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Clozapina combinada con diferentes fármacos antipsicóticos para la esquizofrenia resistente al tratamiento

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References

Referencias de los estudios incluidos en esta revisión

Cipriani 2013a {published data only}

Barbui C, Accordini S, Nose M, Stroup S, Purgato M, Girlanda F, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment‐resistant schizophrenia in routine clinical care a randomized, controlled trial. Journal of Clinical Psychopharmacology 2011;31(3):266‐73. CENTRAL
Cipriani A, Accordini S, Nosè M, Purgato M, Girlanda F, Tansella M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment‐resistant schizophrenia: a 12‐month, randomized, naturalistic trial. Journal of Clinical Psychopharmacology 2013;33(4):533‐7. CENTRAL

Genç 2007 {published data only}

Genç Y, Taner E, Candansayar S. Comparison of clozapine‐amisulpride and clozapine‐quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single‐blind randomized study. Advances in Therapy 2007;24(1):1‐13. CENTRAL

Kong 2001 {published data only}

Kong QR. Clozapine combined with risperidone and sulpiride in treatment resistant schizophrenia. Shandong Archives of Psychiatry 2001;14:119‐20. CENTRAL

Kuwilsky 2010 {published data only}

Kuwilsky A, Krumm B, Englisch S, Dressing H, Zink M. Long‐term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry 2010;43(6):216‐20. CENTRAL
Zink M, Kuwilsky A, Krumm B, Dressing H. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. Journal of Psychopharmacology 2009;23:305‐14. CENTRAL

Wen 2015 {published data only}

Wen RH, Liu S. A comparative study of clozapine combined with ziprasidone or quetiapine for treatment resistant schizophrenia. Medical Journal of Chinese People's Health 2015;27(2):4‐6. CENTRAL

Referencias de los estudios excluidos de esta revisión

Angst 1971 {published data only}

Angst J, Bente D, Berner P, Heimann H, Helmchen H, Hippius H. The clinical effect of clozapine [Das klinische wirkungsbild von clozapin]. Pharmakopsychiatrie und Neuropsychopharmakologie 1971;4:201‐11. CENTRAL

Anil 2009 {published data only}

Anil E. Risperidone augmented with clozapine for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Anonymous 2009 {published data only}

Anonymous. Clinician's desktop reference for clinical & cost utility of latest antipsychotics cutlass. www.iop.kcl.ac.uk/iop/extras/cutlass/Downloads/cutlass.pdf (date accessed 3 April 2009). CENTRAL

Assion 2008 {published data only}

Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double‐blind, placebo‐controlled trial. Pharmacopsychiatry 2008;41(1):24‐8. [MEDLINE: 18203048]CENTRAL

Bao 1988 {published data only}

Bao XQ. A double‐blind study on the effect of clozapine, penfluridol and chlorpromazine in the treatment of schizophrenia. Chung Hua Shen Ching Ching Shen Ko Tsa Chih [Chinese Journal of Neurology and Psychiatry] 1988;21(5):274‐6. CENTRAL

Barnes 2013 {published data only}

Barnes TR, Drake RJ, Dunn G, Hayhurst KP, Jones PB, Lewis SW. Effect of prior treatment with antipsychotic long‐acting injection on randomised clinical trial treatment outcomes. British Journal of Psychiatry 2013;203(3):215‐20. CENTRAL

Bender 1997 {published data only}

Bender S, Olbrich H, Hornstein C, Schöne W, Falkai P. Antipsychotic efficacy of trimipramine: double‐blind comparison with a classical neuroleptic. Pharmacopsychiatry 1997;30(5):151. CENTRAL

Bilder 2001 {published data only}

Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol on treatment‐resistant patients with schizophrenia and schizoaffective disorder. International Congress on Schizophrenia Research; 2001 Apr 28 ‐ May 2; Whistler. British Columbia, Canada, 2001. CENTRAL

Bustillo 2009 {published data only}

Bustillo J. Lamotrigine for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Cao 2003 {published data only}

Cao HJ, You HF, Fan FL, Zhang J. The control study of risperidone and clozapine for the treatment‐resistant schizophrenia. Chinese Journal of Medicine Research 2003;3(4):316‐9. CENTRAL

Chang 2008 {published data only}

Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, et al. Aripiprazole augmentation in clozapine‐treated patients with refractory schizophrenia: an 8‐week, randomized, double‐blind, placebo‐controlled trial. Journal of Clinical Psychiatry2008; Vol. 69, issue 5:720‐31. CENTRAL

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Cooper D, Moisan J, Gaudet M, Abdous B, Gregoire JP. Ambulatory use of olanzapine and risperidone: a population‐based study on persistence and the use of concomitant therapy in the treatment of schizophrenia. Canadian Journal of Psychiatry 2005;50(14):901‐8. CENTRAL

Dai 2014 {published data only}

Dai X. Ziprasidone combined with small dose of clozapine for 44 cases of treatment resistant schizophrenia [齐拉西酮联合小剂量氯氮平治疗44例难治性精神分裂症效果评价]. For All Health 2014;8(9):176‐7. CENTRAL

Daniel 1994 {published data only}

Daniel DG. Comparison of risperidone and clozapine on clinical and cognitive functions in psychotic disorders. Biological Psychiatry 1994;35:667. CENTRAL

Dong 2007 {published data only}

董太新, 阮江红, 李永芝, 李昱. Ziprasidone treatment of the first clinical diagnosis of schizophrenia [齐拉西酮治疗首诊精神分裂症临床分析]. Medical Journal of Chinese People's Health 2007;19(12):1061. CENTRAL

Feifel 2009 {published data only}

Feifel D. Oxytocin for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Fleischhacker 2008a {published data only}

Fleischhacker W, Heikkinen ME, Olie JP, Dewaele P, McQuade R, Hennicken D, et al. Long‐term effect on weight of aripiprazole‐clozapine in schizophrenia patients with suboptimal response on clozapine. European Neuropsychopharmacology 2008;18:S447. CENTRAL

Fleischhacker 2008b {published data only}

Fleischhacker WW, Heikkinen ME, Olie JP, Landsberg W, Dewaele P, McQuade R, et al. Weight change on aripiprazole‐clozapine combination in schizophrenic patients with weight gain and suboptimal response on clozapine: 16‐week double‐blind study. European Psychiatry 2008;23:S114‐5. CENTRAL

Freudenreich 2009 {published data only}

Freudenreich O. Risperidone added to clozapine for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Gerlach 1978 {published data only}

Gerlach J, Simmelsgaard H. Tardive dyskinesia during and following treatment with haloperidol, haloperidol + biperiden, thioridazine, and clozapine. Psychopharmacology 1978;59(2):105‐12. CENTRAL

Glick 2004 {published data only}

Glick ID, Zaninelli R, Hsu C, Young FK, Weiss L, Gunay I, et al. Patterns of concomitant psychotropic medication use during a 2‐year study comparing clozapine and olanzapine for the prevention of suicidal behavior. Journal of Clinical Psychiatry 2004;65(5):679‐85. CENTRAL

Goff 1996 {published data only}

Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT. D‐cycloserine added to clozapine for patients with schizophrenia. American Journal of Psychiatry 1996;153(12):1628‐30. CENTRAL

Goff 2009 {published data only}

Goff D. CX516 for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Gunduz‐Bruce 2009 {published data only}

Gunduz‐Bruce H. Pimozide for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Haro 2009 {published data only}

Haro J. Amisulpride and quetiapine for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

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Hebrani P, Behdani F, Rafiee A. Adjunctive topiramate in hospitalized patients with chronic schizophrenia disorder. European Neuropsychopharmacology 2008;18:S466. CENTRAL

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Henderson D. Rosiglitazone for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Honer 2006 {published data only}

Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. New England Journal of Medicine 2006;354(5):472‐82. CENTRAL

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Honer W. A randomized controlled trial of antipsychotic polypharmacy: clozapine plus risperidone. European Neuropsychopharmacology 2007;17(Suppl 4):S200. CENTRAL

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Honigfeld G, Patin J. Predictors of response to clozapine therapy. Psychopharmacology 1989;99:64‐7. [MEDLINE: 1990047435]CENTRAL

Ji 2005 {published data only}

Ji XW. Serum Level of Homocysteine in Patients with Schizophrenia [Masters thesis]. Shandong University (China), 2005. CENTRAL

Josiassen 2003 {published data only}

Josiassen R, Joseph A, Kohegyi E, Paing W. Clozapine augmentation with risperidone in refractory schizophrenia. Schizophrenia Research 2003;60:288. CENTRAL

Klieser 1993 {published data only}

Klieser E, Strauss WH. Quasi‐experimental comparison of the efficacy of classical and atypical neuroleptics in acute schizophrenia with respect to their cognitive and emotional side effects. Pharmacopsychiatry 1993;26:168. CENTRAL

