gastrointestinal. . . . . . . . . . . . . . . . . . . 524

Analysis 6.9. Comparison 6 COMPARISON 6. ARIPIPRAZOLE versus OLANZAPINE (acutely agitated people - all databy 5 days), Outcome 9 Adverse effects: 5. Metabolic - continuous measures. . . . . . . . . . . . . 525

Analysis 7.1. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 1 Global state: 1. No change (as defined in the study, measured by IAQ). . . . . . . . . . . 525

Analysis 7.2. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 2 Global state: 2. Change in sexual dysfunction (ASEX). . . . . . . . . . . . . . . . 527

Analysis 7.3. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 3 Mental state: Specific - binary outcomes. . . . . . . . . . . . . . . . . . . . . 527

Analysis 7.4. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 4 Preference: Study medication worse than or equal to previous medication. . . . . . . . . . 529

Analysis 7.5. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 5 Quality of life: 1. Unsatisfactory response on health dimension scale. . . . . . . . . . . 530

Analysis 7.6. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 6 Quality of life: 3. Average change score (QLS, high=better)). . . . . . . . . . . . . . 530

Analysis 7.7. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 7 Quality of life: 2. Average score (EQ-5D utility score, high=better). . . . . . . . . . . . 531

Analysis 7.8. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 8 Quality of life: 4a. Weight related - No meaningful change (IWQOL-Lite). . . . . . . . . 531

Analysis 7.9. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 9 Quality of life: 4b. Weight related - average score (IWQOL-Lite, high=better). . . . . . . . 532

Analysis 7.10. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 10 Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . . . . . 533

Analysis 7.11. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 11 Adverse effects: 1. At least one adverse effect. . . . . . . . . . . . . . . . . . . 535

Analysis 7.12. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 12 Adverse effects: 2. Central nervous system. . . . . . . . . . . . . . . . . . . . 536

Analysis 7.13. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 13 Adverse effects: 3a. Endocrine - Prolactin - increase in level. . . . . . . . . . . . . . 537

Analysis 7.14. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 14 Adverse effects: 3b. Endocrine - Prolactin - Change in level. . . . . . . . . . . . . . 538

Analysis 7.15. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 15 Adverse effects: 4. Extrapyramidal - akathisia. . . . . . . . . . . . . . . . . . . 538

Analysis 7.16. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 16 Adverse effects: 5. Gastrointestinal. . . . . . . . . . . . . . . . . . . . . . . 539

Analysis 7.17. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 17 Adverse effects: 6a. Metabolic- binary measures. . . . . . . . . . . . . . . . . . 540

Analysis 7.18. Comparison 7 COMPARISON 7. ARIPIPRAZOLE versus OTHER ANTIPSYCHOTIC DRUGS,Outcome 18 Adverse effects: 6b. Metabolic - continuous measures. . . . . . . . . . . . . . . . 542

542ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .544APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .548WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .549HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .549CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .549DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .550SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .550DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .550INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

viAripiprazole versus other atypical antipsychotics for schizophrenia (Review)


[Intervention Review]

Aripiprazole versus other atypical antipsychotics forschizophrenia

Priya Khanna1, Tao Suo2, Katja Komossa3 , Huaixing Ma4, Christine Rummel-Kluge5, Hany George El-Sayeh6, Stefan Leucht7, JunXia8

1Early Intervention Psychosis, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle, UK. 2Department of GeneralSurgery, Institute of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. 3Department of Psychiatry and Psy-chotherapy, University Hospital of Zurich, Zurich, Switzerland. 4Department of Medical Oncology, Zhongshan Hospital, Fudan Uni-versity, Shanghai, China. 5Clinic and Outpatient Clinic of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.6Briary Wing, Harrogate District Hospital, Harrogate, UK. 7Klinik und Poliklinik für Psychiatrie und Psychotherapie, TechnischeUniversität München Klinikum rechts der Isar, München, Germany. 8Systematic Review Solutions Ltd, Yan Tai, China

Contact address: Tao Suo, Department of General Surgery, Institute of General Surgery, Zhongshan Hospital, Fudan University, 180Fenglin Road, Xuhui District, Shanghai, Shanghai, 200032, China. [email protected].

Editorial group: Cochrane Schizophrenia Group.Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2014.Review content assessed as up-to-date: 24 June 2013.

Citation: Khanna P, Suo T, Komossa K, Ma H, Rummel-Kluge C, El-Sayeh HG, Leucht S, Xia J. Aripiprazole versus otheratypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD006569. DOI:10.1002/14651858.CD006569.pub5.


A B S T R A C T

Background

In most western industrialised countries, second generation (atypical) antipsychotics are recommended as first-line drug treatments forpeople with schizophrenia. In this review, we specifically examine how the efficacy and tolerability of one such agent - aripiprazole -differs from that of other comparable second generation antipsychotics.

Objectives

To review the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-likepsychoses.

Search methods

We searched the Cochrane Schizophrenia Group Trials Register (November 2012), inspected references of all identified studies forfurther trials and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.

Selection criteria

We included all randomised clinical trials (RCTs) comparing aripiprazole (oral) with oral and parenteral forms of amisulpride, clozapine,olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychoses.

Data collection and analysis

We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) onan intention-to-treat basis based on a random-effects model. Where possible, we calculated illustrative comparative risks for primaryoutcomes. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We assessed risk of biasfor each included study and used GRADE approach to rate quality of evidence.

1Aripiprazole versus other atypical antipsychotics for schizophrenia (Review)


mailto:[email protected]

Main results

We now have included 174 trials involving 17,244 participants. Aripiprazole was compared with clozapine, quetiapine, risperidone,ziprasidone and olanzapine. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differencesbetween groups).

