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Augmentation de la dose d'antipsychotique ou changement d'antipsychotique en cas de non‐réponse dans le traitement de la schizophrénie

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Referencias

References to studies included in this review

Ir a:

Kinon 1993 {published data only}

Johns CA, Mayerhoff DI, Lieberman JA, Kane JM. Schizophrenia: alternative neuroleptic strategies. In: Angrist B/Schulz SC editor(s). The Neuroleptic‐Nonresponsive Patient: Characterization and Treatment. Washington, DC, USA: American Psychiatric Press, Inc, 1990:53‐66. CENTRAL
Kane JM, Kinon B, Johns C. Alternative strategies for treating neuroleptic nonresponsive patients. Schizophrenia Research 1993;9:240. CENTRAL
Kinon BJ, Kane JM, Johns C, Perovich R, Ismi M, Koreen A, et al. Treatment of neuroleptic‐resistant schizophrenic relapse. Psychopharmacology Bulletin 1993;29(2):309‐14. CENTRAL

References to studies excluded from this review

Ir a:

Agid 2013 {published data only}

Agid O, Schulze L, Arenovich T, Sajeev G, McDonald K, Foussias G, et al. Antipsychotic response in first‐episode schizophrenia: efficacy of high doses and switching. European Neuropsychopharmacology 2013;23(9):1017‐22. CENTRAL

Bondolfi 1995 {published data only}

Bondolfi G, Baumann P, Patris M, May J, Billeter U, Dufour H, et al. A randomized double‐bind trial of risperidone versus clozapine for treatment‐resistant chronic schizophrenia. European Neuropsychopharmacology 1995;5(3):349. CENTRAL

Buckley 1995 {published data only}

Buckley PF, Cola PA, Hasegawa M, Lys C, Meltzer HY. Plasma levels and dosing strategies in schizophrenic patients receiving clozapine. Schizophrenia Research 1995;15(1‐2):144. CENTRAL

Conley 2003 {published data only}

Conley RR, Kelly DL, Richardson CM, Tamminga CA, Carpenter W. The efficacy of high‐dose olanzapine versus clozapine in treatment‐resistant schizophrenia: a double‐blind, crossover study. Journal of Clinical Psychopharmacology 2003;23(6):668‐71. CENTRAL

Dunn 2005 {published data only}

Dunn J, Kane J, Khanna S, Giller E, Rajadhyaksha S, Loebel A. Ziprasidone in treatment ‐ resistant schizophrenia: long ‐ term efficacy and tolerability. Schizophrenia Bulletin 2005;31:481‐2. CENTRAL
Khanna S, Rajadhyaksha S, Kane J, Giller E. Ziprasidone versus chlorpromazine in treatment‐refractory schizophrenia. Schizophrenia Research 2003;60(1):289‐90. CENTRAL

Ganguli 2003 {published data only}

Ganguli R, Berry S, Gharabawi G, Lonchena C, Mahmoud R, Brar J, et al. Randomized assessment of strategies for switching patients with sub‐optimal treatment outcomes from olanzapine to risperidone. Schizophrenia Research 2003;60(1):283. CENTRAL

Goff 2013 {published data only}

Goff DC, McEvoy JP, Citrome L, Mech AW, Bustillo JR, Gil R, et al. High‐dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: The ZEBRAS study. Journal of Clinical Psychopharmacology 2013;33(4):485‐90. CENTRAL
NCT00403546. High‐dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms. clinicaltrials.gov/show/NCT00403546 (accessed 22 January 2016). CENTRAL

Harvey 2007 {published data only}

Harvey P, Warrington L, Loebel A, Romeo F, Gorini B, Galluzzo A, et al. Cognitive effects of ziprasidone and clozapine: results from an 18‐week double‐blind trial. European Neuropsychopharmacology 2007;17(Suppl 4):S439. CENTRAL