Kluge 2007 {published data only}

Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, et al. Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double‐blind study. Journal of Clinical Psychopharmacology 2007;27(6):662‐6. [MEDLINE: 18004133]CENTRAL

Li 2004 {published data only}

Li YC, Chang HR, Li CS. Control study of loxapine succinate and clozapine on curative effects in treatment of schizophrenics. Health Psychology Journal 2004;3:202. CENTRAL

Liu 2008 {published data only}

刘友夺, 黄文芳, 黄时金. Fluphenazine decanoate combined clozapine treatment of refractory schizophrenia [氯氮平合癸氟奋乃静治疗难治性精神分裂症对照研究]. Medical Journal of Chinese People's Health 2008;20(12):1274. CENTRAL

Ma 2007 {published data only}

Ma Q, Lian HT, Li LX. A study of aripiprazole combined with clozapine in refractory schizophrenia. Medical Journal of Chinese People's Health 2007;19(12):1046‐8. CENTRAL

Marder 1998 {published data only}

Marder SR. Antipsychotics in treatment‐refractory schizophrenia. In: Marder SR, chairperson. Atypical antipsychotic agents in the treatment of schizophrenia and other psychotic disorders. I. Unique patient populations. Journal of Clinical Psychiatry 1998;59:259‐65. [MEDLINE: 1998293803]CENTRAL

Meltzer 1999 {published data only}

Meltzer HY. Risperidone and clozapine for treatment‐resistant schizophrenia. American Journal of Psychiatry 1999;156(7):1126‐7. CENTRAL

Millar 2008 {published data only}

Millar H, Felter C, Landsberg W. The effects of aripiprazole in combination with clozapine: patient functioning results from a double‐blind, 16‐week study in patients with schizophrenia (CN138‐170). Journal of Psychopharmacology 2008;22(5):A17. CENTRAL

Nair 1998 {published data only}

Nair CJ, Abraham G, Stanilla JK, Tracy JI, de Leon J, Simpson GM, et al. Therapeutic effects of clozapine on tardive dyskinesia. Cognitive and Behavioral Practice 1998;1:123‐31. CENTRAL

NCT00628420 {published data only}

NCT00628420. Safety study of ACP‐104: to demonstrate the safety, tolerability, and pharmacokinetics. www.clinicaltrials.gov/show/NCT00628420 Date first received: 24 February 2008. CENTRAL

NCT00649844 {published data only}

NCT00649844. A study comparing the efficacy and tolerability of ziprasidone vs clozapine for the treatment of schizophrenia in patients who continue to have symptoms on or cannot tolerate other antipsychotic drugs. www.clinicaltrials.gov/show/NCT00649844 Date first received: 28 March 2008. CENTRAL

NCT00654576 {published data only}

NCT00654576. Effectiveness of antipsychotic combination with psychosocial intervention on outcome of patients with schizophrenia. www.clinicaltrials.gov/show/NCT00654576 Date first received: 3 April 2008. CENTRAL

NCT00753051 {published data only}

NCT00753051. Treat clozapine‐resistant schizophrenia comparing between clozapine + haloperidol versus clozapine + electroconvulsive therapy (ECT). www.clinicaltrials.gov/show/NCT00753051 Date first received: 15 September 2008. CENTRAL

Petit 1996 {published data only}

Petit M, Raniwalla J, Tweed J, Leutenegger E, Dollfus S, Kelly F. A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel‐group double‐blind trial. Psychopharmacology Bulletin 1996;32(1):81‐7. CENTRAL

Pickar 1994 {published data only}

Pickar D, Litman RE, Hong WW, Su TP, Weissman EM, Hsiao JK, et al. Clinical response to clozapine in patients with schizophrenia. Archives of General Psychiatry 1994;51(2):159‐60. CENTRAL

Potkin 1999 {published data only}

Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B. Effect of clozapine and adjunctive high‐dose glycine in treatment‐resistant schizophrenia. American Journal of Psychiatry 1999;156(1):145‐7. CENTRAL

Potter 1989 {published data only}

Potter WZ, Ko GN, Zhang LD, Yan WW. Clozapine in China: a review and preview of US/PRC collaboration. Psychopharmacology 1989;99 Suppl:S87‐91. [MEDLINE: 7608025]CENTRAL

Qi 1990 {published data only}

Qi SX. Clozapine therapy in schizophrenia. Chinese Journal of Nervous and Mental Disorders 1990;16(2):90‐2. CENTRAL

Remington 2009 {published data only}

Remington G. Tetrabenazine for schizophrenia. Stanley Foundation Research Programs2009. CENTRAL

Riera 2004a {published data only}

Riera L, Tandon R, Stock EG, Kujawa MJ, Torbeyns AF, Borian FE, et al. Broad effectiveness trial with aripiprazole. 12th Biennial Winter Workshop on Schizophrenia; 2004 Feb 7‐13; Davos, Switzerland. 2004. CENTRAL

Riera 2004b {published data only}

Riera L, Hu R, Stock E, Nyilas M, Torbeyns A, Borian F, et al. Broad effectiveness trial with aripiprazole. 157th Annual Meeting of the American Psychiatric Association; 2004 May 1‐6; New York, USA. 2004. CENTRAL

Ruan 2008 {published data only}

Ruan S, Zheng W, Du L. A control study of clozapine plus fluoxetine in schizophrenia with depressive symptoms. Journal of Clinical Psychosomatic Diseases 2008;14(3):211‐3. CENTRAL

Shen 2004 {published data only}

Shen J, Feng Z, Guo J, Wang W, Wang Z. Comparative study on therapy of schizophrenia with quetiapine and clozapine. Tianjin Pharmacy 2004;16(1):38‐9. CENTRAL

Shun 2000 {published data only}

Shun ZJ, Liu BW, Yu FP, Li ZL, Jiang DF, Zhang DQ. A comparison trial of clozapine combined with perphenazine and single clozapine or perphenazine in treatment of schizophrenia. Journal of Hebei Psychological Health 2000;3:142‐4. CENTRAL

Sihloh 1997 {published data only}

Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman‐Etrog P, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double‐blind, placebo‐controlled study. British Journal of Psychiatry 1997;171:569‐73. CENTRAL

Small 2003 {published data only}

Small JG, Klapper MH, Malloy FW, Steadman TM. Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. Journal of Clinical Psychopharmacology 2003;23(3):223‐8. CENTRAL

Stryjer 2004 {published data only}

Stryjer R, Strous R, Bar F, Shaked G, Shiloh R, Rozencwaig S, et al. Donepezil augmentation of clozapine monotherapy in schizophrenia patients: a double blind cross‐over study. Human Psychopharmacology 2004;19(5):343‐6. CENTRAL

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Uzun S, Kozumplik O, Mimica N, Folnegovic‐Smalc V. Treatment with six different antipsychotics: evaluation by scale for the assessment of negative symptoms (SANS). 13th Biennial Winter Workshop on Schizophrenia Research; 2006 Feb 4‐10; Davos, Switzerland. 2006. CENTRAL

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Volavka J, Nolan KA, Kline L, Czobor P, Citrome L, Sheitman B, et al. Efficacy of clozapine, olanzapine, risperidone, and haloperidol in schizophrenia and schizoaffective disorder assessed with nurses observation scale for inpatient evaluation. Schizophrenia Research 2005;76(1):127‐9. CENTRAL

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万好, 李玉芳, 李军, 崔谊. Olanzapine on efficacy in patients with late‐onset schizophrenia and quality of life [奥氮平对晚发精神分裂症患者的疗效及生活质量影响]. 中国医疗前沿 2007;2(23):81‐2. CENTRAL

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Xu 2008 {published data only}

徐儒瑾, 万学东, 杜春秀, 吴乐平. Joint clozapine risperidone treatment of refractory schizophrenia [利培酮联合氯氮平治疗难治性精神分裂症]. 中国现代药物应用 2008;2(16):78. CENTRAL

Xue 2014 {published data only}

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Yagcioglu 2005 {published data only}

Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, et al. A double‐blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. Journal of Clinical Psychiatry 2005;66(1):63‐72. CENTRAL

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Yang X, Hang YL, Jia WLQ, Wei LM. Clozapine combined with chlorpromazine in the treatment of positive symptoms in schizophrenia. Shanghai Psychological Medicine 1994;6(2):71‐2. CENTRAL

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张仁凯, 王建利, 付学凯, 张春鹏. 60 patients with schizophrenia negative symptoms combined application of clozapine and clozapine compared the efficacy of paroxetine [60例精神分裂症的阴性症状应用氯氮平和氯氮平合并帕罗西汀的疗效比较]. Journal of Qiqihar Medical College [Qiqihar Yixueyuan xuebao] 2008;29(14):1709. CENTRAL

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郑景莉, 王保国, 付爱玲, 李蓓. Quetiapine combined clozapine in the treatment of negative symptoms of schizophrenia [奎硫平联合氯氮平治疗精神分裂症阴性症状对照研究]. Medical Recapitulate 2007;13(23):1878‐9. CENTRAL

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Nosè 2009

Nosè M, Accordini S, Artioli P, Barale F, Barbui C, Beneduce R, et al. Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment‐resistant schizophrenia. Trials 2009;15(10):31.