When compared with clozapine, there were no significant differences for global state (no clinically significant response, n = 2132, 29RCTs, low quality evidence); mental state (BPRS, n = 426, 5 RCTs, very low quality evidence); or leaving the study early for any reason(n = 240, 3 RCTs, very low quality evidence). Quality of life score using the WHO-QOL-100 scale demonstrated significant difference,favouring aripiprazole (n = 132, 2 RCTs, RR 2.59 CI 1.43 to 3.74, very low quality evidence). General extrapyramidal symptoms (EPS)were no different between groups (n = 520, 8 RCTs,very low quality evidence). No study reported general functioning or service use.

When compared with quetiapine, there were no significant differences for global state (n = 991, 12 RCTs, low quality evidence); mentalstate (PANSS positive symptoms, n = 583, 7 RCTs, very low quality evidence); leaving the study early for any reason (n = 168, 2 RCTs,very low quality evidence), or general EPS symptoms (n = 348, 4 RCTs, very low quality evidence). Results were significantly in favourof aripiprazole for quality of life (WHO-QOL-100 total score, n = 100, 1 RCT, MD 2.60 CI 1.31 to 3.89, very low quality evidence).No study reported general functioning or service use.

When compared with risperidone, there were no significant differences for global state (n = 6381, 80 RCTs, low quality evidence); orleaving the study early for any reason (n = 1239, 12 RCTs, very low quality evidence). Data were significantly in favour of aripiprazolefor improvement in mental state using the BPRS (n = 570, 5 RCTs, MD 1.33 CI 2.24 to 0.42, very low quality evidence); with higheradverse effects seen in participants receiving risperidone of general EPS symptoms (n = 2605, 31 RCTs, RR 0.39 CI 0.31 to 0.50, lowquality evidence). No study reported general functioning, quality of life or service use.

When compared with ziprasidone, there were no significant differences for global state (n = 442, 6 RCTs, very low quality evidence);mental state using the BPRS (n = 247, 1 RCT, very low quality evidence); or leaving the study early for any reason (n = 316, 2 RCTs,very low quality evidence). Weight gain was significantly greater in people receiving aripiprazole (n = 232, 3 RCTs, RR 4.01 CI 1.10 to14.60, very low quality evidence). No study reported general functioning, quality of life or service use.

When compared with olanzapine, there were no significant differences for global state (n = 1739, 11 RCTs, very low quality evidence);mental state using PANSS (n = 1500, 11 RCTs, very low quality evidence); or quality of life using the GQOLI-74 scale (n = 68, 1 RCT,very low quality of evidence). Significantly more people receiving aripiprazole left the study early due to any reason (n = 2331, 9 RCTs,RR 1.15 CI 1.05 to 1.25, low quality evidence) and significantly more people receiving olanzapine gained weight (n = 1538, 9 RCTs,RR 0.25 CI 0.15 to 0.43, very low quality evidence). None of the included studies provided outcome data for the comparisons of ’serviceuse’ or ’general functioning’.

Authors’ conclusions

Information on all comparisons is of limited quality, is incomplete and problematic to apply clinically. The quality of the evidence isall low or very low. Aripiprazole is an antipsychotic drug with an important adverse effect profile. Long-term data are sparse and thereis considerable scope for another update of this review as new data emerge from ongoing larger, independent pragmatic trials.

P L A I N L A N G U A G E S U M M A R Y

Aripiprazole versus other atypical antipsychotics

In many countries in the industrialised world there has been a huge growth in the prescription of medication for people with mentalhealth problems, taken orally as a tablet or by injection. Atypical and second generation antipsychotic drugs have become ever morepopular, because they are thought to help people with mental health problems who do not respond quite so well to initial treatment.These newer drugs hold the promise of both reducing symptoms, such as hearing voices or seeing things, and reducing problematicside effects, such as sleepiness, weight gain, and shaking.

However, there is little research and comparison of the ways in which drugs differ from one another. This review examines theeffectiveness of aripiprazole with other new antipsychotics.



Originally the review included 12 research trials. After an update search carried out in November 2012, 162 trials were added. Mostof these trials were from China and although new data were added to the review, overall conclusions did not change. The review nowhas five comparisons with aripiprazole being compared with clozapine, olanzapine, quetiapine, risperidone and ziprasidone.

For people with schizophrenia it may be important to know that aripiprazole may not be as good or effective as olanzapine but thatit has less side effects. Aripiprazole is similar in effectiveness to risperidone and somewhat better than ziprasidone. Aripiprazole hadless side- effects than olanzapine and risperidone (such as weight gain, sleepiness, heart problems, shaking and increased cholesterollevels). Aripiprazole was not as good as ziprasidone for dealing with restlessness or people’s inability to sit still. Comparison with otherantipsychotic drugs as a group showed that people preferred taking aripiprazole. However, people with schizophrenia as well as mentalhealth professionals and policy makers should know that the evidence is limited and mostly of low or very low quality. More trials andresearch is required, including on outcomes such as: quality of life; the views of service users and carers; and patient preference.

This plain language summary has been written by a consumer from Rethink Mental Illness, Benjamin Gray. Email: [email protected]



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE for schizophrenia

Patient or population: patients with schizophrenia

Settings: inpatient and outpatient

Intervention: COMPARISON 1. ARIPIPRAZOLE versus CLOZAPINE

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 COMPAR-

ISON 1. ARIPIPRAZOLE

versus CLOZAPINE

Global state: No clin-

ically significant re-

sponse

Follow-up: up to 12

weeks

Low1 RR 1.05

(0.87 to 1.27)

2132

(29 studies)

⊕⊕©©

low2,3

100 per 1000 105 per 1000

(87 to 127)

Moderate1

150 per 1000 157 per 1000

(131 to 190)

High1

200 per 1000 210 per 1000

(174 to 254)

Mental state: as mea-

sured by BPRS

BPRS (high score =

poor)

Themeanmental state: as

measured by BPRS in the

intervention groups was

0.22 lower

(1.44 lower to 1 higher)