Hatta 2012 {published data only}

Hatta K, Otachi T, Sudo Y, Kuga H, Takebayashi H, Hayashi H, et al. A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non‐response to risperidone. Psychiatry Research 2012;198(2):194‐201. CENTRAL

Honer 2010 {published data only}

Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A double blind, placebo controlled study of the safety and tolerability of quetiapine 1200 mg/d versus 800 mg/d in patients with persistent symptoms of schizophrenia or schizoaffective disorder. Schizophrenia Research 2010;117(2‐3):375. CENTRAL
Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double‐blind, placebo‐controlled study of the safety and tolerability of high‐dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. Journal of Clinical Psychiatry 2012;73(1):13‐20. CENTRAL

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Janicak PG, Javaid JI, Sharma RP, Leach A, Dowd S, Blake L, et al. Random assignment to 3 haloperidol plasma‐levels for acute‐psychosis. Biological Psychiatry 1994;35(9):666. CENTRAL

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Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment‐resistant schizophrenic. A double‐blind comparison with chlorpromazine. Archives of General Psychiatry 1988;45(9):789‐96. CENTRAL

Kane 2007 {published data only}

Kane JM, Meltzer HY, Carson W, McQuade RD, Marcus RN, Sanchez R. Aripiprazole for treatment‐resistant schizophrenia: results of a multicenter, randomized, double‐blind, comparison study versus perphenazine. Journal of Clinical Psychiatry 2007;68(2):213‐23. CENTRAL

Kim 2013 {published data only}

Kim EY, Chang SM, Shim JC, Joo EJ, Kim JJ, Kim YS, et al. Long‐term effectiveness of flexibly dosed paliperidone extended‐release: comparison among patients with schizophrenia switching from risperidone and other antipsychotic agents. Current Medical Research and Opinion 2013;29(10):1231‐40. CENTRAL

Kinon 2010 {published data only}

Kinon B, Chen L, Stauffer V, Ascher‐Svanum H, Zhou W, Kollack‐Walker S, et al. Differences between early responders and early non‐responders to atypical antipsychotics on symptom and functional outcomes in the treatment of schizophrenia. Schizophrenia Research 2010;117(2‐3):132. CENTRAL
Kinon BJ, Chen L, Ascher‐Svanum H, Stauffer V, Kollack‐Walker S, Zhou W, et al. Early response as a response predictor: Use of individual variability in clinical trials. European Neuropsychopharmacology 2009;19(Suppl 3):S183. CENTRAL
Kinon BJ, Chen L, Ascher‐Svanum H, Stauffer VL, Kollack‐Walker S, Zhou W, et al. Challenging the assumption that improvement in functional outcomes is delayed relative to improvement in symptoms in the treatment of schizophrenia. Schizophrenia Research 2010;118(1‐3):176‐82. CENTRAL
Kinon BJ, Chen L, Ascher‐Svanum H, Stauffer VL, Kollack‐Walker S, Zhou W, et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology 2010;35(2):581‐90. CENTRAL
Kinon BJ, Stauffer V, Ascher‐Svanum H, Tomori O, Kollack‐Walker S. Predicting response to risperidone treatment through identification of early‐onset of antipsychotic drug action in schizophrenia. Proceedings of the 161st Annual Meeting of the American Psychiatric Association. Washington DC, May 3‐8, 2008. CENTRAL
Stauffer V, Chen L, Ascher‐Svanum H, Kollack‐Walker S, Zhou W, Kapur S, et al. Switching antipsychotic drugs enhances improvement in patients who show lack of an early response to their initial antipsychotic therapy. Proceedings of the 162nd Annual Meeting of the American Psychiatric Association. San Francisco, CA, 2009 May 16‐21. CENTRAL

Lindenmayer 2011 {published data only}

Lindenmayer JP, Citrome L, Khan A, Kaushik S. A randomized, double‐blind, parallel‐group, fixed‐dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment‐resistant schizophrenia or schizoaffective disorder. Journal of Clinical Psychopharmacology 2011;31(2):160‐8. CENTRAL