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Referencias de otras versiones publicadas de esta revisión

Cipriani 2009

Cipriani A, Boso M, Barbui C. Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD006324.pub2; PUBMED: 19588385]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Cipriani 2013a

Methods

Allocation: randomised (using centralised randomisation procedure), allocation concealed.

Blinding: open‐label (participants and clinicians not blind to treatment, assessors for rating scales blind).

Duration: 52 weeks.

Design: multicentre, naturalistic, parallel.

Setting: inpatients and outpatients.

Country: Italy.

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 106.

Age: mean 41.5 years in haloperidol group, 40.3 years in aripiprazole group.

Sex: 32% female in haloperidol group, 37% female in aripiprazole group.

History: partial response to clozapine after at least 6 months of treatment stable dose, mean disease duration 18 years in haloperidol group, 14 years in aripiprazole group.

Interventions

1. Clozapine + haloperidol: clozapine mean baseline dose = 413 mg/day (SD 157) and haloperidol mean baseline dose = 2.1 mg/day (SD 1.3). N = 53.

2. Clozapine + aripiprazole: clozapine mean baseline dose = 418 mg/day (SD 141) and aripiprazole mean baseline dose = 8.7 mg/day (SD 3.9). N = 53.

Outcomes

Mental state: change in BPRS score from baseline.

Leaving the study early.

Adverse effects: change in LUNSERS score from baseline.

Notes

Underpowered: target sample size 216, total recruited 106.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants randomised (quote) "using a computer generated random number program."

Allocation concealment (selection bias)

Low risk

Quote: "A randomisation procedure by telephone was used to keep treatment allocation concealed."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "...the patients and clinicians were not blind to pharmacological treatments."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "...all outcome assessments based on rating scales were performed by trained assessors masked to the allocated treatment."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All randomised participants who received at least 1 dose of investigation drugs were included in the intention‐to‐treat analysis of the primary outcome (leaving the study early). Only 1 patient was not included in the analysis of the BPRS and LUNSERS continuous outcomes due to missing data.

Selective reporting (reporting bias)

Low risk

All outcomes expected and specified in the protocol were reported.

Other bias

Low risk

We found no other bias.

Genç 2007

Methods

Allocation: unclear.

Blindness: unclear.

Duration: 8 weeks.

Design: multicentre, parallel.

Setting: inpatients and outpatients.

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 56.

Age: mean 37.29 years in amisulpride group, mean "7.30" in quetiapine group, likely misreported as no significant difference between groups.

Sex: 55.6% female in amisulpride group, 60.9% female in quetiapine group.

History: partial response to clozapine after 12 weeks' treatment at stable dose, demonstrated by BPRS total > 45.

Interventions

1. Clozapine plus amisulpride: clozapine mean baseline dose 550 mg/day (SD 127.09) and amisulpride mean baseline dose 437.03 mg/day (SD 104.32). N = 27.

2. Clozapine plus quetiapine: clozapine mean baseline dose 536.95 mg/day (SD 125.42) and quetiapine mean baseline dose 595.65 mg/day (SD 125.21). N = 23.

Outcomes

Clinical response: global state (CGI), mental state (BPRS, SAPS, SANS).

Leaving the study early.

Unable to use:

Extrapyramidal adverse effect: UKU, SAS (no mean endpoint scores).

Notes

Baseline characteristics reported after participants left early.

8‐week rating scale scores estimated from graph by two review authors (SB and SD) calculated from t score of difference in means.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "patients were randomly assigned...". Probably done.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was not mentioned.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information on blindness of participants given.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessor blinded. Quote: "The first author, who was the rater remained blind throughout the study."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

5 participants in the quetiapine group dropped out and 1 participant in the amisulpride group was missed at follow‐up at 2 weeks. These 6 participants were excluded from the analysis and from the reporting of baseline characteristics. There was no significant difference between groups, but this does not confirm the absence of bias, especially because this was a small study (N = 56). Moreover, reasons for incomplete data were not balanced between groups.

Selective reporting (reporting bias)

High risk

No protocol available, no SDs given for various scales (BPRS, SAPS, SANS, CGI).

Other bias

Unclear risk

We could not rule out the potential for other bias.

Kong 2001

Methods

Allocation: unclear.

Blindness: unclear.

Duration: 8 weeks.

Design: multicentre.

Setting: inpatients.

Participants

Diagnosis: schizophrenia (CCMD‐2‐R)*.

N = 60.

Age: < 42 years.

Sex: 38 male and 22 female.

History: partial response to clozapine, but criteria not clearly specified.

Interventions

1. Clozapine plus risperidone: clozapine mean dose 400 mg/day and risperidone mean dose 4 mg/day to 6 mg/day. SDs not provided. N = 30.

2. Clozapine plus sulpiride: clozapine mean dose 500 mg/day and sulpiride mean dose 800 mg/day to 1200 mg/day. SDs not provided. N = 30.

Outcomes

Clinically significant response: 20% to 50% reduction PANSS total.

Clinical response: mental state (PANSS total, PANSS positive, PANSS negative).

Adverse effects: weight gain, hypersalivation.

Leaving the study early.

Unable to use:

Adverse effects: TESS score.

Notes

*It is unclear whether patients with schizoaffective disorder were enrolled.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Insufficient information.

Allocation concealment (selection bias)

Unclear risk

Insufficient information. Allocation done by hospital number so possibly not concealed.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No one left early.

Selective reporting (reporting bias)

Unclear risk

No protocol available.

Other bias

Unclear risk

We could not rule out the potential for other bias.

Kuwilsky 2010

Methods

Allocation: randomised (by random number generator).

Blindness: open label.

Duration: 52 weeks.

Design: multicentre, naturalistic, parallel.

Setting: inpatients and outpatients.

Country: Germany.

Participants

Diagnosis: schizophrenia or schizoaffective disorder (DSM‐IV).

N = 24.

Age: mean 31.8 years in risperidone group, 37.25 years in ziprasidone group.

Sex: 41.7% female in risperidone group, 41.7% female in ziprasidone group.

History: partial response to clozapine after at least 3 months with stable dose as demonstrated by PANSS total score > 65.

Interventions

1. Clozapine plus risperidone: clozapine mean dose 437.5 mg/day (SD 140.4) and risperidone mean dose 3.82 mg/day (SD 1.8). N = 12.

2. Clozapine plus ziprasidone: clozapine mean dose 370.8 mg/day (SD 150.0) and ziprasidone mean dose 134 mg/day (SD 34.4). N = 12.

Outcomes

Clinically significant response: 20% reduction PANSS.

Clinical response global state (CGI subscales, GAF), mental state (PANSS total, PANSS positive, PANSS negative, PANS global psychopathology, SANS, HAMD).

Leaving the study early.

Adverse effects: EPS, CGI adverse effects.

Unable to use:

Global state: CGI and GAF (26 and 52 weeks) (no SDs reported).

Adverse effects: HAS (data from figure not extractable).

Notes

Dichotomous outcomes available from text.

Baseline rating scores provided in table with SDs. 6‐week, 26‐week, and 52‐week scores and SDs estimated from graphs by 1 review author (SB).

Baseline and 6‐week CGI and GAF score provided in table with SDs. No SDs for 26‐week or 52‐week scores.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "...the patients were randomized...using a random number generator."

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not mentioned.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "open label"; "antipsychotics were applied in an open manner."

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No mention of blinded assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

> 50% of participants had dropped out by 52 weeks and there was no intention‐to‐treat analysis.

Selective reporting (reporting bias)

High risk

The study protocol was available but not all of the study's prespecified (primary and secondary) outcomes that were of interest in the review were reported in the prespecified way. There were no SDs reported for some outcomes.

Other bias

Unclear risk

We could not rule out the potential for other bias.

Wen 2015

Methods

Allocation: randomised (no detailed information).

Blindness: single blind.

Duration: 12 weeks.

Design: multicentre, parallel.

Setting: inpatients and outpatients.

Country: China.

Participants

Diagnosis: schizophrenia (DSM‐IV).

N = 63.

Age: mean age 37.1 years.

Sex: 43% female.

History: treatment with clozapine for > 12 weeks at a dose > 400 mg with no improvement observed, PANSS score ≥ 80 and CGI‐S ≥ 4.

Interventions

1. Clozapine plus ziprasidone: clozapine mean baseline dose = 479 mg/day (SD 56.5), ziprasidone was titrated from 80 mg/day up to 120 mg/day to 160 mg/day, 1 week after ziprasidone was added, the dose of clozapine was reduced accordingly. N = 31.