426

(5 studies)

⊕©©©

very low2,3,4,5

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Leaving the study early -

Any reason

Follow-up: up to 12

weeks

Low1 RR 1.41

(0.46 to 4.29)

240

(3 studies)

⊕©©©

very low2,3

0 per 1000 0 per 1000

(0 to 0)

Moderate1

50 per 1000 70 per 1000

(23 to 214)

High1

100 per 1000 141 per 1000

(46 to 429)

Quality of life: as mea-

sured by WHO-QOL-100

WHO-QOL-100 (low

score = poor)

Follow-up: up to 12

weeks

The mean quality of life:

as measured by WHO-

QOL-100 in the interven-

tion groups was

2.59 higher

(1.43 to 3.74 higher)

132

(2 studies)

⊕©©©

very low6

Adverse effects: ex-

trapyramidal effects

Follow-up: up to 12

weeks

Low1 RR 1.91

(0.75 to 4.85)

520

(8 studies)

⊕©©©

very low2,3,5

0 per 1000 0 per 1000

(0 to 0)

Moderate1

50 per 1000 96 per 1000

(38 to 242)

High1

100 per 1000 191 per 1000

(75 to 485)

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General functioning - not

measured

See comment See comment Not estimable - See comment No study measured or re-

ported this outcome.

Service use - not mea-

sured

See comment See comment Not estimable - See comment No study measured or re-

ported this outcome.

*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: moderate risk approximately equates to that of the control group risk in the study population.2 Risk of bias: rated ’serious’ - majority of the included studies had inadequate study design - unclear randomisation, allocation

concealment and blinding. Some also had selective reporting concerns.3 Imprecision: rated ’serious’ - most of these included studies are of small samples with small effect size and wide confidence interval.

The combined effect was not statistically significant.4 Imprecision: rated ’serious’ - we were unable to obtain direct binary measure of mental state, thus used BPRS score as an indicator.5 Publication bias: rated ’strongly suspected’ - only a small number of studies favouring intervention group were identified.6 Indirectness: rated ’serious’ - we were unable to obtain direct binary measure of quality of life, thus employed WHO-QOL-100 rating

score as an indicator.

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B A C K G R O U N D

Description of the condition

Schizophrenia is usually a chronic and disabling psychiatric dis-order, which afflicts approximately one per cent of the popula-tion worldwide, affecting male and female patients in similar pro-portions. The annual incidence of schizophrenia averages 15 per100,000 population and the risk of developing the illness overone’s lifetime averages 0.7% (Tandon 2008). Its typical manifesta-tions include ’positive’ symptoms such as fixed, false beliefs (delu-sions) and perceptions without cause (hallucinations), ’negative’symptoms such as apathy and lack of drive, disorganisation of be-haviour and thought, and catatonic symptoms such as mannerismsand bizarre posturing (Carpenter 1994). The degree of sufferingand disability is considerable with 80% to 90% of those affectednot working (Marvaha 2004) and up to 10% dying prematurely(Tsuang 1978). In the age group of 15 to 44 years, schizophreniais among the top 10 leading causes of disease-related disability inthe world (WHO 2001). Conventional antipsychotic drugs, suchas chlorpromazine and haloperidol, have traditionally been usedas first line antipsychotics for people with schizophrenia (Kane1993). The introduction and subsequent use of clozapine in theUnited States of America identified that clozapine seemed to bemore effective, and was associated with fewer movement disordersthan existing agents such as chlorpromazine (Kane 1988). Theseresults boosted the development and marketing of new/second/atypical generation antipsychotics (SGAs).

Description of the intervention

There is no good definition of what constitutes an atypical/sec-ond generation antipsychotic, but they were initially said to dif-fer from older generation drugs in that they did not cause move-ment disorders (catalepsy) in rats at clinically effective doses (Arnt1998). The terms new or second generation to describe clozapine,a very old drug, are equally poor descriptors. According to treat-ment guidelines (APA 2004; Gaebel 2006), SGAs include drugssuch as amisulpride, aripiprazole, clozapine, olanzapine, quetiap-ine, risperidone, sertindole, ziprasidone and zotepine. It is unclearwhether some old and inexpensive compounds such as sulpiride,perazine or even low-dose chlorpromazine, have similar properties(Möller 2000). High expectations were raised for these SGAs as re-gards their alleged superiority in a number of areas such as compli-ance, cognitive functioning, negative symptoms, movement disor-ders, quality of life and efficacy in treatment-resistant schizophre-nia.

How the intervention might work

Aripiprazole is said to be the prototype of a new and third gener-ation of antipsychotics; the so called dopamine-serotonin systemstabilisers. It is reported to exert its antipsychotic effects by act-ing as a partial agonist at D2 dopamine and 5-HT1a serotoninreceptors and as an agonist at 5-HT2 serotonin receptors. It hasbeen postulated that through the above receptor site actions, andhence dopamine and serotonin system stabilisation, a partial D2agonist would be able to act as an antagonist in pathways wherean abundance of dopamine was producing psychosis, yet it wouldstimulate receptors as an agonist at sites in which low dopaminer-gic tone would produce adverse effects (e.g. areas mediating mo-tor movement and prolactin release (Rivas-Vasquez 2003)). Arip-iprazole, however, also has an affinity to other receptors includ-ing D3, D4, 5-HT2c, 5HT7, alpha-1 adrenergic and histaminereceptors. This may explain adverse effects associated with thiscompound such as somnolence, headache, gastrointestinal upsetand light headedness (FDA 2002). The recommended target dosefor aripiprazole is 10-15 mg per day (dose range 10-30 mg/day).Phase III trials were initially conducted in Japan in 1995 and thedrug was granted Approved Status by the FDA (USA) on the 15November 2002 for the treatment of schizophrenia. Aripiprazolehas since been licensed in most countries worldwide.