McEvoy 2013 {published data only}

McEvoy J, Citrome L, Hsu J, Werner P, Pikalov A, Cucchiaro J, et al. Switching to lurasidone in patients with schizophrenia: Tolerability and effectiveness at 6 weeks and 6 months. European Psychiatry 2013;28(Suppl. 1):Article: 1046. CENTRAL
McEvoy JP, Citrome L, Hernandez D, Cucchiaro J, Hsu J, Pikalov A, et al. Effectiveness of lurasidone in patients with schizophrenia or schizoaffective disorder switched from other antipsychotics: A randomized, 6‐week, open‐label study. Journal of Clinical Psychiatry 2013;74(2):170‐9. CENTRAL
McEvoy JP, Citrome L, Hernandez D, Hsu J, Werner P, Pikalov A, et al. Switching to lurasidone in patients with schizophrenia: tolerability and effectiveness at 6 weeks and 6 months. European Neuropsychopharmacology 2013;23(2):S486. CENTRAL
McEvoy JP, Citrome L, Hsu J, Werner P, Pikalov A, Cucchiaro J, et al. Switching to lurasidone in patients with schizophrenia: Tolerability and effectiveness at 6 weeks and 6 months. Schizophrenia Bulletin 2013;39:S343. CENTRAL

NCT00161018 {published data only}

NCT00161018. New antipsychotic strategies: quetiapine and risperidone vs. fluphenazine in treatment resistant schizophrenia. clinicaltrials.gov/show/NCT00161018 (accessed 22 January 2016). CENTRAL

NCT00191555 {published data only}

NCT00191555. Efficacy study of switching stabilized schizophrenic patients from conventional to atypical antipsychotic treatment. clinicaltrials.gov/ct2/show/NCT00191555 (accessed 22 January 2016). CENTRAL

Potkin 1994 {published data only}

Potkin SG, Bera R, Gulasekaram B, Costa J, Hayes S, Jin Y, et al. Plasma clozapine concentrations predict clinical response in treatment‐resistant schizophrenia. Journal of Clinical Psychiatry 1994;55(Suppl B):133‐6. CENTRAL

Sacchetti 2009 {published data only}

Sacchetti E, Galluzzo A, Valsecchi P, Romeo F, Gorini B, Warrington L. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophrenia Research 2009;110(1‐3):80‐9. CENTRAL

Simpson 1999 {published data only}

Simpson GM, Josiassen RC, Stanilla JK, de Leon J, Nair C, Abraham G, et al. Double blind study of clozapine dose response in chronic schizophrenia. American Journal of Psychiatry 1999;156(11):1744‐50. CENTRAL

Suzuki 2007 {published data only}

Suzuki T, Uchida H, Watanabe K, Nomura K, Takeuchi H, Tomita M, et al. How effective is it to sequentially switch among olanzapine, quetiapine and risperidone? ‐ A randomized, open‐label study of algorithm‐based antipsychotic treatment to patients with symptomatic schizophrenia in the real‐world clinical setting. Psychopharmacology [psychopharmacologia] 2007;195(2):285‐95. CENTRAL

Weiden 2003 {published data only}

Weiden PJ, Simpson GM, Potkin SG, O'Sullivan RL. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. Journal of Clinical Psychiatry 2003;64(5):580‐8. CENTRAL

Wirshing 1999 {published data only}

Wirshing DA, Marshall B, Green MF, Mintz J, Marder SR, Wirshing WC. Risperidone in treatment‐refractory schizophrenia. American Journal of Psychiatry 1999;156(9):1374‐9. CENTRAL

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References to other published versions of this review

Ir a:

Samara 2015a

Samara MT, Helfer B, Rothe PH, Leucht S. Increasing antipsychotic dose versus switching antipsychotic for non response in schizophrenia. Cochrane Database of Systematic Reviews 2015, Issue 10. [DOI: 10.1002/14651858.CD011884]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

Kinon 1993

Methods

Randomisation: randomised
Blinding: double, no further details.
Duration: 8 weeks; 4 weeks non‐randomised open‐label run‐in phase and 4 weeks randomised double‐blind phase.
Design: parallel.
Location: single‐centre (USA).
Setting: inpatients.

