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Meta-Analysis
. 2017 Jun 28;6(6):CD009005.
doi: 10.1002/14651858.CD009005.pub2.

Antipsychotic combinations for schizophrenia

Javier Ortiz-Orendain  1 , Santiago Castiello-de Obeso, Luis Enrique Colunga-Lozano, Yue Hu, Nicola Maayan, Clive E Adams
Affiliations
Meta-Analysis

Antipsychotic combinations for schizophrenia

Javier Ortiz-Orendain et al. Cochrane Database Syst Rev. .

Abstract

Background: Many people with schizophrenia do not achieve a satisfactory treatment response with their initial antipsychotic drug treatment. Sometimes a second antipsychotic, in combination with the first, is used in these situations.

Objectives: To examine whether:1. treatment with antipsychotic combinations is effective for schizophrenia; and2. treatment with antipsychotic combinations is safe for the same illness.

Search methods: We searched the Cochrane Schizophrenia Group's register which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran searches in September 2010, August 2012 and January 2016. We checked for additional trials in the reference lists of included trials.

Selection criteria: We included all randomised and quasi-randomised controlled trials comparing antipsychotic combinations with antipsychotic monotherapy for the treatment of schizophrenia and/or schizophrenia-like psychoses.

Data collection and analysis: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CIs. For the meta-analysis we used a random-effects model. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for included studies.

Main results: Sixty-two studies are included in the review, 31 of these compared clozapine monotherapy with clozapine combination. We considered the risk of bias in the included studies to be moderate to high. The majority of trials had unclear allocation concealment, method of randomisation and blinding, and were not free of selective reporting.There is some limited evidence that combination therapy is superior to monotherapy in improving clinical response (RR 0.73, 95% CI 0.63 to 0.85; participants = 2364; studies = 29, very low-quality evidence), although subgroup analyses show that the positive result was due to the studies with clozapine in both the monotherapy and combination groups (RR 0.66, 95% CI 0.53 to 0.83; participants = 1127; studies = 17). Few studies reported on rate of relapse, most likely due to the short length of the studies. Overall, a combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in preventing relapse (RR 0.63, 95% CI 0.31 to 1.29; participants = 512; studies = 3, very low-quality evidence), but the pooled data showed high heterogeneity (I² = 82%). A combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in reducing the number of participants discontinuing treatment early (RR 0.89, 95% CI 0.73 to 1.07; participants = 3103; studies = 43, low-quality evidence). No difference was found between treatment groups in the number of participants hospitalised (RR 0.96, 95% CI 0.36 to 2.55; participants = 202; studies = 3, low-quality evidence) . We did not find evidence of a difference between treatment groups in serious adverse events or those requiring discontinuation (RR 1.05, 95% CI 0.65 to 1.69; participants = 2398; studies = 30, very low-quality evidence). There is as lack of evidence on clinically important change in quality of life, with only four studies reporting average endpoint or change data for this outcome on three different scales, none of which showed a difference between treatment groups.

Authors' conclusions: Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials, limiting the assessment of long-term efficacy and safety. We found very low-quality evidence that a combination of antipsychotics may improve the clinical response. We also found low-quality evidence that a combination of antipsychotics is may make no difference at preventing participants from leaving the study early, preventing relapse and/or causing more serious adverse events than monotherapy.

PubMed Disclaimer

Conflict of interest statement

Javier Ortiz‐Orendain – participated in clinical trials sponsored by drug companies but received no payment for his contribution.

Santiago Castiello‐de Obeso ‐ none known.

Luis Enrique Colunga‐Lozano ‐ none known.

Yue Hu ‐ works for Systematic Review Solutions Ltd, a company that carries out systematic reviews.

Nicola Mayaan ‐ worked for Enhance Reviews Ltd during the preparation of this review, a company that carried out systematic reviews mostly for the public sector. Now works for Cochrane Respose.