Why it is important to do this review

The debate as to how far the second generation antipsychotic drugsimprove these outcomes compared to conventional antipsychoticscontinues (Duggan 2005) and results from recent studies weresobering (Jones 2006; Lieberman 2005). Nevertheless, in someparts of the world, particularly in western industrialised countries,SGAs have become the mainstay of treatment. Second generationantipsychotics also differ in terms of their costs. Amisulpride andrisperidone, for example, are already generic in many countries.Therefore, the question as to whether they differ from each otherin their clinical efficacy becomes increasingly important. In thisreview we aim to summarise evidence from randomised controlledtrials comparing aripiprazole with other SGAs. This acts as acontinuum to the comparisons previously published by EL-Sayeh2006, Leucht 2008 and Komossa 2009.This review was published in early 2013 with a vast number ofChinese studies in awaiting classification, thus we have updated itagain in June 2013.

O B J E C T I V E S

To review the effects of aripiprazole compared with other secondgeneration/atypical antipsychotics for people with schizophrenia.

M E T H O D S



Criteria for considering studies for this review

Types of studies

We included both open and double-blinded, randomised con-trolled trials. We included open trials as we felt that important datathat could potentially have an impact on the results might other-wise be overlooked. Where a trial was described as “double-blind”but it was only implied that the study was randomised, we includedthese trials in a sensitivity analysis. If there was no substantive dif-ference within primary outcomes (see Types of outcome measures)when these ’implied randomisation’ studies were added, then weincluded these in the final analysis. If there was a substantive dif-ference, we only used clearly randomised trials and described theresults of the sensitivity analysis in the text. We excluded quasi-randomised studies, such as those allocating by using alternatedays of the week.

Types of participants

We included people with schizophrenia and other types ofschizophrenia-like psychosis (e.g. schizophreniform and schizoaf-fective disorders), irrespective of the diagnostic criteria used. Thereis no clear evidence that the schizophrenia-like psychoses arecaused by fundamentally different disease processes or require dif-ferent treatment approaches (Carpenter 1994).

Types of interventions

1. Aripiprazole

Any oral form of application, any dose.

2. Other new/atypical antipsychotic drugs

These include amisulpride, clozapine, olanzapine, quetiapine,risperidone, sertindole, ziprasidone, zotepine: any oral or par-enteral form of application, any dose.

Types of outcome measures

We grouped outcomes into the short term (up to 12 weeks),medium term (13-26 weeks) and long term (over 26 weeks).

Primary outcomes

1. Global state

No clinically important response - as defined by the individualstudies (e.g. global impression less than much improved or lessthan 50% reduction on a rating scale) - medium term

2. General functioning

No clinically important change in general functioning - mediumterm

3. Adverse effects

Clinically important specific adverse effects - medium term

Secondary outcomes

1. Global state

1.1 No clinically important change in global state (as defined byindividual studies)1.2 Relapse (as defined by the individual studies)2. Mental state

2.1 No clinically important change in general mental state score2.2 Average endpoint general mental score2.3 Average change in general mental state score2.4 No clinically important change in specific symptoms (positivesymptoms of schizophrenia, negative symptoms of schizophrenia)2.5 Average endpoint specific symptom score2.6 Average change in specific symptom score3. Leaving the studies early

3.1 Any reason, adverse events, inefficacy of treatment4. Quality of life/satisfaction with treatment

4.1 No clinically important change in general quality of life4.2 Average endpoint general quality of life score4.3 Average change in general quality of life score5. General functioning

5.1 No clinically important change in general functioning,- shortand long term5.2 Average endpoint general functioning score5.3 Average change in general functioning score

6. Cognitive functioning

6.1 No clinically important change in overall cognitive functioning6.2 Average endpoint of overall cognitive functioning score6.3 Average change of overall cognitive functioning score

7. Service use

7.1 Number of patients hospitalised

8. Adverse effects

8.1 Number of participants with at least one adverse effect8.2 Clinically important specific adverse effects (cardiac effects,death, movement disorders, prolactin increase and associated ef-fects, weight gain, effects on white blood cell count), short andlong term8.3 Average endpoint in specific adverse effects8.4 Average change in specific adverse effects



9. ’Summary of findings’ table

We used the GRADE approach to interpret findings (Schünemann2008) and used the GRADE profiler to import data from ReviewManager (RevMan) to create ’Summary of findings’ tables. Thesetables provide outcome-specific information concerning the over-all quality of evidence from each included study in the compar-ison, the magnitude of effect of the interventions examined, andthe sum of available data on all outcomes we rated as important topatient-care and decision making. We selected the following mainoutcomes for inclusion in the ’Summary of findings’ tables.

1. Global state2. Mental state3. Leaving the study early4. Quality of Life5. Adverse effects6. General functioning7. Service use

Search methods for identification of studies

No language restriction was applied within the limitations of thesearch tools.

Electronic searches

1. Update search

We searched the Cochrane Schizophrenia Group Trials Register(5 November 2012) using the phrase:[ ( (aripiprazol* AND (amisulprid* OR clozapin* OR olanzapin*OR quetiapin* OR risperidon* OR sertindol* OR ziprasidon* ORzotepin*)) in title, abstract or index terms of REFERENCE) or( (aripiprazol* AND (amisulprid* OR clozapin* OR olanzapin*OR quetiapin* OR risperidon* OR sertindol* OR ziprasidon* ORzotepin*)) in interventions of STUDY)]The Cochrane Schizophrenia Group’s Trials Register is compiledby systematic searches of major databases, handsearches of journalsand conference proceedings (see Group Module). Incoming trialsare assigned to relevant existing or new review titles.

2. Previous electronic search

Please see Appendix 1.

Searching other resources

1. Reference searching

We inspected the reference lists of all studies identified in the searchfor more trials.