Participants

Diagnosis: schizophrenia, schizoaffective disorder or schizophreniform disorder (DSM‐III‐R).

58 participants entered the double‐blind phase, but only 29 participants were of interest for the purpose of the present review*.
Sex: 64.1% males (for participants entering open label run‐in phase (N = 156)), not indicated for randomised participants.
Age: mean 29.4 years (SD = 7.0), range 18 to 50 years for all participants entering the open label run‐in phase (N = 156), not indicated for randomised participants.
History: age at first hospitalisation ‒ mean 23.0 years (SD = 6.5); number of previous hospitalisations ‒ mean 2.6 (SD = 2.2); data for all participants entering the open label run‐in phase (N = 156), not indicated for randomised participants alone.

Interventions

1. Antipsychotic dose increase: fluphenazine 80 mg/day. N = 16*.

2. Antipsychotic switching: haloperidol 20 mg/day. N = 13*.

3. Antipsychotic dose maintenance: fluphenazine 20 mg/day. N = 18*.

Rescue medication: benztropine, no further details.

Outcomes

Global state: clinically relevant response (defined as CGI‐I ≤ 2 = at least much improved).

Mental state: overall mental state (BRPS total score), negative symptoms (modified SANS).

Unable to use:

Adverse effects: extrapyramidal symptoms (modified SAS, no mean).

Notes

*58 non‐responders entered the double‐blind phase and were randomised to the three treatment options (fluphenazine 20 mg/day, fluphenazine 80 mg/day and haloperidol 20 mg/day). Data were presented for 47 of 58 initially randomised participants (fluphenazine 20 mg/day, N = 18; fluphenazine 80 mg/day, N = 16; and haloperidol 20 mg/day, N = 13). For the purpose of the review, we were interested in the comparison between fluphenazine 80 mg/day, N = 16 and haloperidol 20 mg/day, N = 13; i.e. 29 participants in total.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Nonresponders were then randomly assigned to double‐blind treatment for...", "Subjects were stratified
based on Week 3 serum fluphenazine levels..." (p. 310); no further details.

Allocation concealment (selection bias)

Unclear risk

No details were presented.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

"...double‐blind treatment..." (p. 310); no further details.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"...double‐blind treatment..." (p. 310); no further details.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Outcome not addressed. Data were presented for 81% (47/58) of all randomised participants.

Selective reporting (reporting bias)

High risk

SAS was used but scores were available only for two items, not total.

Other bias

Low risk

No obvious risk for other bias.

Scales

BPRS: Brief Psychiatric Rating Scale

CGI‐I: Clinical Global impression‐Improvement

SANS: Scale for the Assessment of Negative Symptoms

SAS: Simpson Angus Scale

Diagnostic Tools

DSM‐III‐R: Diagnostic and Statistical Manual of Mental Disorders, third edition, revised

Others

mg: milligram

N: number

SD: standard deviation

Characteristics of excluded studies [ordered by study ID]

Ir a:

Study

Reason for exclusion

Agid 2013

Allocation: not randomised

Bondolfi 1995

Allocation: randomised, no further details
Participants: schizophrenia, treatment‐resistant (defined by unresponsiveness or intolerance to appropriate doses of 2 different classes of conventional antipsychotics for at least 4 weeks each); no run‐in phase to confirm that participants have not responded to their current antipsychotic treatment.
Interventions: risperidone versus clozapine; no antipsychotic dose increase versus antipsychotic switching group comparison; drug dosages could be changed after day 14 depending on each participant's response.

Buckley 1995

Allocation: not indicated
Participants: people with schizophrenia whose baseline clozapine concentrations fell below 370 ng/ml.
Interventions: clozapine dose increase versus maintenance; no antipsychotic switching group.