Clive Adams ‐ none known.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Naming of the subgroups: The studies were arranged into four subgroups according to the type of antipsychotics used in both arms: clozapine, atypical antipsychotics other than clozapine, typical antipsychotics and any antipsychotics. Naming of the studies: The study tag starts with the duration category (A = long term (over 26 weeks); B = medium term (13 to 26 weeks) and C = short term (up to 12 weeks); the remainder of the tag is the additional drug in the combination antipsychotic group.
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C +risperidone 2005b {published data only}
    1. Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double‐blind, placebo‐controlled trial. 9th International Congress on Schizophrenia Research; 2003 Mar 29‐Apr 2; Colorado Springs, CO. 2003:130‐6. [MEDLINE: ] - PubMed
    1. Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double‐blind, placebo‐controlled trial. American Journal of Psychiatry 2005;162(1):130‐6. [0002‐953X: (Print); DOI: 10.1176/appi.ajp.162.1.130; MEDLINE: ] - DOI - PubMed
C +risperidone 2006 {published data only}
    1. Gerson SL. Clozapine alone versus clozapine and risperidone for refractory schizophrenia. New England Journal of Medicine 2006;354(17):1846‐8. [1533‐4406: (Electronic); MEDLINE: ] - PubMed
    1. Grass G, Hellmich M, Leweke FM. Clozapine alone versus clozapine and risperidone for refractory schizophrenia. New England Journal of Medicine 2006;354(17):1846‐8. [1533‐4406: (Electronic); MEDLINE: ] - PubMed
    1. Honer W. A randomized controlled trial of antipsychotic polypharmacy: clozapine plus risperidone. European Neuropsychopharmacology 2007;17(Suppl 4):S200. [DOI: 10.1016/S0924-977X(07)70237-7; MEDLINE: ] - DOI
    1. Honer W. International study of improving treatment for the most severely ill with schizophrenia. www.clinicaltrials.gov/ct2/show/NCT00272584?term=NCT00272584&rank=1 (first received 3 January 2006). [MEDLINE: ]
    1. 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. [1533‐4406: (Electronic); DOI: 10.1056/NEJMoa053222; MEDLINE: ] - DOI - PubMed
C +risperidone 2007 {published data only}
    1. Freudenreich O. Risperidone added to clozapine for schizophrenia. Stanley Foundation Research Programs 2009. [Walsh 2006 b1]
    1. Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double‐blind, placebo‐controlled trial. Schizophrenia Research 2007;92(1‐3):90‐4. [0920‐9964: (Print); DOI: 10.1016/j.schres.2006.12.030; Walsh 2006 b2] - DOI - PubMed
    1. Walsh JP, Freudenreich O, Goff DC. Risperidone augmentation in patients with schizophrenia partially responsive to clozapine. www.clinicaltrials.gov/ct2/show/NCT00289861?term=NCT00289861&rank=1 (first received 8 February 2006). [MEDLINE: ]
C +sertindole 2006 {published data only}