2. Personal contact

Where possible, we contacted the first author of each includedstudy for missing information.

3. Drug companies

We contacted the manufacturers of all atypical antipsychotics in-cluded for additional data in the 2011 update.

Data collection and analysis

For previous data collection and analysis methods please seeAppendix 2.

Selection of studies

Review author TS inspected the reports for this update. TS re-solved any doubts by discussion with other review authors, andwhere there was still doubt, TS acquired the full article for fur-ther inspection. Once the full articles were obtained, TS decidedwhether the studies met the review criteria. Twenty per cent of thereferences were randomly checked by HXM for reliability. Anydisagreements were resolved by discussion. For any persistent dis-agreement, TS sought further information from authors of studiesand added these trials to the list of those awaiting assessment. (Seealso Figure 1, Figure 2 and Figure 3 for detailed flow chart of theselection process).



http://szg.cochrane.org/cszg-specialised-registerhttp://szg.cochrane.org/cszg-specialised-register

Figure 1. Study flow diagram: original search



Figure 2. Study flow diagram: update 2011



Figure 3. Study flow diagram: update 2012



Data extraction and management

1. Extraction

For this update, TS and HXM extracted data from included stud-ies. If data were presented only in graphs and figures, TS andHXM extracted data whenever possible. When further informa-tion was necessary, TS contacted authors of studies in order toobtain missing data or for clarification. If studies were multicen-tre, where possible, TS extracted data relevant to each componentcentre separately.

2. Management

2.1 Forms

We extracted data onto standard, simple forms.

2.2 Scale-derived data

We included continuous data from rating scales only if:a. the psychometric properties of the measuring instrument havebeen described in a peer-reviewed journal (Marshall 2000); andb. the measuring instrument has not been written or modified byone of the trialists for that particular trial.Ideally, the measuring instrument should either be i. a self-reportor ii. completed by an independent rater or relative (not the ther-apist). We realise that this is not often reported clearly; we havenoted whether or not this is the case in Description of studies.

2.3 Endpoint versus change data

There are advantages of both endpoint and change data. Changedata can remove a component of between-person variability fromthe analysis. On the other hand, calculation of change needs twoassessments (baseline and endpoint), which can be difficult inunstable and difficult to measure conditions such as schizophrenia.We decided primarily to use endpoint data, and only use changedata if the former were not available. We combined endpoint andchange data in the analysis as we used mean differences (MD)rather than standardised mean differences (SMD) throughout (Higgins 2011, Chapter 9.4.5.2).

2.4 Skewed data

Continuous data on clinical and social outcomes are often notnormally distributed. To avoid the pitfall of applying parametrictests to non-parametric data, we aimed to apply the followingstandards to all data before inclusion:a) standard deviations (SDs) and means are reported in the paperor obtainable from the authors;b) when a scale starts from the finite number zero, the SD, whenmultiplied by two, is less than the mean (as otherwise the mean isunlikely to be an appropriate measure of the centre of the distri-bution (Altman 1996));c) if a scale started from a positive value (such as the Positive andNegative Syndrome Scale (PANSS, (Kay 1986)), which can havevalues from 30 to 210), we modified the calculation describedabove to take the scale starting point into account. In these casesskew is present if 2 SD > (S-S min), where S is the mean score andS min is the minimum score.Endpoint scores on scales often have a finite start and end pointand these rules can be applied. We entered skewed endpoint datafrom studies of fewer than 200 participants in as other data withinthe data and analyses tables rather than into an analysis. Skeweddata pose less of a problem when looking at mean if the samplesize is large; we entered such endpoint data into syntheses.When continuous data are presented on a scale that includes apossibility of negative values (such as change data), it is difficultto tell whether data are skewed or not; we entered skewed changedata into analyses regardless of the size of study.

2.5 Common measure

To facilitate comparison between trials, we intended to convertvariables that can be reported in different metrics, such as days inhospital (mean days per year, per week or per month) to a commonmetric (e.g. mean days per month).

2.6 Conversion of continuous to binary

Where possible, we made efforts to convert outcome measuresto dichotomous data. This can be done by identifying cut-offpoints on rating scales and dividing participants accordingly into’clinically improved’ or ’not clinically improved’. It is generallyassumed that if there is a 50% reduction in a scale-derived scoresuch as the Brief Psychiatric Rating Scale (BPRS, Overall 1962)or the PANSS (Kay 1986), this could be considered as a clinicallysignificant response (Leucht 2005a; Leucht 2005). If data basedon these thresholds were not available, we used the primary cut-off presented by the original authors.



2.7 Direction of graphs

Where possible, we entered data in such a way that the area tothe left of the line of no effect indicated a favourable outcome foraripiprazole.

Assessment of risk of bias in included studies

For this update, review author TS worked independently by usingcriteria described in the Cochrane Handbook for Systematic Reviewsof Interventions (Higgins 2011) to assess trial quality. This newset of criteria is based on evidence of associations between over-estimate of effect and high risk of bias of the article such as se-quence generation, allocation concealment, blinding, incompleteoutcome data and selective reporting.Where inadequate details of randomisation and other characteris-tics of trials were provided we contacted the authors of the studiesin order to obtain additional information.We have noted the level of risk of bias in both the text of thereview and in the Summary of findings for the main comparison;Summary of findings 2; Summary of findings 3; Summary offindings 4; Summary of findings 5.

Measures of treatment effect

1. Binary data

For binary outcomes, we calculated a standard estimation of therisk ratio (RR) and its 95% confidence interval (CI). It has beenshown that RR is more intuitive (Boissel 1999) than odds ratiosand that odds ratios tend to be interpreted as RR by clinicians(Deeks 2000). The Number Needed to Treat/Harm (NNT/H)statistic with its CI is intuitively attractive to clinicians but is prob-lematic both in its accurate calculation in meta-analyses and inter-pretation (Hutton 2009). For binary data presented in the ’Sum-mary of findings’ tables, where possible, we calculated illustrativecomparative risks.