2. Clozapine plus quetiapine: clozapine mean baseline dose = 481.3 mg/day (SD 51.7), quetiapine was titrated from 200 mg/day up to 400 mg/day to 750 mg/day, 1 week after quetiapine was added, the dose of clozapine was reduced accordingly. N = 32.

Outcomes

Clinically significant response: > 50% reduction PANSS.

Clinical response: global state (CGI‐S), mental state (PANSS total, PANSS positive, PANSS negative).

Adverse effects: rate, agitation, constipation, drowsiness, dry mouth, extrapyramidal adverse effects, headache, insomnia, orthostatic hypotension, tachycardia, vertigo.

Leaving the study early.

Notes

Chinese language.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation was performed, no detailed information provided.

Allocation concealment (selection bias)

Unclear risk

No data.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Described as single blind.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The participants were evaluated by 3 doctors who did not have knowledge about the treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 participants who dropped out were excluded from the analyses of global and mental state outcomes, but included in the analyses of adverse events. Since the attrition rate was < 5%, and reasons were balanced between groups, the study was rated as low risk.

Selective reporting (reporting bias)

Unclear risk

No protocol available.

Other bias

Unclear risk

We could not rule out the potential for other bias.

General

n: number of participants

SD: standard deviation

Diagnostic tools

CCDM‐2‐R: Chinese Classification of Mental disorders

DSM‐IV: Diagnostic and Statistical Manual of mental disorders, fourth edition

Global effects scales

CGI: Clinical Global Impression

CGI‐S: Clinical Global Impression ‐ Severity

GAF: Global assessment of functioning

Mental state scales

BPRS: Brief Psychiatric Rating Scale

HAMD: Hamilton Depression Scale

PANSS: Positive and Negative Syndrome Scale

SANS: Scale for the Assessment of Negative Symptoms

SAPS: Scale for the Assessment of Positive Symptoms

Adverse effect scales

EPS: Extrapyramidal Symptoms Scale

HAS: Hillside Akathisia Scale

LUNSERS: Liverpool University Neuroleptic Side Effect Rating Scale

SAS: Simpson‐Angus Extrapyramidal Symptoms Rating Scale

TESS: Treatment Emergent Symptom Scale

UKU: Udvalg for Kliniske Undersgelser Side Effect Rating Scale

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Angst 1971

Allocation: randomised.

Participants: people with schizophrenia and manic psychoses.

Intervention: no combination treatment ‐ levomepromazine vs clozapine.

Anil 2009

Allocation: randomised, double‐blind.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ risperidone + clozapine vs placebo + clozapine.

Anonymous 2009

Allocation: non‐randomised (handbook written for the CUTLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) trial).

Assion 2008

Allocation: randomised, double‐blind.

Participants: people with treatment‐resistant schizophrenia partially responsive or unresponsive to clozapine.

Intervention: no active comparison with combination treatment ‐ amisulpride + clozapine vs clozapine + placebo.

Bao 1988

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment resistant.

Barnes 2013

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia enrolled in 2 separate trials.

Intervention: no combination treatment ‐ oral first‐generation antipsychotic drug vs non‐clozapine second‐generation antipsychotic drug or non‐clozapine second‐generation antipsychotic drug vs clozapine.

Bender 1997

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ trimipramine vs perazine.

Bilder 2001

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ clozapine vs olanzapine vs risperidone vs haloperidol.

Bustillo 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ lamotrigine vs placebo.

Cao 2003

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ risperidone vs clozapine.

Chang 2008

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + aripiprazole vs clozapine + placebo.

Cooper 2005

Allocation: non‐randomised (population‐based study).

Dai 2014

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with other clozapine combination treatment ‐ clozapine + ziprasidone vs ziprasidone + risperidone.

Daniel 1994

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ risperidone vs clozapine.

Dong 2007

Allocation: randomised.

Participants: people with first‐episode of schizophrenia, not treatment‐resistant.

Feifel 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison to combination treatment ‐ antipsychotic + oxytocin vs antipsychotic + placebo (cross‐over design).

Fleischhacker 2008a

Allocation: randomised.

Participants: people with schizophrenia and suboptimal efficacy/safety on clozapine.

Intervention: no comparison with combination treatment ‐ clozapine + aripiprazole vs clozapine.

Fleischhacker 2008b

Allocation: randomised.

Participants: people with schizophrenia and suboptimal efficacy/safety on clozapine.

Intervention: no comparison with combination treatment ‐ clozapine + aripiprazole vs clozapine.

Freudenreich 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: placebo controlled trial ‐ clozapine + risperidone vs clozapine + placebo.

Gerlach 1978

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no clozapine combination treatment ‐ haloperidol vs haloperidol + biperiden vs thioridazine vs clozapine.

Glick 2004

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no randomisation to combination treatments ‐ clozapine vs olanzapine with uncontrolled use of concomitant psychotropic medications in both groups.

Goff 1996

Allocation: randomised.

Participants: people with schizophrenia receiving clozapine, not defined as treatment‐resistant.

Goff 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: placebo controlled trial ‐ CX516 + clozapine vs placebo.

Gunduz‐Bruce 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + pimozide vs clozapine + placebo.

Haro 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with clozapine combination treatment ‐ amisulpride + quetiapine vs clozapine.

Hebrani 2008

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + topiramate vs clozapine + placebo.

Henderson 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + rosiglitazone vs clozapine + placebo.

Honer 2006

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + risperidone vs clozapine + placebo.

Honer 2007

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + risperidone vs clozapine + placebo.

Honigfeld 1989

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ non‐responders to haloperidol assigned to clozapine vs chlorpromazine.

Ji 2005

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ chlorpromazine vs clozapine.

Josiassen 2003

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + risperidone vs clozapine + placebo.

Klieser 1993

Allocation: non‐randomised (quasi‐experimental).

Kluge 2007

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment resistant.

Li 2004

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ loxapine vs clozapine.

Liu 2008

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with combination treatment ‐ clozapine + fluphenazine decanoate vs clozapine.

Ma 2007

Allocation: randomised, double‐blind.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with combination treatment ‐ aripiprazole + clozapine vs clozapine.

Marder 1998

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ haloperidol vs clozapine.

Meltzer 1999

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ risperidone vs clozapine.

Millar 2008

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with active combination treatment ‐ clozapine + aripiprazole vs clozapine + placebo.

Nair 1998

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ clozapine 100 mg vs clozapine 300 mg vs clozapine 600 mg.

NCT00628420

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ N‐desmethylclozapine vs placebo.

NCT00649844

Allocation: randomised, double‐blind.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ ziprasidone vs clozapine.

NCT00654576

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no drug combination treatment ‐ antipsychotic vs antipsychotic + psychosocial intervention.

NCT00753051

Allocation: randomised, double‐blind.

Participants: people with treatment‐resistant schizophrenia partially responsive or unresponsive to clozapine.

Intervention: no comparison with drug combination treatment ‐ haloperidol + clozapine vs electroconvulsive therapy + clozapine.

Petit 1996

Allocation: randomised.

Participants: people with acute exacerbation of schizophrenia.

Pickar 1994

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Potkin 1999

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + glycine vs clozapine + placebo.

Potter 1989

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ chlorpromazine vs clozapine.

Qi 1990

Allocation: non‐randomised (review).

Remington 2009

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + tetrabenazine vs clozapine + placebo.

Riera 2004a

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ aripiprazole vs another antipsychotic medication.

Riera 2004b

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ aripiprazole vs another antipsychotic medication.

Ruan 2008

Allocation: randomised.

Participants: people with schizophrenia and depression.

Shen 2004

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Shun 2000

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Sihloh 1997

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + sulpiride vs clozapine + placebo.

Small 2003

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Stryjer 2004

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Uzun 2006

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Volavka 2005

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ clozapine vs olanzapine vs risperidone vs haloperidol.

Wan 2007

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ olanzapine vs clozapine.

Wang 2002

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ risperidone vs clozapine.

Welbel 1980

Allocation: non‐randomised (review).

Xu 2008

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no comparison with combination treatment ‐ clozapine + risperidone vs clozapine.

Xue 2014

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Yagcioglu 2005

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + risperidone vs clozapine + placebo.

Yang 1994

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Zhang 2008a

Allocation: randomised.

Participants: people with negative symptoms of schizophrenia.

Intervention: no combination treatment ‐ clozapine + paroxetine vs clozapine.

Zhang 2008b

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + paroxetine vs clozapine + placebo.

Zhang 2013

Allocation: randomised.

Participants: people with no use of antipsychotic medication 2 weeks prior to hospitalisation ‐ not taking clozapine.

Zheng 2007

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no combination treatment ‐ quetiapine vs clozapine.

Zhu 1999

Allocation: randomised.

Participants: people with schizophrenia but not defined as treatment‐resistant.

Zhu 2002

Allocation: randomised.

Participants: people with treatment‐resistant schizophrenia.

Intervention: no active comparison with combination treatment ‐ clozapine + pipotiazine palmitate vs clozapine + placebo.