    1. Nielsen J, Emborg C, Gydesen S, Dybbro J, Aagaard J, Haderup K, et al. Augmenting clozapine with sertindole: a double‐blind, randomized, placebo‐controlled study. Journal Clincal Psychopharmacology 2012;32(2):173‐8. [DOI: 10.1097/JCP.0b013e318248dfb8] - DOI - PubMed
    1. Nielsen J, Munk‐Jorgensen P. Augmenting clozapine with sertindole ‐ a double blinded randomized placebo study. www.clinicaltrials.gov/ct2/show/NCT00345982?term=NCT00345982&rank=1 (first received 28 June 2006). [Nielsen 2006]
    1. Nielsen RE, Levander S, Thode D, Nielsen J. Effects of sertindole on cognition in clozapine‐treated schizophrenia patients. Acta Psychiatrica Scandinavica 2012;126(1):31‐9. [DOI: 10.1111/j.1600-0447.2012.01840.x] - DOI - PubMed
C +sulpiride 1997 {published data only}
    1. 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. [0007‐1250: (Print); Shiloh 1997] - PubMed
    1. Shiloh R, Zemishlany Z, Aizenberg D, Weizman A. Sulpiride adjunction to clozapine in treatment‐resistant schizophrenic patients: a preliminary case series study. European Psychiatry 1997;12(3):152‐5. [0924‐9338: (Print); MEDLINE: ] - PubMed
C +sulpiride 1999 {published data only}
    1. Si S, Yuan C. A comparative trial of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Shandong Archives of Psychiatry 1999;12:17‐20.
C +sulpiride 1999b {published data only}
    1. Xao H. A double‐blind comparative study of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Sichuan Mental Health 1999;12:250‐1.
C +sulpiride 1999c {published data only}
    1. Zhu Y, Zhang S, Zhang D. A controlled trial comparing chlorimipramine and sulpiride as adjunct to clozapine in the treatment of negative symptoms of schizophrenia. Journal of Clinical Psychology in Medical Settings 1999;9(4):204‐5. [MEDLINE: ]
C +sulpiride 2003 {published data only}
    1. Zou G, Huang Y, Zou S, Yang Y. A comparative trial of the beneficial effects of sulpiride combined with clozapine in the treatment of refractory schizophrenia. Journal of Yichun University 2003;25:94‐6.
C +sulpiride 2004 {published data only}
    1. Kotler M, Strous RD, Reznik I, Shwartz S, Weizman A, Spivak B. Sulpiride augmentation of olanzapine in the management of treatment‐resistant chronic schizophrenia: evidence for improvement of mood symptomatology. International Clinical Psychopharmacology 2004;19(1):23‐6. [0268‐1315: (Print); MEDLINE: ] - PubMed
C +sulpiride 2006 {published data only}
    1. Xu B. Observation on the effect of clozapine and sulpiride on negative symptom schizophrenia patients. China Tropical Medicine 2006;6(5):806.
C +sulpiride 2013 {published and unpublished data}
    1. Lin CH, Wang FC, Lin SC, Huang YH, Chen CC, Lane HY. Antipsychotic combination using low‐dose antipsychotics is as efficacious and safe as, but cheaper, than optimal‐dose monotherapy in the treatment of schizophrenia: a randomized, double‐blind study. International Clinical Psychopharmacology 2013;28(5):267‐74. [DOI: 10.1097/YIC.0b013e3283633a83.] - DOI - PubMed