Conley 2003

Allocation: randomised, no further details
Participants: were eligible if they met criteria for treatment resistance; all receiving conventional antipsychotics, risperidone or olanzapine prior to study initiation.
Interventions: olanzapine versus clozapine; no antipsychotic dose increase versus antipsychotic switching group comparison.

Dunn 2005

Allocation: double‐blind phase: randomised; open‐label phase: not randomised.
Participants: were eligible if they had received haloperidol for 6 weeks and showed lack of response.
Interventions: double‐blind phase: no antipsychotic dose increase group; open‐label phase: no comparison, only ziprasidone was administered.

Ganguli 2003

Allocation: randomised, no further details
Participants: were eligible due to tolerability issues as well; not only non‐responders.
Interventions: 3 switching paradigms; no dose increase group

Goff 2013

Allocation: randomised, no further details
Participants: were eligible if they had firstly received open‐label ziprasidone treatment, titrated up to 160 mg/day, for a minimum of 3 weeks and had persistent psychotic symptoms defined by a score of 4 (moderate) or greater on any item of PANSS.
Interventions: ziprasidone dose increase versus ziprasidone dose maintenance; no antipsychotic switching group.

Harvey 2007

Allocation: randomised, no further details
Participants: were eligible due to tolerability issues as well; not only non‐responders.
Interventions: clozapine versus ziprasidone; no dose increase group.

Hatta 2012

Allocation: randomised and concealed; "a random number table", "sequentially numbered, opaque, sealed envelopes" (p. 195).
Participants: were eligible if they had firstly received flexible‐dose oral risperidone treatment for 2 weeks and were considered to be non‐responders according to the Clinical Global Impressions‐Improvement scale (a score of 4 or higher).
Interventions: risperidone dose increase versus risperidone augmented with olanzapine; no antipsychotic switching group.

Honer 2010

Allocation: randomised and concealed; "with a computerized schedule", "the person who generated the randomization schedule was not involved in determining subject eligibility, administering treatment, or determining outcome" (p. 14).
Participants: were eligible if they had firstly received open‐label quetiapine treatment of 800 mg/day for 4 weeks and had persistent positive and negative symptoms and a rating in the Clinical Global Impressions scale of at least 4.
Interventions: quetiapine dose increase versus quetiapine dose maintenance; no antipsychotic switching group.

Janicak 1994

Allocation: randomised, no further details
Participants: acutely psychotic (primarily people with schizophrenia) that were non‐responders to haloperidol treatment for 2 weeks.
Interventions: low versus middle versus high haloperidol plasma level; no antipsychotic switching group.

Kane 1988

Allocation: randomised, no further details
Participants: were eligible if they had firstly received single‐blind flexible haloperidol treatment (up to 60 mg/day or higher) for 6 weeks and were considered to be non‐responders.
Interventions: clozapine versus chlorpromazine; no antipsychotic dose increase group.

Kane 2007

Allocation: randomised, no further details.
Participants: were eligible if they had received at least 15 mg/day olanzapine or 6 mg/day risperidone for a minimum of 3 weeks and showed no significant improvement.
Interventions: aripiprazole versus perphenazine; no antipsychotic dose increase group.

Kim 2013

Allocation: not randomised.

Kinon 2010

Allocation: randomised and concealed; "interactive voice response system", "the precise response criterion was withheld from research staff but defined a priori in the Institutional Review Board (IRB) Supplement, and early responder/non‐responder status was identified and treatment randomization was implemented using an interactive voice response (IVR) system" (p583).
Participants: were eligible if they had received single‐blind (i.e. to dose and dose adjustments), flexible‐dose therapy with risperidone 2 mg/day to 6 mg/day for 2 weeks and did not respond to treatment.
Interventions: risperidone versus olanzapine; no antipsychotic dose increase group.