Data and analyses

Open in table viewer
Comparison 1. CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good).

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good).

1.1 Medium term (12 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐1.40 [‐5.59, 2.79]

1.2 Medium term (24 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐4.81, 3.41]

1.3 Long term (52 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

0.90 [‐4.38, 6.18]

2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor).

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor).

2.1 Medium term (12 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.9 [‐8.48, ‐1.32]

2.2 Medium term (24 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.9 [‐8.25, ‐1.55]

2.3 Long term (52 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.8 [‐9.79, 0.19]

3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

3.1 Medium term (12 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.34, 2.24]

3.2 Medium term (24 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.60, 2.28]

3.3 Long term (52 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.72, 2.22]

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Comparison 2. CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.1

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor).

1.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐0.90 [‐1.38, ‐0.42]

2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.2

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor).

2.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐5.86, ‐2.14]

3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.3

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor).

3.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐6.90 [‐12.82, ‐0.98]

4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 2.4

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor).

4.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐5.20 [‐7.14, ‐3.26]

5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

56

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.02, 1.60]

Analysis 2.5

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

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Comparison 3. CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.1

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score.

1.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.40, 1.68]

2 Adverse effect: weight gain Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.2

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 2 Adverse effect: weight gain.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 2 Adverse effect: weight gain.

2.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.08, 1.90]

3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 3.3

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor).

3.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐2.28 [‐7.41, 2.85]

4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 3.4

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor).

4.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐2.55 [‐4.64, ‐0.46]

5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 3.5

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor).

5.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐3.19, 2.11]

6 Adverse effects: specific adverse effects: hypersalivation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.6

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 6 Adverse effects: specific adverse effects: hypersalivation.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 6 Adverse effects: specific adverse effects: hypersalivation.

6.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.03]

7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 3.7

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

7.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

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Comparison 4. CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 4.1

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score.

1.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.13, 3.30]

1.2 Medium term (26 weeks)

1

24

Risk Ratio (M‐H, Fixed, 95% CI)

0.8 [0.28, 2.27]

2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 4.2

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore.

2.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.36, 24.92]

3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.3

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor).

3.1 Severity of illness

1

22

Mean Difference (IV, Random, 95% CI)

0.20 [‐0.32, 0.72]

3.2 Global improvement

1

22

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.82, 0.22]

3.3 Therapeutic efficacy

1

22

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.79, 0.19]

4 Clinical response: 1b mean score/change global state: mean GAF score (high = good) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.4

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 4 Clinical response: 1b mean score/change global state: mean GAF score (high = good).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 4 Clinical response: 1b mean score/change global state: mean GAF score (high = good).

4.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

0.0 [‐7.84, 7.84]

5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.5

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor).

5.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐3.40 [‐6.71, ‐0.09]

5.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐5.35, 3.95]

6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.6

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor).

6.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐3.10 [‐11.38, 5.18]

6.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.0 [‐7.91, 9.91]

7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.7

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor).

7.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.84, 1.44]

7.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐2.58, 2.18]

8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.8

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor).

8.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐4.63, 2.23]

8.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.5 [‐2.66, 5.66]

9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.9

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor).

9.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐17.55, 9.55]

9.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.80 [‐14.31, 17.91]

10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.10

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor).

10.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐1.60 [‐6.60, 3.40]

10.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

0.0 [‐5.83, 5.83]

11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.11

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor).

11.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

0.60 [‐0.67, 1.87]

11.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

0.30 [‐0.63, 1.23]

12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 4.12

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor).

12.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.53, 0.33]

13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 4.13

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

13.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.21]

13.2 Medium term (26 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.6 [0.18, 1.97]

13.3 Long term (52 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.6 [0.73, 3.49]

Open in table viewer
Comparison 5. CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50% Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.1

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50%.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50%.

1.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.35, 0.81]

2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25% Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.2

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25%.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25%.

2.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.38, 1.10]

3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 5.3

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor).

3.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐1.18, ‐0.22]

4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 5.4

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor).

4.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐12.30 [‐22.43, ‐2.17]

5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 5.5

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor).

5.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐3.10 [‐5.52, ‐0.68]

6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Analysis 5.6

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor).

6.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

0.80 [‐1.99, 3.59]

7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.7

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects.

7.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

2.06 [0.41, 10.47]

8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.8

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate.

8.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.50, 1.13]

9 Adverse effects: other adverse effects (general or specific): agitation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.9

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 9 Adverse effects: other adverse effects (general or specific): agitation.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 9 Adverse effects: other adverse effects (general or specific): agitation.

9.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.15, 6.88]

10 Adverse effects: other adverse effects (general or specific): constipation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.10

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 10 Adverse effects: other adverse effects (general or specific): constipation.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 10 Adverse effects: other adverse effects (general or specific): constipation.

10.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.15 [0.01, 2.74]

11 Adverse effects: other adverse effects (general or specific): drowsiness Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.11

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 11 Adverse effects: other adverse effects (general or specific): drowsiness.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 11 Adverse effects: other adverse effects (general or specific): drowsiness.

11.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.18, 1.19]

12 Adverse effects: other adverse effects (general or specific): dry mouth Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.12

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 12 Adverse effects: other adverse effects (general or specific): dry mouth.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 12 Adverse effects: other adverse effects (general or specific): dry mouth.

12.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.02, 1.35]

13 Adverse effects: other adverse effects (general or specific): headache Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.13

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 13 Adverse effects: other adverse effects (general or specific): headache.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 13 Adverse effects: other adverse effects (general or specific): headache.

13.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.28, 3.77]

14 Adverse effects: other adverse effects (general or specific): insomnia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.14

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 14 Adverse effects: other adverse effects (general or specific): insomnia.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 14 Adverse effects: other adverse effects (general or specific): insomnia.

14.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.12, 3.84]

15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.15

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension.

15.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.01, 4.13]

16 Adverse effects: other adverse effects (general or specific): tachycardia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.16

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 16 Adverse effects: other adverse effects (general or specific): tachycardia.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 16 Adverse effects: other adverse effects (general or specific): tachycardia.

16.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.12, 3.84]

17 Adverse effects: other adverse effects (general or specific): vertigo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Analysis 5.17

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 17 Adverse effects: other adverse effects (general or specific): vertigo.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 17 Adverse effects: other adverse effects (general or specific): vertigo.

17.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.03, 1.67]

18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 5.18

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

18.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.41]

Study flow diagram (2015 update).
Figures and Tables -
Figure 1

Study flow diagram (2015 update).

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figures and Tables -
Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good).
Figures and Tables -
Analysis 1.1

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good).

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor).
Figures and Tables -
Analysis 1.2

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor).

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.
Figures and Tables -
Analysis 1.3

Comparison 1 CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL, Outcome 3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor).
Figures and Tables -
Analysis 2.1

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor).
Figures and Tables -
Analysis 2.2

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor).
Figures and Tables -
Analysis 2.3

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor).
Figures and Tables -
Analysis 2.4

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor).

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.
Figures and Tables -
Analysis 2.5

Comparison 2 CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE, Outcome 5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score.
Figures and Tables -
Analysis 3.1

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 2 Adverse effect: weight gain.
Figures and Tables -
Analysis 3.2

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 2 Adverse effect: weight gain.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor).
Figures and Tables -
Analysis 3.3

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor).
Figures and Tables -
Analysis 3.4

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor).
Figures and Tables -
Analysis 3.5

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor).

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 6 Adverse effects: specific adverse effects: hypersalivation.
Figures and Tables -
Analysis 3.6

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 6 Adverse effects: specific adverse effects: hypersalivation.

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.
Figures and Tables -
Analysis 3.7

Comparison 3 CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE, Outcome 7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score.
Figures and Tables -
Analysis 4.1

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore.
Figures and Tables -
Analysis 4.2

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore.

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor).
Figures and Tables -
Analysis 4.3

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 4 Clinical response: 1b mean score/change global state: mean GAF score (high = good).
Figures and Tables -
Analysis 4.4

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 4 Clinical response: 1b mean score/change global state: mean GAF score (high = good).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor).
Figures and Tables -
Analysis 4.5

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor).
Figures and Tables -
Analysis 4.6

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor).
Figures and Tables -
Analysis 4.7

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor).
Figures and Tables -
Analysis 4.8

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor).
Figures and Tables -
Analysis 4.9

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor).
Figures and Tables -
Analysis 4.10

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor).
Figures and Tables -
Analysis 4.11

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor).
Figures and Tables -
Analysis 4.12

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor).

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.
Figures and Tables -
Analysis 4.13

Comparison 4 CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE, Outcome 13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50%.
Figures and Tables -
Analysis 5.1

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50%.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25%.
Figures and Tables -
Analysis 5.2

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25%.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor).
Figures and Tables -
Analysis 5.3

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor).
Figures and Tables -
Analysis 5.4

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor).
Figures and Tables -
Analysis 5.5

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor).
Figures and Tables -
Analysis 5.6

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor).