References to studies excluded from this review

Ahn 2002 {published data only}
    1. Ahn YM, Kweon YS, Kwon JS, Min SH, Park DB, Yang MJ, et al. The study for switching methods to olanzapine in Korean schizophrenic patients treated with other antipsychotics (II): comparison of safety [항정신병약물 사용 중인 정신분열병 환자에서 올란자핀으로의 교체 방법에 관한 연구: 안전성 비교]. Journal of Korean Neuropsychiatric Association 2002;41(5):890‐4.
Alptekin 2012 {published data only}
    1. Alptekin K, Akdede B, Soygur H. TRIES: An open, randomized, prospective, multicenter study, searching the best switch policy of sertindole in patients with schizophrenia. Schizophrenia Research 2012;136:S164‐5. [DOI: 10.1016/s0920-9964(12)70519-4] - DOI
Awad 2014 {published data only}
    1. Awad G, Hassan M, Loebel A, Hsu J, Pikalov A, Rajagopalan K. Health‐related quality of life among patients treated with lurasidone: results from a switch trial in patients with schizophrenia. BMC Psychiatry 2014;14(1):53. [DOI: 10.4088/jcp.12m07992] - DOI - PMC - PubMed
Barbui 2011 {published data only}
    1. 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. [DOI: 10.1097/JCP.0b013e318219cba3.] - DOI - PubMed
    1. Cipriani A, Accordini S, Nose 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. [DOI: 10.1097/JCP.0b013e318296884f.] - DOI - PubMed
    1. Nose 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;10(31):31. [1745‐6215: (Electronic); MEDLINE: ] - PMC - PubMed
Cazorla 2012 {published data only}
    1. Cazorla P, Mackle M, Zhao J, Ha X, Szegedi A. Safety and tolerability of switching to asenapine from other antipsychotic agents: pooled results from two randomized multicenter trials in stable patients with persistent negative symptoms in schizophrenia. Neuropsychiatric Disease and Treatment 2012;8:247‐57. [DOI: 10.2147/NDT.S29891] - DOI - PMC - PubMed
ChiCTR‐TRC‐14004854 {published data only}
    1. ChiCTR‐TRC‐14004854. A randomized, controlled, multi‐center clinical trial to study the treatment resistant schizophrenia (TRS) in Zhejiang province. www.chictr.org.cn/showprojen.aspx?proj=4719 (first received 26 June 2014).
Citrome 2012 {published data only}
    1. Citrome L, Kianifard F, Meng X, Winseck A, Hochfeld M, Stahl S. Discontinuations following a switch from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia: The i‐fans study. Neuropsychopharmacology 2012;38(S1):S413‐S4.
Dai 2012 {published data only}
    1. Dai J, Gao H, Sheng J. The effect of synthetical intervention to schizophrenic and hyperlipidemia patients [精神分裂症并发高脂血症患者的综合干预对生活质量的影响]. Medical Journal of Chinese People’s Health 2012;24(5):541‐2. [DOI: 10.3969/j.issn.1672-0369.2012.05.011] - DOI
Dai 2012a {published data only}
    1. Dai T, Xu L, Houzhan L, Chen R, Fan R, Zhao H, et al. Group therapy in combination with antipsychotic medication for the treatment of schizophrenia patients in recovery period [团体治疗联合抗精神病药物对精神分裂症康复期治疗的 效果观察]. Chinese Journal of Clinical Rational Drug Use 2012;5(12A):66.
DRKS00008018 {published data only}
    1. DRKS00008018. Are antipsychotics neurotoxic or neuroprotective? A long‐term comparison of two treatment strategies. drks‐neu.uniklinik‐freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DR... (first received 24 April 2015).
Fang 2012 {published data only}
    1. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. International Clinical Psychopharmacology 2012;27(2):107‐13. [DOI: ] - PubMed
Fleischhacker 2012 {published data only}
    1. Fleischhacker WW, Sanchez R, Perry PP, Jin N, Peters‐Strickland T, Johnson BR, et al. Aripiprazole once‐monthly for the treatment of schizophrenia: A double‐blind, randomized, non‐inferiority study versus oral aripiprazole. Neuropsychopharmacology 2012;38(S1):S339. - PubMed