2. Continuous data

For continuous outcomes, we estimated the mean difference (MD)between groups. We would prefer not to calculate effect size mea-sures (standardised mean difference (SMD). However, if scales ofvery considerable similarity were used, we presumed there was asmall difference in measurement, and we calculated effect size andtransformed the effect back to the units of one or more of thespecific instruments.

Unit of analysis issues

1. Cluster trials

Studies increasingly employ ’cluster randomisation’ (such as ran-domisation by clinician or practice), but analysis and pooling ofclustered data poses problems. Authors often fail to account forintra-class correlation in clustered studies, leading to a ’unit ofanalysis’ error (Divine 1992) whereby P values are spuriously low,CIs unduly narrow and statistical significance overestimated. Thiscauses type I errors (Bland 1997; Gulliford 1999).No cluster-randomised trials were identified in our search; how-ever, if reviews in the future include such trials, where clusteringis not accounted for in primary studies, we will present data in atable, with a (*) symbol to indicate the presence of a probable unitof analysis error. In subsequent versions of this review, we will seekto contact first authors of such studies to obtain intra-class corre-lation coefficients (ICCs) for their clustered data and to adjust forthis by using accepted methods (Gulliford 1999). Where cluster-ing is been incorporated into the analysis of primary studies, wewill present these data as if from a non cluster-randomised study,but adjust for the clustering effect.We have sought statistical advice and have been advised that thebinary data as presented in a report should be divided by a ’designeffect’. This is calculated using the mean number of participantsper cluster (m) and the ICC [Design effect = 1+(m-1)*ICC] (Donner 2002). If the ICC was not reported it was assumed to be0.1 (Ukoumunne 1999).If, in future updates of this review cluster trials are identified,cluster studies will be appropriately analysed taking into accountICCs and relevant data documented in the report, synthesis withother studies would be possible using the generic inverse variancetechnique.

2. Cross-over trials

A major concern of cross-over trials is the carry-over effect. It oc-curs if an effect (e.g. pharmacological, physiological or psycho-logical) of the treatment in the first phase is carried over to thesecond phase. As a consequence, on entry to the second phasethe participants can differ systematically from their initial statedespite a wash-out phase. For the same reason cross-over trials arenot appropriate if the condition of interest is unstable (Elbourne2002). As both effects are very likely in severe mental illness, if weencountered such trials, we planned only to use data of the firstphase of cross-over studies.

3. Studies with multiple treatment groups

Where a study involves more than two treatment arms, if rele-vant, we presented the additional treatment arms in comparisons.If data were binary, we simply added these and combined themwithin the two-by-two table. If data were continuous, we com-bined data following the formula in section 7.7.3.8 (Combininggroups) of the Cochrane Handbook for Systemic reviews of Interven-tions (Higgins 2011). Where the additional treatment arms werenot relevant, we did not reproduce these data.



Dealing with missing data

1. Overall loss of credibility

At some degree of loss of follow-up, data must lose credibility(Xia 2009). Although high rates of premature discontinuation area major problem in this field, we felt that it was unclear whichdegree of attrition leads to a high degree of bias. We, therefore,did not exclude outcomes on the basis of the percentage of par-ticipants completing them. However, we addressed the attritionproblem in all parts of the review, including the abstract. For thispurpose, we calculated, presented and commented on frequencystatistics (overall rates of leaving the studies early in all studies andcomparators pooled and their ranges). We assumed that the peo-ple who discontinued the studies for any reason did not show anyresponse to the treatment.

2. Binary

We presented data on a ’once-randomised-always-analyse’ basis(an intention-to-treat (ITT) analysis). We undertook a sensitivityanalysis to test how prone the primary outcomes are to changewhen data only from people who complete the study to that pointare compared with the ITTanalysis using the above assumptions.

3. Continuous

3.1 Attrition

In the case of continuous outcomes, we preferred to use ITT re-sults, but if not available we used completer data.

3.2 Standard deviations

If SDs were not reported, we first tried to obtain the missing valuesfrom the authors. If not available, where there are missing mea-sures of variance for continuous data, but an exact standard error(SE) and CIs available for group means, and either a P value orT value available for differences in mean, we can calculate themaccording to the rules described in the Cochrane Handbook for Sys-temic reviews of Interventions (Higgins 2011): When only the SE isreported, SDs are calculated by the formula SD = SE* square root(n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Sys-temic reviews of Interventions (Higgins 2011) present detailed for-mulae for estimating SDs from P values, T or F values, CIs, rangesor other statistics. If these formulae do not apply, we would havecalculated the SDs according to a validated imputation method,which is based on the SDs of the other included studies (Furukawa2006). Although some of these imputation strategies can intro-duce error, the alternative would be to exclude a given study’s out-come and thus to lose information. We nevertheless would have

examined the validity of the imputations in a sensitivity analysisexcluding imputed values, had we imputed any values.

3.3 Last observation carried forward

We anticipated that in many studies the method of last observationcarried forward (LOCF) would be employed within the studyreport. As with all methods of imputation to deal with missingdata, LOCF introduces uncertainty about the reliability of theresults (Leucht 2007). We nevertheless used LOCF data beingaware that many results are the product of LOCF assumptions.

Assessment of heterogeneity

1. Clinical heterogeneity

We considered all included studies initially, without seeing com-parison data, to judge clinical heterogeneity. We simply inspectedall studies for clearly outlying people or situations which we hadnot predicted would arise. When such situations or participantgroups arose, we discussed these fully.

2. Methodological heterogeneity

We considered all included studies initially, without seeing com-parison data, to judge methodological heterogeneity. We simplyinspected all studies for clearly outlying methods which we had notpredicted would arise. When such methodological outliers arose,we discussed these fully.

