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Cited by 301Schizophrenia research and treatmentTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia

Leucht, Stefan, Crippa, Alessio, Siafis, Spyridon, Patel, Maxine X., Orsini, Nicola, Davis, John M.·2020·American Journal of Psychiatry
DOI 10.1176/appi.ajp.2019.19010034
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Abstract

OBJECTIVE: The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses. METHODS: A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses. RESULTS: Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice. CONCLUSIONS: In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

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  • LAIs have more restrictive dose limitations than oral treatments; however, high-dose LAI treatment has not been shown to be superior to LAI treatment at doses within the identified therapeutic range.

    “Also, LAIs have more restrictive dose limitations than oral treatments; however, high-dose LAI treatment has not been shown to be superior to LAI treatment at doses within the identified therapeutic range [106–108].”

    From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [107]

  • A recent meta-analysis found a continuous hyperbolic relationship between antipsychotic dose and clinical response, mirroring the relationship between dose and D2 occupancy.

    “However, a recent meta-analysis has found a continuous hyperbolic relationship between antipsychotic dose and clinical response,109 mirroring the relationship between dose and D2 occupancy.”

    From A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse (2021) · cites this paper as [109]

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Authors
Leucht, S., Crippa, A., Siafis, S., Patel, M. X., Orsini, N., & Davis, J. M.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2020-04-01
Volume
177
Issue
4
Pages
342-353
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.2019.19010034
OpenAlex
W2995680584
Cited by
301
References
100
Citations by year
2026: 37 · 2025: 64 · 2024: 63 · 2023: 37 · 2022: 38 · 2021: 46 · 2020: 16
FWCI
4.20
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Funders
  • Sanofi
  • Teva Pharmaceutical Industries
  • Sunovion
  • National Institute for Health and Care Research (NIHR/CS/009/010)
  • Gedeon Richter
  • H. Lundbeck A/S
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
dose-response relationship, antipsychotic drugs, acute schizophrenia, atypical antipsychotics, haloperidol, long-acting injectable antipsychotics, positive symptoms, negative symptoms, Brief Psychiatric Rating Scale, risperidone, olanzapine, aripiprazole, amisulpride
MeSH terms
Aripiprazole, Paliperidone Palmitate, Lurasidone Hydrochloride, Quetiapine Fumarate, Olanzapine, Acute Disease, Administration, Oral, Clozapine, Delayed-Action Preparations, Dose-Response Relationship, Drug, Haloperidol, Humans, Imidazoles, Indoles, Isoxazoles, Piperazines, Piperidines, Schizophrenia, Schizophrenic Psychology, Thiazoles, Thiophenes, Antipsychotic Agents, Quinolones, Risperidone

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