Fleischhacker 2013 {published data only}
    1. Fleischhacker WW, Sanchez R, Johnson B, Jin N, Forbes RA, McQuade R, et al. Long‐term safety and tolerability of aripiprazole once‐monthly in maintenance treatment of patients with schizophrenia. International Clinical Psychopharmacology 2013;28:171‐6. [DOI: 10.1097/YIC.0b013e3283615dba] - DOI - PubMed
Goff 2008 {published data only}
    1. Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J, et al. A placebo‐controlled add‐on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008;33(3):465‐72. [0893‐133X: (Print); DOI: 10.1038/sj.npp.1301444; MEDLINE: ] - DOI - PMC - PubMed
Henderson 2009 {published data only}
    1. Henderson DC, Fan X, Copeland PM, Sharma B, Borba CP, Boxill R, et al. Aripiprazole added to overweight and obese olanzapine‐treated schizophrenia patients. Joural of Clinical Psychopharmacology 2009;29(2):165‐9. [1533‐712X: (Electronic); DOI: 10.1097/JCP.0b013e31819a8dbe; MEDLINE: ] - DOI - PMC - PubMed
Hwang 2015 {published data only}
    1. Hwang TJ, Lo WM, Chan HY, Lin CF, Hsieh MH, Liu CC, et al. Fast versus slow strategy of switching patients with schizophrenia to aripiprazole from other antipsychotics. Journal of Clinical Psychopharmacology 2015;35(6):635‐44. [DOI: 10.1097/JCP.0000000000000426.] - DOI - PubMed
JPRN‐UMIN000011710 {published and unpublished data}
    1. JPRN‐UMIN000011710. New Chiba Refractory Schizophrenia Treatment (CREST)‐LAI study: Effectiveness of risperidone long‐acting injectable for treatment‐resistant schizophrenia. apps.who.int/trialsearch/Trial.aspx?TrialID=JPRN‐UMIN000011710 (first received 2013).
JPRN‐UMIN000012729 {published data only}
    1. JPRN‐UMIN000012729. A comparison of medication adherence of blonanserin and aripiprazole in schizophrenic patients: a multicenter, randomized, open‐label study. apps.who.int/trialsearch/Trial.aspx?TrialID=JPRN‐UMIN000012729 (first received 2013).
JPRN‐UMIN000017047 {published data only}
    1. JPRN‐UMIN000017047. A randomized, open‐label clinical trial on the efficacy of blonanserin and olanzapine in patients with schizophrenia and dopamine supersensitivity psychosis. apps.who.int/trialsearch/Trial.aspx?TrialID=JPRN‐UMIN000017047 (first received 2015).
Kelly 2005 {published data only}
    1. Kelly D, Fischer G, Suppes T. Divalproex extended release and placebo, lithium, or quetiapine for mania. www.clinicaltrials.gov/ct2/show/NCT00183443?term=Divalproex+extended+rel... (first received 13 September 2005). [MEDLINE: ]
Kreinin 2006 {published data only}
    1. Kreinin A, Novitski D, Weizman A. Amisulpiride treatment of clozapine‐induced hypersalivation in schizophrenia patients: a randomized, double‐blind, placebo‐controlled cross‐over study. International Clinical Psychopharmacology 2006;21:99‐103. - PubMed
Kwon 2012 {published data only}
    1. Kwon JS, Mittoux A, Hwang JY, Ong A, Cai ZJ, Su TP. The efficacy and safety of 12 weeks of treatment with sertindole or olanzapine in patients with chronic schizophrenia who did not respond successfully to their previous treatments: A randomized, double‐blind, parallel‐group, flexible‐dose study. International Clinical Psychopharmacology 2012;27(6):326‐35. [DOI: 10.1097/YIC.0b013e32835767a0] - DOI - PubMed
Lerner 2004 {published data only}
    1. Lerner V, Libov I, Kotler M, Strous RD. Combination of "atypical" antipsychotic medication in the management of treatment‐resistant schizophrenia and schizoaffective disorder. Progress in Neuro‐Psychopharmacology and Biological Psychiatry 2004;28(1):89‐98. [0278‐5846: (Print); DOI: 10.1016/j.pnpbp.2003.09.024; MEDLINE: ] - DOI - PubMed
Li 2013 {published data only}