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects.
Figures and Tables -
Analysis 5.7

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate.
Figures and Tables -
Analysis 5.8

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 9 Adverse effects: other adverse effects (general or specific): agitation.
Figures and Tables -
Analysis 5.9

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 9 Adverse effects: other adverse effects (general or specific): agitation.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 10 Adverse effects: other adverse effects (general or specific): constipation.
Figures and Tables -
Analysis 5.10

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 10 Adverse effects: other adverse effects (general or specific): constipation.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 11 Adverse effects: other adverse effects (general or specific): drowsiness.
Figures and Tables -
Analysis 5.11

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 11 Adverse effects: other adverse effects (general or specific): drowsiness.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 12 Adverse effects: other adverse effects (general or specific): dry mouth.
Figures and Tables -
Analysis 5.12

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 12 Adverse effects: other adverse effects (general or specific): dry mouth.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 13 Adverse effects: other adverse effects (general or specific): headache.
Figures and Tables -
Analysis 5.13

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 13 Adverse effects: other adverse effects (general or specific): headache.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 14 Adverse effects: other adverse effects (general or specific): insomnia.
Figures and Tables -
Analysis 5.14

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 14 Adverse effects: other adverse effects (general or specific): insomnia.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension.
Figures and Tables -
Analysis 5.15

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 16 Adverse effects: other adverse effects (general or specific): tachycardia.
Figures and Tables -
Analysis 5.16

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 16 Adverse effects: other adverse effects (general or specific): tachycardia.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 17 Adverse effects: other adverse effects (general or specific): vertigo.
Figures and Tables -
Analysis 5.17

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 17 Adverse effects: other adverse effects (general or specific): vertigo.

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.
Figures and Tables -
Analysis 5.18

Comparison 5 CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE, Outcome 18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial.

Table 1. Suggested design of study

Methods

Allocation: proper randomisation (e.g. by computer‐generated number sequence) and adequate allocation concealment (e.g. by central randomisation by a third party).

Blinding: ideally double blind, but pragmatically blinding the participant and the outcome assessor is adequate.

Setting: inpatients and outpatients.

Duration: short‐term primary outcome (at 12 weeks), and then medium‐ to long‐term follow‐up (up to 52 week).

Participants

Diagnosis: treatment‐resistant schizophrenia, defined by persistent positive symptoms despite at least 6 months of treatment with clozapine ≥ 400 mg/day.

N = 200.

Sex: men and women.

Age: > 18 years.

Interventions

1. Clozapine plus risperidone (or paliperidone).

2. Clozapine plus aripiprazole (or amisulpride).

Outcomes

Measure of clinical response to include both dichotomous measures of global (e.g. CGI score) and mental state (e.g. BPRS score).

Adverse effects to include weight gain, extrapyramidal symptoms, haematological problems, and hypersalivation.

Acceptability assessed by leaving the study early.

Service utilisation (e.g. hospital admission).

Quality of life/satisfaction measure.

Notes

The study should be funded by an independent funding body, such as the National Institute for Health Research or Wellcome Trust.

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; n: number of participants.

Figures and Tables -
Table 1. Suggested design of study
Summary of findings for the main comparison. CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL (Cipriani 2013)

Clozapine + aripi prazole versus clozapine + haloperidol for treatment‐resistant schizophrenia

Patient or population: people with treatment‐resistant schizophrenia

Setting: inpatients and outpatients

Intervention: aripiprazole (+ CLO)

Comparison: haloperidol (+ CLO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with haloperidol (+ CLO)

Risk with aripiprazole (+ CLO)

Clinical response: no clinically significant response in mental state

See comment

See comment

Not estimable

No data reported.

Adverse effects: weight gain

See comment

See comment

Not estimable

No data reported.

Clinical response: mean score/change in global state

See comment

See comment

No data reported.

Clinical response: mean score/change in mental state: change in BPRS score from baseline (high = good),

Long term (12 months)

The mean score/change in mental state (change in BPRS from baseline) ‐ long term (12 months) was 0

The mean score/change in mental state ‐ defined by change in BPRS from baseline ‐ long term (12 months) in the intervention group was 0.9 more (4.38 fewer to 6.18 more)

105
(1 RCT)

⊕⊕⊝⊝
Low 1,2,3,4

Leaving the study early: acceptability of treatment ‐ as measured by completion of trial

Long term (12 months)

Study population

RR 1.27
(0.72 to 2.22)

106
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,5,6

283 per 1000

359 per 1000
(204 to 628)

Moderate

283 per 1000

359 per 1000
(204 to 628)

Service utilisation outcomes: hospital admission or days in hospital

See comment

See comment

Not estimable

No data reported.

Quality of life/satisfaction with care for either recipients of care or carers: significant change in quality of life/satisfaction

See comment

See comment

Not estimable

No data reported.

*The risk in the intervention group (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).

BPRS: Brief Psychiatric Rating Scale; CI: confidence interval; CLO: clozapine; RCT: randomised controlled trial; RR: risk ratio.

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

1 Risk of bias: downgraded by 1 level because high risk for performance bias (open label), but low risk for other biases (selection, detection, attrition, reporting).

2 Inconsistency and publication bias: not applicable (no meta‐analysis).

3 Indirectness: not downgraded because good applicability in terms of participants and interventions and rating scale measures participant‐important outcome (mental state).

4 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because CI around mean difference did not include appreciable benefit and appreciable harm (total score on BPRS = 126).

5 Indirectness: downgraded by 1 level because leaving the study early a surrogate measure of acceptability of treatment.

6 Imprecision: downgraded by 2 level because underpowered to detect difference and CI around relative effect included appreciable benefit and harm (from less likely to leave study early to over two times more likely to leave study early).

Figures and Tables -
Summary of findings for the main comparison. CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL (Cipriani 2013)
Summary of findings 2. CLOZAPINE + AMISULPIRIDE versus CLOZAPINE + QUETIAPINE (Genc 2007)

Clozapine + amisulpride versus clozapine + quetiapine for treatment‐resistant schizophrenia

Patient or population: people with treatment‐resistant schizophrenia

Setting: inpatients and outpatients

Intervention: amisulpride (+ CLO)

Comparison: quetiapine (+ CLO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with quetiapine (+ CLO)

Risk with amisulpride (+ CLO)

Clinical response: no clinically significant response in mental state

See comment

See comment

Not estimable

(1 RCT)

No data reported.

Adverse effects: weight gain

See comment

See comment

Not estimable

(1 RCT)

No data reported.

Clinical response: mean score/change in global state: mean CGI score (high = poor)

Short term (8 weeks)

The mean score/change in global state (CGI) ‐ short term (8 weeks) was 0

The mean score/change in global state (CGI) ‐ short term (8 weeks) in the intervention group was 0.9 fewer (1.38 fewer to 0.42 fewer)

50
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,3,4

Clinical response: mean score/change in mental state: mean BPRS score (high = poor)

Short term (8 weeks)

The mean score/change in mental state (BPRS) ‐ short term (8 weeks) was 0

The mean score/change in mental state (BPRS) ‐ short term (8 weeks) in the intervention group was 4 fewer (5.86 fewer to 2.14 fewer)

50
(1 RCT)

⊕⊕⊝⊝
Low 1,2,4,5,6

Leaving the study early: acceptability of treatment ‐ as measured by completion of trial

Study population

RR 0.20
(0.02 to 1.60)

56
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,4,7

179 per 1000

36 per 1000
(4 to 286)

Moderate

179 per 1000

36 per 1000
(4 to 286)

Service utilisation outcomes: hospital admission or days in hospital

See comment

See comment

Not estimable

(1 RCT)

No data reported.

Quality of life/satisfaction with care for either recipients of care or carers: significant change in quality of life/satisfaction

See comment

See comment

Not estimable

(1 RCT)

No data reported.

*The risk in the intervention group (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).

BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; CI: confidence interval; CLO: clozapine; RCT: randomised controlled trial; RR: risk ratio.

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

1 Risk of bias: downgraded by 2 levels because high risk of reporting bias and unclear (so potentially high) risk of other biases (selection, performance, attrition).

2 Inconsistency and publication bias: not applicable (no meta‐analysis).

3 Indirectness: not downgraded because good applicability in terms of participants and interventions and rating score measures a participant‐important outcome (global state).

4 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because CI around mean difference did not include appreciable benefit and appreciable harm (total score on CGI = 7).

5 Indirectness: not downgraded because good applicability in terms of participants and interventions and rating score measures a participant‐important outcome (mental state).

6 Imprecision: not downgraded because powered to detect difference and narrow CI.

7 Indirectness: downgraded by 1 level because leaving study early surrogate measure of participant‐important outcome (acceptability of treatment).