Lindenmayer 2011

Allocation: randomised, no further details
Participants: were eligible if they had firstly received open label quetiapine 600 mg/day for 4 weeks and did not demonstrate an initial response defined as ≤ 15% PANSS total score reduction.
Interventions: quetiapine 600 mg/day versus 1200 mg/day; no antipsychotic switching group.

McEvoy 2013

Allocation: randomised, no further details.
Participants: non‐acute patients appropriate for switching current antipsychotic medication; not indicated if they were non‐responders.
Interventions: 3 switching strategies to lurasidone; no antipsychotic dose increase group.

NCT00161018

Allocation: randomised, no further details.
Participants: optimised with routine antipsychotic treatment for 4 to 6 weeks to prospectively establish lack of response to conventional antipsychotic therapy.
Interventions: lack of response to 4 to 6 weeks' conventional antipsychotic therapy, then randomisation to quetiapine, risperidone or fluphenazine; no antipsychotic dose increase group.

NCT00191555

Allocation: randomised, no further details.
Participants: were eligible due to tolerability issues as well; not only non‐responders.

Potkin 1994

Allocation: randomised, no further details.
Participants: were eligible if they were judged to be non‐responders to conventional antipsychotics.
Interventions: randomised to clozapine 400 mg/day or 800 md/day; no antipsychotic switching group.

Sacchetti 2009

Allocation: randomised; "randomised on a centralized basis" (p. 82).
Participants: were eligible due to lack of tolerance as well; not only non‐responders.
Interventions: ziprasidone versus clozapine; no antipsychotic dose increase group.

Simpson 1999

Allocation: randomised, no further details.
Participants: people with treatment refractory symptoms of schizophrenia.
Interventions: clozapine 100, 300 or 600 mg/day; if no improvement was observed after 16 weeks, participants were randomised to one of the other two dosages, no switching group.

Suzuki 2007

Allocation: not randomised; randomisation to treatment algorithms, switching of all non‐responders.

Weiden 2003

Allocation: randomised, no further details
Participants: stable outpatients with persistent symptoms or troublesome side effects; not non‐responders.
Interventions: 3 switching strategies to ziprasidone; no antipsychotic dose increase group.

Wirshing 1999

Allocation: randomised; "a computerized random‐number‐generating program" (p. 1375).
Participants: were eligible due to lack of tolerance as well; not only non‐responders.
Interventions: risperidone versus haloperidol; no antipsychotic dose increase group.

Data and analyses

Open in table viewer
Comparison 1. Increasing the antipsychotic dose versus switching the atipsychotic drug

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Global state: clinically relevant response – as defined by trial Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.17, 15.99]
Analysis 1.1
Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 1 Global state: clinically relevant response – as defined by trial.

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 1 Global state: clinically relevant response – as defined by trial.

2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor) Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

2.0 [‐4.20, 8.20]
Analysis 1.2
Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor).

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor).

3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor) Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

3.40 [‐12.56, 19.36]
Analysis 1.3
Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor).

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor).

Study flow diagram for trial selection up to March 2017
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Figure 1

Study flow diagram for trial selection up to March 2017

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 1 Global state: clinically relevant response – as defined by trial.
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Analysis 1.1

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 1 Global state: clinically relevant response – as defined by trial.

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Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor).
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Analysis 1.2

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor).

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Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor).
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Analysis 1.3

Comparison 1 Increasing the antipsychotic dose versus switching the atipsychotic drug, Outcome 3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor).

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Table 1. Suggested design for future study

Methods

Randomisation: random
Allocation: concealed
Blinding: double blind
Duration: at least 2 weeks run‐in phase to confirm non response to initial treatment and at least 4 weeks' randomised double‐blind phase.
Setting: in‐ or out‐patients

Participants

Diagnosis: people with schizophrenia, schizoaffective disorder or schizophreniform disorder

N > 450
Gender: male and female
Age: mean 30 years (SD = 7.0), range 18 to 65 years

Interventions

All participants firstly receive treatment with one antipsychotic drug for at least 2 weeks. Those participants who do not at least minimally improve after 2 weeks, are considered non‐responders and are randomised to:

1. increasing the dose of the initial antipsychotic drug above the officially recommended dose range; or

2. switching the initial antipsychotic drug to another one with a different receptor profile; or

3. continuing treatment with the initial antipsychotic drug and at the same, initial dose (within the officially recommended dose range).