    1. Li J. Liqi xingshen method for the treatment of TanQi Yujie type schizophrenia: a random parallel control study [理气醒神方治疗痰气郁结型精神分裂症随机平行对照研究]. Journal of Practical Traditional Chinese Internal Medicine 2013;27(5):19‐20. [DOI: 10.3969/j.issn.1671-7813.2013.05(s).84] - DOI
Lieberman 2009 {published data only}
    1. Lieberman J, Farr G, Seoane F. TC‐5619 as augmentation therapy to improve cognition in outpatients with cognitive dysfunction in schizophrenia. www.clinicaltrials.gov (first received 27 October 2009). [MEDLINE: ]
    1. NCT01003379. TC‐5619 as augmentation therapy to improve cognition in outpatients with cognitive dysfunction in schizophrenia. clinicaltrials.gov/ct2/show/NCT01003379 (first received 27 October 2009). [MEDLINE: ]
Lieberman 2013 {published data only}
    1. Lieberman JA, Cutler AJ, Lu K, Laszlovszky I, Migliore R, Durgam S. Cariprazine in acute exacerbation of schizophrenia: a fixed‐dose phase III, randomized, double‐blind, placebo‐ and active‐controlled trial. CNS Spectrums 2013;18(6):368. - PubMed
    1. Lieberman JA, Cutler AJ, Wan S, Migliore R, Ruth A, Laszlovszky I, et al. Cariprazine in acute exacerbation of schizophrenia: a fixed‐dose, randomised, double‐blind, placebo‐ and active‐controlled trial. European Neuropsychopharmacology 2013;23:S477‐8.
Lundbeck 2004 {published data only}
    1. Lundbeck H. A prospective randomised double‐blind parallel‐group active‐controlled cognition study of bifeprunox in schizophrenia (add‐on study to studies 10199 and 10200). www.lundbecktrials.com (first accessed 2004). [MEDLINE: ]
Lundbeck 2008 {published data only}
    1. Lundbeck H. Efficacy study exploring the effect of Lu AE58054 as augmentation therapy in patients with schizophrenia. www.clinicaltrials.gov/ct2/show/NCT00810667?term=Efficacy+study+explorin... (first received 17 December 2008). [MEDLINE: ]
Mantovani 2013 {published data only}
    1. Mantovani C, Labate CM, Sponholz AJ, Azevedo Marques JM, Guapo V G, Simone Brito dos Santos ME, et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated‐blind trial of four intramuscular interventions. Journal of Clinical Psychopharmacology 2013;33:306‐12. - PubMed
Meltzer 2008 {published data only}
    1. Johnson, Johnson. Randomized, Double‐blind, Placebo‐ and Active‐controlled Parallel Group, Dose‐response Study to Evaluate the Efficacy and Safety of 3 Fixed Dosages of Paliperidone Extended Release (6, 9, and 12 mg/Day) and Olanzapine (10 mg/Day) With Open‐label Extension in Treatment of Schizophrenia. www.clinicaltrials.gov/ct2/show/NCT00078039?term=Randomized%2C+Double‐bl... (first received 17 February 2004).
    1. Meltzer H, Bobo W, Nuamah I, Lane R, Hough D, Kramer M, et al. Efficacy and tolerability of oral paliperidone extended‐release tablets in the treatment of acute schizophrenia: pooled data from three 6‐week, placebo‐controlled studies. Journal Of Clinical Psychiatry 2008;69(5):817‐29. - PubMed
Meltzer 2012 {published data only}
    1. Meltzer HY, Elkis H, Vanover K, Weiner DM, Kammen DP, Peters P, et al. Pimavanserin, a selective serotonin (5‐ht)2a‐inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophrenia Research 2012;141:144‐52. [DOI: 10.1016/j.schres.2012.07.029.; MEDLINE: ] - DOI - PubMed
Mi 2013 {published data only}
    1. MI Z, Shi S. Antipsychotic medication combined psychological intervention for the treatment of patients with schizophrenia [药物联合心理干预治疗精神分裂症患者的临床研究]. Chinese Medicine Guide 2013;11(4):505‐6.
Mir 2008 {published data only}
    1. Mir A, Shivakumar K, Williamson RJ, McAllister V, O'Keane V, Aitchison KJ. Change in sexual dysfunction with aripiprazole: A switching or add‐on study. Journal of Psychopharmacology 2008;22(3):244‐53. [DOI: 10.1177/0269881107082901] - DOI - PubMed
