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The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis

The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis
The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose–response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose–response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

1359-4184
1562–1572
Farhat, Luis C.
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Flores, José M.
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Behling, Emily
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Avila-quintero, Victor J.
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Lombroso, Adam
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Cortese, Samuele
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Polanczyk, Guilherme V.
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Bloch, Michael H.
b0629a2d-eef2-4dc4-894f-c1d1779db227
Farhat, Luis C.
c4eb65e6-7fd3-43ed-891e-3584e83ce20b
Flores, José M.
a2227a0b-ab8c-4326-ab02-49ca5666fa02
Behling, Emily
bde4e9b9-c304-4715-b736-4180510b5bc8
Avila-quintero, Victor J.
b0297f01-33cb-460c-8b32-1fe03672c48c
Lombroso, Adam
bb9426d2-b522-4e37-b6d6-5e73e2b4bd91
Cortese, Samuele
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Polanczyk, Guilherme V.
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Bloch, Michael H.
b0629a2d-eef2-4dc4-894f-c1d1779db227

Farhat, Luis C., Flores, José M., Behling, Emily, Avila-quintero, Victor J., Lombroso, Adam, Cortese, Samuele, Polanczyk, Guilherme V. and Bloch, Michael H. (2022) The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: a meta-analysis. Molecular Psychiatry, 27 (3), 1562–1572. (doi:10.1038/s41380-021-01391-9).

Record type: Article

Abstract

Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose–response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose–response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.

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The effects of stimulant dose and dosing strategy
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Accepted/In Press date: 12 November 2021
e-pub ahead of print date: 14 January 2022
Published date: March 2022

Identifiers

Local EPrints ID: 456821
URI: http://eprints.soton.ac.uk/id/eprint/456821
ISSN: 1359-4184
PURE UUID: 31fd37a7-fa39-4ae6-ae70-19e1e32f91f1
ORCID for Samuele Cortese: ORCID iD orcid.org/0000-0001-5877-8075

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Date deposited: 12 May 2022 16:36
Last modified: 16 Dec 2022 05:01

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Contributors

Author: Luis C. Farhat
Author: José M. Flores
Author: Emily Behling
Author: Victor J. Avila-quintero
Author: Adam Lombroso
Author: Samuele Cortese ORCID iD
Author: Guilherme V. Polanczyk
Author: Michael H. Bloch

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