Outcomes

Response (defined as PANSS or BPRS decrease ≥ 50%)*

Relapse

Leaving the study early due to any reason

Leaving the study early due to side effects

General mental state: average change in general mental state scores

Adverse effects: at least one adverse effect; clinically important general adverse effects; sudden and unexpected death

Service use: time in hospital

Quality of life

All outcomes by time ‒ short term (up to 12 weeks), medium term (13 to 26 weeks) and long term (over 26 weeks)

Notes

*Primary outcome of interest
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Table 1. Suggested design for future study
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Summary of findings for the main comparison. Increasing the antipsychotic dose compared to switching the antipsychotic drug for non response in schizophrenia

Increasing the antipsychotic dose compared to switching the antipsychotic drug for non responsein schizophrenia

Patient or population: patients with non response in schizophrenia
Settings: inpatients
Intervention: increasing the antipsychotic dose
Comparison: switching the antipsychotic drug

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Switching the atipsychotic drug

Increasing the antipsychotic dose

Global state: Clinically relevant response – as defined by trial
Risk ratio
Follow‐up: mean 4 weeks

77 per 1000

125 per 1000
(13 to 1000)

RR 1.63
(0.17 to 15.99)

29
(1 study)

⊕⊝⊝⊝
very low1,2

Leaving the study early: Tolerability ‒leaving the study early due to side effects

See comment

See comment

Not estimable

0
(0)

See comment

No studies reported on this outcome.

Leaving the study early: Acceptability ‒leaving the study early due to any reason

See comment

See comment

Not estimable

0
(0)

See comment

No studies reported on this outcome,

General mental state ‒BPRS total score at endpoint*
Weighted mean difference
Follow‐up: mean 4 weeks

The mean general mental state ‒ BPRS total score at endpoint in the control groups was
38.2 points in BPRS

The mean general mental state ‐ BPRS total score at endpoint in the intervention groups was
2 higher
(4.2 lower to 8.2 higher)

29
(1 study)

⊕⊝⊝⊝
very low1,2

Data for prespecified outcome: Clinically important change were not reported.

Adverse effects ‒at least one adverse effect

See comment

See comment

Not estimable

0
(0)

See comment

No studies reported on this outcome.

Service use ‒time in hospital

See comment

See comment

Not estimable

0
(0)

See comment

No studies reported on this outcome.

Quality of life ‒average change in quality of life

See comment

See comment

Not estimable

0
(0)

See comment

No studies reported on this outcome.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

1 Imprecision: total (cumulative) sample size was just 29 participants and 95% confidence interval around the estimate of effect included no effect and appreciable benefit and appreciable harm; thus, very serious imprecision was present.
2 Publication bias: strongly suspected as there is only one study.

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Summary of findings for the main comparison. Increasing the antipsychotic dose compared to switching the antipsychotic drug for non response in schizophrenia
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Comparison 1. Increasing the antipsychotic dose versus switching the atipsychotic drug

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Global state: clinically relevant response – as defined by trial Show forest plot

1

29

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.17, 15.99]

2 Mental state: general mental state ‐ average endpoint score (BPRS total, high =poor) Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

2.0 [‐4.20, 8.20]

3 Mental state: negative symptoms ‐ average endpoint score (SANS, high = poor) Show forest plot

1

29

Mean Difference (IV, Random, 95% CI)

3.40 [‐12.56, 19.36]
Figuras y tablas -
Comparison 1. Increasing the antipsychotic dose versus switching the atipsychotic drug
Ir a la tabla de la revisión