Mythri 2013 {published data only}
    1. Mythri SV, Tharyan P, Sunder S, Kattula D, Kirubakaran R, Adams CE. Rapid tranquillization of violent or agitated patients in a psychiatric emergency setting: Pragmatic, randomized, allocation concealed, participant and assessor blinded trial of intramuscular zuclopenthixol acetate versus intramuscular haloperidol plus promethazine [A comparative study of the effects of an intramuscular injection of zuclopenthixol acetate versus an intramuscular injection of a combination of haloperidol plus promethazine in people with violence or agitation presenting to a psychiatric hospital as an emergency]. Study Protocol (as supplied 2013).
NCT01003379 {published data only}
    1. NCT01003379. TC‐5619 as augmentation therapy to improve cognition in outpatients with cognitive dysfunction in schizophrenia. clinicaltrials.gov/ct2/show/record/NCT01003379 (first received 27 October 2009).
NCT01234779 {published data only}
    1. NCT01234779. A study of ro4917838 in patients with acute exacerbation of schizophrenia. clinicaltrials.gov/show/NCT01234779 (first received 3 November 2010).
NCT01939548 {published data only}
    1. NCT01939548. A 12‐week, randomized, phase 2, double‐blind, parallel‐group study of two dose levels of PF‐02545920 compared to placebo in the adjunctive treatment of outpatients with sub‐optimally controlled symptoms of schizophrenia. clinicaltrials.gov/show/NCT01939548 (first received 9 August 2013).
NCT02477670 {published data only}
    1. NCT02477670. Efficacy, safety, and tolerability of AVP‐786 for the treatment of residual schizophrenia. clinicaltrials.gov/show/NCT02477670 (first received 18 June 2015).
Pfizer 2009 {published data only}
    1. Pfizer. A study of PF‐03463275 as add‐on therapy in outpatients with persistent negative symptoms of schizophrenia. clinicaltrials.gov/ct2/show/NCT00977522?term=A+study+of+PF‐03463275+as+a... (first received 14 September 2009). [MEDLINE: ]
Ruiz‐Doblado 2010 {published data only}
    1. Ruiz‐Doblado S, Baena‐Baldomero A, Esparrago‐Llorca G. Pharmacological augmentation strategies in clozapine‐resistant schizophrenia: Overcoming the resistance. Psiquiatria Biologica 2010;17(3):96‐101. [DOI: 10.1016/j.psiq.2010.07.002] - DOI
Rupnow 2005 {published data only}
    1. Rupnow M, Greenspan A, Kosik‐Gonzalez C, Bossie C, Zhu Y, Gharabawi G, et al. Polypharmacy in schizophrenia: data from a randomized, double‐blind study. 158th Annual Meeting of the American Psychiatric Association; 2005 May 21‐26; Atlanta, Georgia, USA. 2005. [MEDLINE: ]
Sacchetti 2006 {published data only}
    1. Sacchetti E, Galluzzo A, Valsecchi P, Romeo F, Gorini B, Warrington L. Comparative efficacy and safety of ziprasidone and clozapine in treatment refractory schizophrenic patients: results of a randomized, double‐blind, 18‐week trial. 13th Biennial Winter Workshop on Schizophrenia Research; 2006 Feb 4‐10; Davos, Switzerland 2006. [MEDLINE: ]
Semenikhin 2013 {published data only}
    1. Semenikhin DG, Kuchaeva AV, Karpov AM, Mikhailova EB, Murav'eva AV. Additional possibilities for correction of movement disorders induced by neuroleptics in patients with schizophrenia. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova 2013;113(11):78‐80. - PubMed
Sofronov 2013 {published data only}
    1. Sofronov A, Spikina A, Savelyev A. The role of modern antipsychotics in correction of neurocognitive deficit in schizophrenia patients. European Psychiatry 2013;28:1247. [DOI: 10.1016/S0924-9338(13)76320-X] - DOI
Spyker 2015 {published data only}
    1. Spyker DA, Riesenberg RA, Cassella JV. Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens. Journal of Clinical Pharmacology 2015;55(9):985‐94. [DOI: 10.1002/jcph.502] - DOI - PMC - PubMed