3. Statistical heterogeneity

3.1 Visual inspection

We visually inspected graphs to investigate the possibility of sta-tistical heterogeneity.

3.2 Employing the I2 statistic

We investigated heterogeneity between studies by considering theI2 method alongside the ChI2 P value. The I2 provides an estimateof the percentage of inconsistency thought to be due to chance(Higgins 2003). The importance of the observed value of I2 de-pends on i. magnitude and direction of effects and ii. strengthof evidence for heterogeneity (e.g. P value from ChI2 test, or aconfidence interval for I2). An I2 estimate greater than or equal toaround 50% accompanied by a statistically significant ChI2 statis-tic was interpreted as evidence of substantial levels of heterogene-ity (Higgins 2011). When substantial levels of heterogeneity werefound in the primary outcome, we explored reasons for hetero-geneity (Subgroup analysis and investigation of heterogeneity).



Assessment of reporting biases

Reporting biases arise when the dissemination of research findingsis influenced by the nature and direction of results (Egger 1997).These are described in Section 10 of the Handbook (Higgins 2011).We are aware that funnel plots may be useful in investigatingreporting biases but are of limited power to detect small-studyeffects. We did not use funnel plots for outcomes where there were10 or fewer studies, or where all studies were of similar sizes. Inother cases, where funnel plots were possible, we sought statisticaladvice in their interpretation.

Data synthesis

We understand that there is no closed argument for preference foruse of fixed-effect or random-effects models. The random-effectsmethod incorporates an assumption that the different studies areestimating different, yet related, intervention effects. This oftenseems to be true to us and the random-effects model takes intoaccount differences between studies even if there is no statisticallysignificant heterogeneity. There is, however, a disadvantage to therandom-effects model: it puts added weight onto small studies,which often are the most biased ones. Depending on the directionof effect, these studies can either inflate or deflate the effect size.Where possible, for both dichotomous and continuous data weused the random-effects model for data synthesis.

Subgroup analysis and investigation of heterogeneity

1. Subgroup analyses - only primary outcomes

We did not anticipate any subgroup analyses.

2. Investigation of heterogeneity

If inconsistency was high, we reported this. First, we investigatedwhether data had been entered correctly. Second, if data were cor-rect, we visually inspected the graph and successively removed out-lying studies to see if homogeneity was restored. For this reviewwe decided that should this occur with data contributing to thesummary finding of no more than around 10% of the total weight-ing, we would present data. If not, then we did not pool data anddiscussed relevant issues. We know of no supporting research forthis 10% cut-off, but we used prediction intervals as an alternativeto this unsatisfactory state.

When unanticipated clinical or methodological heterogeneity wasobvious, we simply stated hypotheses regarding these for futurereviews or versions of this review. We did not anticipate undertak-ing analyses relating to these.

Sensitivity analysis

1. Implication of randomisation

We aimed to include trials in a sensitivity analysis if they weredescribed in some way so as to imply randomisation. For the pri-mary outcomes, we included these studies and, if there was nosubstantive difference when the implied randomised studies wereadded to those with better description of randomisation, then weentered all data from these studies.

2. Assumptions for lost binary data

Where assumptions had to be made regarding people lost to follow-up (see Dealing with missing data), we compared the findings ofthe primary outcomes when we used our assumptions and whenwe used data only from people who completed the study to thatpoint. If there was a substantial difference, we reported results anddiscussed them, but continued to employ our assumption.Where assumptions had to be made regarding missing SDs data(see Dealing with missing data), we compared the findings of theprimary outcomes when we used our assumptions and when weused data only from people who completed the study to that point.A sensitivity analysis was undertaken to test how prone resultswere to change when completer-only data only were comparedto the imputed data using the above assumption. If there was asubstantial difference, we reported results and discussed them, butcontinued to employ our assumption.

3. Risk of bias

We analysed the effects of excluding trials that were judged to beat high risk of bias across one or more of the domains of randomi-sation (implied as randomised with no further details available):allocation concealment, blinding and outcome reporting for themeta-analysis of the primary outcome. If the exclusion of trials athigh risk of bias did not substantially alter the direction of effector the precision of the effect estimates, then we included data fromthese trials in the analysis.

4. Imputed values

We planned to undertake a sensitivity analysis to assess the effectsof including data from trials where we used imputed values forICC in calculating the design effect in cluster randomised trials.However, no cluster-randomised trials were identified for this up-date.In future updates, if cluster randomised trials are included we willundertake sensitivity analyses. If we note substantial differences inthe direction or precision of effect estimates in any of the sensitivityanalyses listed above, we will not pool data from the excluded trialswith the other trials contributing to the outcome, but present themseparately.



5. Skewed data

We planned sensitivity analyses a priori for examining the changein the robustness of the sensitivity to including studies with po-tentially skewed data.

6. Comparator dose

A recent report showed that some of the comparisons of atyp-ical antipsychotics may have been biased by using inappropri-ate comparator doses (Heres 2006). We, therefore, also analysedwhether the exclusion of studies with inappropriate comparatordoses changed the results of the primary outcome and the generalmental state.Comparator doses were considered inappropriate where theyexceeded BNF and Martindale recommended maximum doses(BNF 2013; Martindale 2013).

• Aripiprazole: usual maintenance dose of 15 mg daily; range10 to 15 mg once daily; maximum dose 30 mg daily.

• Clozapine: usual dose 200 to 450 mg daily; maximum dose900 mg daily.

• Quetiapine: usual range 300 to 450 mg daily in two divideddoses; maximum dose 750 mg daily.

• Risperidone: usual dose 4 mg daily; maximum dose 50 mgevery two weeks.

• Ziprasidone: (oral) 20 mg twice daily, increased if necessaryup to maximum 80 mg twice daily; usual maintenance dose 20mg twice daily; (intramuscular (IM) for acute agitation) 10 to 20mg as required; maximum dose 40 mg daily for three consecutivedays (to switch to oral therapy as soon as possible).