Figures and Tables -
Summary of findings 2. CLOZAPINE + AMISULPIRIDE versus CLOZAPINE + QUETIAPINE (Genc 2007)
Summary of findings 3. CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE (Kong 2001)

Clozapine + risperidone versus clozapine + sulpiride for treatment‐resistant schizophrenia

Patient or population: people with treatment‐resistant schizophrenia

Setting: inpatients

Intervention: risperidone (+ CLO)

Comparison: sulpiride (+ CLO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with Sulpiride (+ CLO)

Risk with Risperidone (+ CLO)

Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score

Study population

RR 0.82
(0.40 to 1.68)

60
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,3,4

367 per 1000

301 per 1000
(147 to 616)

Moderate

367 per 1000

301 per 1000
(147 to 616)

Adverse effects: weight gain

Study population

RR 0.40
(0.08 to 1.90)

60
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,4,5

167 per 1000

67 per 1000
(13 to 317)

Moderate

167 per 1000

67 per 1000
(13 to 317)

Clinical response: mean score/change in global state

See comment

See comment

(1 RCT)

No data reported.

Clinical response: mean score/change in mental state: mean PANSS total score (high = poor)

The mean score/change in mental state (PANSS total) was 0

The mean score/change in mental state (PANSS total) in the intervention group was 2.28 undefined fewer (7.41 fewer to 2.85 more)

60
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,6,7

Leaving the study early: acceptability of treatment ‐ as measured by completion of trial

Study population

Not estimable

60
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,8,9

0 per 1000

0 per 1000
(0 to 0)

Service utilisation outcomes: hospital admission or days in hospital

See comment

See comment

Not estimable

No data reported.

Quality of life/satisfaction with care for either recipients of care or carers: significant change in quality of life/satisfaction

See comment

See comment

Not estimable

No data reported.

*The risk in the intervention group (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; CLO: clozapine; PANSS: Positive and Negative Syndrome Scale; RCT: randomised controlled trial; RR: risk ratio.

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

1 Risk of bias: downgraded by 2 levels because unclear (so potentially high) risk of biases (selection, performance, detection, reporting).

2 Inconsistency and publication bias: not applicable (no meta‐analysis).

3 Indirectness: downgraded by 1 level because unclear population applicability (inclusion criteria not clearly specified). Not downgraded by 2 levels because rating scale measures participant‐important outcome (mental state).

4 Imprecision: downgraded by 2 levels because underpowered to detect difference and CI around relative effect includes appreciable benefit and harm.

5 Indirectness: downgraded by 1 level because unclear population applicability (inclusion criteria not clearly specified). Not downgraded by 2 levels because weight gain a direct measure of a participant‐important outcome.

6 Indirectness: downgraded by 1 level because unclear population applicability (inclusion criteria not clearly specified). Not downgraded by 2 levels because rating scale measures participant‐important outcome (mental state).

7 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because CI around mean difference did not include appreciable benefit and appreciable harm (total score on PANSS = 120).

8 Indirectness: downgraded by 2 levels because unclear population applicability (inclusion criteria not clearly specified) and leaving the study early a surrogate measure of acceptability of treatment.

9 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because no CI.

Figures and Tables -
Summary of findings 3. CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE (Kong 2001)
Summary of findings 4. CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE (Kuwilsky 2010)

Clozapine + risperidone versus clozapine + ziprasidone for treatment‐resistant schizophrenia

Patient or population: people with treatment‐resistant schizophrenia

Setting: inpatients and outpatients

Intervention: risperidone (+ CLO)

Comparison: ziprasidone (+ CLO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with ziprasidone (+ CLO)

Risk with risperidone (+ CLO)

Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score
Medium term (26 weeks)

Study population

RR 0.80
(0.28 to 2.27)

24
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,3,4

417 per 1000

333 per 1000
(117 to 946)

Moderate

417 per 1000

333 per 1000
(117 to 946)

Adverse effects: weight gain

See comment

See comment

Not estimable

No SDs reported.

Clinical response: mean score/change in global state: mean CGI‐II Global improvement score (high = poor)

Short term (6 weeks)

The mean score/change in global state (CGI‐II Global improvement) ‐ short term (6 weeks) was 0

The mean score/change in global state (CGI‐II global improvement) ‐ short term (6 weeks) in the intervention group was 0.3 fewer (0.82 fewer to 0.22 more)

22
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,5,6

Clinical response: mean score/change in mental state: mean PANSS total score (high = poor)

Medium term (26 weeks)

The mean score/change in mental state (PANSS total) ‐ medium term (26 weeks) was 0

The mean score/change in mental state (PANSS total) ‐ medium term (26 weeks) in the intervention group was 1 more (7.91 fewer to 9.91 more)

16
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,3,7

Leaving the study early: acceptability of treatment ‐ as measured by completion of trial

Long term (52 weeks)

Study population

RR 1.60
(0.73 to 3.49)

24
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,8,9

417 per 1000

667 per 1000
(304 to 1000)

Moderate

417 per 1000

667 per 1000
(304 to 1000)

Service utilisation outcomes: hospital admission or days in hospital

See comment

See comment

Not estimable

No data reported.

Quality of life/satisfaction with care for either recipients of care or carers: significant change in quality of life/satisfaction

See comment

See comment

Not estimable

No data reported.

*The risk in the intervention group (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; CLO: clozapine; PANSS: Positive and Negative Syndrome Scale; RCT: randomised controlled trial; RR: risk ratio.

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

1 Risk of bias: downgraded by 2 levels because high risk of performance bias, detection bias, attrition bias, and reporting bias.

2 Inconsistency and publication bias: not applicable (no meta‐analysis).

3 Indirectness: not downgraded because good applicability in terms of participants and interventions and rating score measures a participant‐important outcome (mental state).

4 Imprecision: downgraded by 2 levels because underpowered to detect difference and CI around relative effect includes appreciable benefit and harm (from less likely to over two times more likely to have no clinical response in mental state defined by PANSS 20% reduction).

5 Indirectness: not downgraded because good applicability (participants and interventions), and rating score measures a participant‐important outcome (global state).

6 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because CI around mean difference does not include appreciable benefit and appreciable harm (total score on CGI = 7).

7 Imprecision: downgraded by 1 level because underpowered to detect difference. Not downgraded by 2 levels because CI around mean difference does not include appreciable benefit and appreciable harm (total score on PANSS = 120).

8 Indirectness: downgraded by 1 level because leaving the study early a surrogate for participant‐important outcome (acceptability of treatment).

9 Indirectness: downgraded by 2 levels because underpowered to detect difference and CI around relative effect includes appreciable benefit and harm (from less likely to over three times more likely to leave the study early).

Figures and Tables -
Summary of findings 4. CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE (Kuwilsky 2010)
Summary of findings 5. CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE (Wen 2015)

Clozapine + ziprasidone versus clozapine + quetiapine for treatment‐resistant schizophrenia

Patient or population: people with treatment‐resistant schizophrenia

Setting: inpatients and outpatients

Intervention: ziprasidone (+ CLO)

Comparison: quetiapine (+ CLO)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with quetiapine (+ CLO)

Risk with ziprasidone (+ CLO)

Clinical response: no clinically significant response in mental state: ≥ 50% reduction in PANSS total score

Medium term (12 weeks)

Study population

RR 0.54
(0.35 to 0.81)

63
(1 RCT)

⊕⊕⊝⊝
Low 1,2,3,4

844 per 1000

456 per 1000
(295 to 683)

Moderate

844 per 1000

456 per 1000
(295 to 683)

Adverse effects: weight gain

See comment

See comment

Not estimable

No data reported.

Clinical response: mean score/change in global state: mean CGI‐S score (high = poor)

Medium term (12 weeks)

The mean score/change in global state (CGI‐S) ‐ medium term (12 weeks) was 0

The mean score/change in global state (CGI‐S) ‐ medium term (12 weeks) in the intervention group was 0.7 fewer (1.18 fewer to 0.22 fewer)

60
(1 RCT)

⊕⊕⊝⊝
Low 1,2,4,5

Clinical response: mean score/change in mental state: mean PANSS total score (high = poor)

Medium term (12 weeks)

The mean score/change in mental state (PANSS total) ‐ medium term (12 weeks) was 0

The mean score/change in mental state (PANSS total) ‐ medium term (12 weeks) in the intervention group was 12.3 fewer (22.43 fewer to 2.17 fewer)

60
(1 RCT)

⊕⊕⊝⊝
Low 1 2 3 4

Leaving the study early: acceptability of treatment ‐ as measured by completion of trial

Study population

RR 0.52
(0.05 to 5.41)

63
(1 RCT)

⊕⊝⊝⊝
Very low 1,2,6,7

63 per 1000

33 per 1000
(3 to 338)

Moderate

63 per 1000

33 per 1000
(3 to 338)

Service utilisation outcomes: hospital admission or days in hospital

See comment

See comment

Not estimable

No data reported.

Quality of life/satisfaction with care for either recipients of care or carers: significant change in quality of life/satisfaction

See comment

See comment

Not estimable

No data reported.