Stahl 2010b {published data only}
    1. Stahl S, Cucchiaro J, Simonelli D, Loebel A. Long‐term safety and tolerability of lurasidone in subjects with schizophrenia: results of a 6‐month, open‐label study. 49th Annual meeting of the Americam College of Neuropsychopharmacology; 5‐9 December 2010; Miami, Florida. 2010.
Sukegawa 2008 {published data only}
    1. Sukegawa T, Ito T, Hasegawa M, Mizuno Y, Inagaki A, Sakamoto H, et al. A randomized controlled trial on the dose reduction and simplification for polypharmacy of antipsychotics. Tottori Journal of Clinical Research 2008;1(1):169‐81.
Sukegawa 2014 {published data only}
    1. Sukegawa T, Inagaki A, Yamanouchi Y, Inada T, Yoshio T, Yoshimura R, et al. Study protocol: safety correction of high dose antipsychotic polypharmacy in Japan. BMC Psychiatry 2014;14(1):103. [DOI: 10.1186/1471-244X-14-103] - DOI - PMC - PubMed
UMIN000004931 {published data only}
    1. Hirano J, Watanabe K, Suzuki T, Uchida H, et al. An open‐label study of algorithm‐based treatment versus treatment‐as‐usual for patients with schizophrenia. Neuropsychiatric Disease and Treatment 2013;9:1553–64. [DOI: 10.2147/ndt.s46108] - DOI - PMC - PubMed
    1. UMIN000004931. An intervention study of optimizing algorism‐based pharmacological treatment for schizophrenia. www.umin.ac.jp/ctr/index.htm (first received 22 January 2011).
Wang 2013 {published data only}
    1. Wang W, Chen H, Zhao L. Antipsychotic medication combined with acupuncture therapy for the treatment of schizophrenia [抗精神病药物联合针刺治疗精神分裂症 60 例疗效分析]. Medical Journal of Chinese People's Health 2013;25(10):63‐4. [DOI: 10.3969/j.issn.1672-0369.2013.10.043] - DOI
Weiden 2013 {published data only}
    1. Weiden PJ, Citrome L, Glick ID, Alva G, Winseck A, Kianifard F, et al. Initial 2‐week outcomes following 2 methods of switching to iloperidone from risperidone in patients with schizophrenia. CNS Spectrums 2013;18(6):348.
Wilson 1994 {published data only}
    1. Wilson WH. Open clozapine treatment following a controlled clinical trial of lithium augmentation of haloperidol for refractory schizophrenia. Lithium 1994;5(2):113‐4.
Winseck 2013 {published data only}
    1. Winseck A, Glick ID, Weiden PJ, Citrome L, Alva G, Kianifard F, et al. Initial 2‐week outcomes following 2 methods of switching to iloperidone from aripiprazole in patients with schizophrenia. CNS Spectrums 2013;18(6):362‐3.
Wu 2002 {published data only}
    1. Wu L. A control study of risperidone and clozapine combination for the treatment of refractory schizophrenia. Health Psychology 2002;10:135‐7.
Wu 2015 {published data only}
    1. 吴士玲, 张金香. Clinical study of aripiprazole combined with ziprasidone for schizophrenia [阿立哌唑结合齐拉西酮治疗精神分裂症的临床护理观察]. 全国高血压防治知识推广培训班暨健康血压中国行福建漳州会 2015;22(1):145.
Xia 2014 {published data only}
    1. Xia SY, Zhang YR, Yu H, Meng X, Zhang P, Liu J. Treatment of antipsychotic drug‐induced phlegm dampness type amenorrhea by Wuji Powder and a small dose aripiprazole: a clinical study. Chinese Journal of Integrated Traditional and Western Medicine 2014;34(12):1440‐3. - PubMed
Xu 2008 {published data only}
    1. Xu. Clinical observation of sertraline combined with sulpiride for first onset schizophrenia [舍曲林合并舒必利治疗首发精神分裂症临床观察]. Ningxia Medical Journal [宁夏医学杂志] 2008;30(6):542‐3.
Yamanouchi 2015 {published data only}
    1. UMIN000004511. The clinical study to correct multiple and large amount of administering to antipsychotic safely and effectively. www.umin.ac.jp/ctr/index.htm (first received 10 November 2010).
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Yue 2004 {published data only}
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