• Olanzapine: usual range 5 to 20 mg daily; maximum dose20 mg daily.

R E S U L T S

Description of studies

For a substantive description of studies please see Characteristicsof included studies and Characteristics of excluded studies tables.

Results of the search

1. Original search (2005/2007)

The first search yielded 3620 reports of which 28 were closely in-spected. After excluding 22 studies, six publications on four trialsand two comparisons could be included: aripiprazole versus olan-zapine (two) and aripiprazole versus risperidone (two) (Komossa2009) (Figure 1).

2. Updated search (November 2011)

The search we undertook for the first update of the review (Khanna2013) identified 618 further results and, after close inspection,we included eight more studies; making a total of 12 studies alto-gether. We excluded 38 trials, added 216 trials to ’Studies awaitingclassification’ (due to the need for translation or data extraction)and 16 trials to ’Ongoing studies’ category (Khanna 2013) (Figure2).

3. Updated search (November 2012)

The 2012 updated search for this current version of the reviewyielded 215 new citations; 209 full-text articles were assessed foreligibility, and ultimately 162 studies (from 167 references) wereincluded. The total amount of included studies in this currentreview is 174 (Figure 3).

Included studies

The 174 included studies randomised 17,244 participants with thediagnosis of schizophrenia or schizoaffective disorder. All studieswere described as randomised. We included both double blindand open label studies. Many were sponsored by pharmaceuticalcompanies with some pecuniary interest in the result.

1. Length of studies

One trial was only five days long. The vast majority were shortterm with a duration of three to eight weeks. Seven medium-termstudies ranged from 20 to 26 weeks, and long-term studies from28 weeks to two years.

2. Setting

Studies reported inpatient and outpatient settings; the vast major-ity of studies were undertaken in China, where, it seems, aripipra-zole is being heavily marketed.

3. Participants

Participants were diagnosed with varying diagnostic criteria; Di-agnostic Statistical Manual version 4 (DSM-IV); clinical diagno-sis (or no mention). The vast majority of participants in includedstudies were diagnosed using the Chinese Classification of MentalDisorders (CCMD-3). Participants were usually relatively chron-ically ill with mean ages in the late thirties.

4. Study size

The sample size varied from n = 40 (Zhang 2008b) to n = 1599(Tandon 2006) people.



5. Interventions

5.1 Aripiprazole

Doses ranged between 2.5 to 30 mg/day.

5.2 Control drugs

Other atypical drugs, namely olanzapine, risperidone, ziprasidoneand quetiapine were used as controls. As some studies did notelucidate doses it can only be presumed that therapeutic doseswere employed.

6. Outcomes

6.1 Leaving the study early

Thirty-five studies reported on participants leaving the study earlydue to any reason.

6.2 Rating scales

Details of scales that provided usable data are shown below. Rea-sons for exclusion of data from other instruments are given under’Outcomes’ in the Characteristics of included studies.

6.2.1 Global state scales

6.2.1.1 Clinical Global Impression Scale - CGI Scale (Guy 1976)This is used to assess both severity of illness and clinical improve-ment, by comparing the conditions of the person standardisedagainst other people with the same diagnosis. A seven-point scor-ing system is used with low scores showing decreased severity and/or overall improvement.6.2.1.2 Investigator’s Assessment Questionnaire - IAQ (Tandon2005)The IAQ is a quantifiable clinical tool that can provide detailed in-formation regarding common safety, efficacy and tolerability con-cerns that patients experience while taking antipsychotics. It hasbeen shown to highly correlate with time to study discontinuationwhich is a common measure of effectiveness.6.2.1.3 Arizona Sexual Experience Scale - ASEX (McGahuey2000)This is a brief scale for self-rating of sexual function. It has fiveitems and is rated in five steps. Possible scores range from five to30 with higher scores indicating more sexual dysfunction.

6.2.2 Mental state scales

6.2.2.1 Positive and Negative Syndrome Scale - PANSS (Kay1986)This schizophrenia scale has 30 items, each of which can be definedon a seven-point scoring system varying from one - absent to seven- extreme. It can be divided into three sub scales for measuring theseverity of general psychopathology, positive symptoms (PANSS-P), and negative symptoms (PANSS-N). A low score indicateslesser severity.6.2.2.2 Positive and Negative Syndrome Scale-Excited Compo-nent - PANSS-EC (Chaichan 2008)The PANSS-EC scale is derived as a sub scale of PANSS andis a simple scale used to measure the degree of agitation. Thescale consists of five items (poor impulse control, tension, hostility,uncooperativeness, excitement), each being ranked from one toseven giving a potential maximum score of 35 points.6.2.2.3 Brief Psychiatric Rating Scale - BPRS (Overall 1962)This consists of 18 to 24 items (depending on the version) eachrated on a scale from one (absent) to seven (extreme).

6.2.3 Adverse effects scales

6.2.3.1 Abnormal Involuntary Movement Scale - AIMS (Guy1976)This scale has been used to assess tardive dyskinesia, a long-term,drug-induced movement disorder and short-term movement dis-orders such as tremor.6.2.3.2 Simpson Angus Scale - SAS (Simpson 1970)This 10-item scale (with a scoring system of zero to four on eachitem) measures drug-induced parkinsonism, a short-term drug-induced movement disorder. A low score indicates low levels ofparkinsonism.6.2.3.3 Barnes Akathisia Scale - BAS (Barnes 1989)The scale comprises items rating the observable, restless move-ments that characterise akathisia, a subjective awareness of restless-ness, and any distress associated with the condition. These itemsare rated from zero (normal) to three (severe). In addition, thereis an item for rating global severity (from zero (absent) to five (se-vere)). A low score indicates low levels of akathisia.

6.2.4 Quality

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