*The risk in the intervention group (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).

CGI ‐S: Clinical Global Impression – Severity; CI: confidence interval; CLO: clozapine; PANSS: Positive and Negative Syndrome Scale; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation.

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

1 Risk of bias: downgraded by 2 levels because unclear (so potentially high) risk of biases (selection, performance, reporting).

2 Inconsistency and publication bias: not applicable (no meta‐analysis).

3 Indirectness: not downgraded because good applicability in terms of participants and interventions and rating scale measures a participant‐important outcome (mental state).

4 Imprecision: not downgraded because powered to detect difference and narrow CI.

5 Indirectness: not downgraded because good applicability (participants and interventions) and rating scale measures a participant‐important outcome (global state).

6 Indirectness: downgraded by 1 level because leaving the study early surrogate measure for participant‐important outcome (acceptability of treatment).

7 Imprecision: downgraded by 2 levels because underpowered to detect difference and CI around relative effect includes appreciable benefit and harm (from less likely to leave study early to five times more likely to leave study early).

Figures and Tables -
Summary of findings 5. CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE (Wen 2015)
Comparison 1. CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: mean score/change in mental state: mean change in BPRS score from baseline (high = good) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Medium term (12 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐1.40 [‐5.59, 2.79]

1.2 Medium term (24 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐4.81, 3.41]

1.3 Long term (52 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

0.90 [‐4.38, 6.18]

2 Adverse effects: other adverse effects (general or specific): mean change in LUNSERS score from baseline (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.1 Medium term (12 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.9 [‐8.48, ‐1.32]

2.2 Medium term (24 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.9 [‐8.25, ‐1.55]

2.3 Long term (52 weeks)

1

105

Mean Difference (IV, Random, 95% CI)

‐4.8 [‐9.79, 0.19]

3 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Medium term (12 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.34, 2.24]

3.2 Medium term (24 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.60, 2.28]

3.3 Long term (52 weeks)

1

106

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.72, 2.22]

Figures and Tables -
Comparison 1. CLOZAPINE + ARIPIPRAZOLE versus CLOZAPINE + HALOPERIDOL
Comparison 2. CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: 1 mean score/change in global state: mean CGI score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

1.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐0.90 [‐1.38, ‐0.42]

2 Clinical response: 2a mean score/change in mental state: mean BPRS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

2.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐5.86, ‐2.14]

3 Clinical response: 2b mean score/change in mental state: mean SAPS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐6.90 [‐12.82, ‐0.98]

4 Clinical response: 2c mean score/change in mental state: means SANS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Short term (8 weeks)

1

50

Mean Difference (IV, Random, 95% CI)

‐5.20 [‐7.14, ‐3.26]

5 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

56

Risk Ratio (M‐H, Fixed, 95% CI)

0.2 [0.02, 1.60]

Figures and Tables -
Comparison 2. CLOZAPINE + AMISULPRIDE versus CLOZAPINE + QUETIAPINE
Comparison 3. CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: no clinically significant response in mental state: 20% to 50% reduction in PANSS total score Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.40, 1.68]

2 Adverse effect: weight gain Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.08, 1.90]

3 Clinical response: 2a mean score/change in mental state: mean PANSS total score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐2.28 [‐7.41, 2.85]

4 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐2.55 [‐4.64, ‐0.46]

5 Clinical response: 2c. mean score/change in mental state (negative symptoms): mean PANSS negative score at endpoint (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 Short term (8 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐0.54 [‐3.19, 2.11]

6 Adverse effects: specific adverse effects: hypersalivation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.04, 3.03]

7 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Short term (8 weeks)

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 3. CLOZAPINE + RISPERIDONE versus CLOZAPINE + SULPIRIDE
Comparison 4. CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: no clinically significant response in mental state: 20% reduction in PANSS total score Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.13, 3.30]

1.2 Medium term (26 weeks)

1

24

Risk Ratio (M‐H, Fixed, 95% CI)

0.8 [0.28, 2.27]

2 Clinical response: no clinically significant response in mental state (positive symptoms) 20% reduction in PANSS positive subscore Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

3.0 [0.36, 24.92]

3 Clinical response: 1a mean score/change global state: mean CGI subscale score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Severity of illness

1

22

Mean Difference (IV, Random, 95% CI)

0.20 [‐0.32, 0.72]

3.2 Global improvement

1

22

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.82, 0.22]

3.3 Therapeutic efficacy

1

22

Mean Difference (IV, Random, 95% CI)

‐0.30 [‐0.79, 0.19]

4 Clinical response: 1b mean score/change global state: mean GAF score (high = good) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

0.0 [‐7.84, 7.84]

5 Clinical response: 2a. mean score/change mental state: mean HAMD score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐3.40 [‐6.71, ‐0.09]

5.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐5.35, 3.95]

6 Clinical response: 2b mean score/change mental state: mean PANSS total score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐3.10 [‐11.38, 5.18]

6.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.0 [‐7.91, 9.91]

7 Clinical response: 2c mean score/change in mental state (positive symptoms) mean PANSS positive score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

7.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐1.84, 1.44]

7.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐2.58, 2.18]

8 Clinical response: 2d mean score/change in mental state (negative symptoms) mean PANSS negative score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

8.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐4.63, 2.23]

8.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.5 [‐2.66, 5.66]

9 Clinical response: 2e mean score/change in mental state (negative symptoms) mean SANS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

9.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐4.0 [‐17.55, 9.55]

9.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

1.80 [‐14.31, 17.91]

10 Clinical response: 2f mean score/change in global state: mean PANSS global psychopathology score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

10.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐1.60 [‐6.60, 3.40]

10.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

0.0 [‐5.83, 5.83]

11 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: mean EPS score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

11.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

0.60 [‐0.67, 1.87]

11.2 Medium term (26 weeks)

1

16

Mean Difference (IV, Random, 95% CI)

0.30 [‐0.63, 1.23]

12 Adverse effects: other adverse effects (general or specific): mean CGI adverse effect scores (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

12.1 Short term (6 weeks)

1

22

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.53, 0.33]

13 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

13.1 Short term (6 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.07, 14.21]

13.2 Medium term (26 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

0.6 [0.18, 1.97]

13.3 Long term (52 weeks)

1

24

Risk Ratio (M‐H, Random, 95% CI)

1.6 [0.73, 3.49]

Figures and Tables -
Comparison 4. CLOZAPINE + RISPERIDONE versus CLOZAPINE + ZIPRASIDONE
Comparison 5. CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical response: 1a. no clinically significant response in mental state: PANSS reduction ≥ 50% Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.35, 0.81]

2 Clinical response: 1b. no clinically significant response in mental state: PANSS reduction ≥ 25% Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.38, 1.10]

3 Clinical response: 1. mean score/change global state: mean CGI‐S score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

3.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐0.70 [‐1.18, ‐0.22]

4 Clinical response: 2a. mean score/change mental state: mean PANSS total score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

4.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐12.30 [‐22.43, ‐2.17]

5 Clinical response: 2b. mean score/change in mental state (positive symptoms): mean PANSS positive score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

5.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

‐3.10 [‐5.52, ‐0.68]

6 Clinical response: 2b. mean score/change in mental state (negative symptoms): mean PANSS negative score (high = poor) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.1 Medium term (12 weeks)

1

60

Mean Difference (IV, Random, 95% CI)

0.80 [‐1.99, 3.59]

7 Adverse effects: specific adverse effects: mean score/change in extrapyramidal adverse effects: reported extrapyramidal adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

2.06 [0.41, 10.47]

8 Adverse effects: other adverse effects (general or specific): overall adverse effect rate Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.75 [0.50, 1.13]

9 Adverse effects: other adverse effects (general or specific): agitation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

9.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.15, 6.88]

10 Adverse effects: other adverse effects (general or specific): constipation Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

10.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.15 [0.01, 2.74]

11 Adverse effects: other adverse effects (general or specific): drowsiness Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.18, 1.19]

12 Adverse effects: other adverse effects (general or specific): dry mouth Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

12.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.02, 1.35]

13 Adverse effects: other adverse effects (general or specific): headache Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

13.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.28, 3.77]

14 Adverse effects: other adverse effects (general or specific): insomnia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

14.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.12, 3.84]

15 Adverse effects: other adverse effects (general or specific): orthostatic hypotension Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

15.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.01, 4.13]

16 Adverse effects: other adverse effects (general or specific): tachycardia Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

16.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.12, 3.84]

17 Adverse effects: other adverse effects (general or specific): vertigo Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

17.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.03, 1.67]

18 Leaving the study early: acceptability of treatment ‐ as measured by completion of trial Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

18.1 Medium term (12 weeks)

1

63

Risk Ratio (M‐H, Fixed, 95% CI)

0.52 [0.05, 5.41]

Figures and Tables -
Comparison 5. CLOZAPINE + ZIPRASIDONE versus CLOZAPINE + QUETIAPINE