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, 10 (2), e0116407

Effect of Treatment Modality on Long-Term Outcomes in Attention-Deficit/Hyperactivity Disorder: A Systematic Review


Effect of Treatment Modality on Long-Term Outcomes in Attention-Deficit/Hyperactivity Disorder: A Systematic Review

L Eugene Arnold et al. PLoS One.


Background: Evaluation of treatments for attention-deficit/hyperactivity disorder (ADHD) previously focused on symptom control, but attention has shifted to functional outcomes. The effect of different ADHD treatment periods and modalities (pharmacological, non-pharmacological, and combination) on long-term outcomes needs to be more comprehensively understood.

Methods: A systematic search of 12 literature databases using Cochrane's guidelines yielded 403 English-language peer-reviewed, primary studies reporting long-term outcomes (≥2 years). We evaluated relative effects of treatment modalities and durations and effect sizes of outcomes reported as statistically significantly improved with treatment.

Results: The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes. A majority of outcomes improved regardless of age of treatment initiation (60%-75%) or treatment duration (62%-72%). Studies with short treatment duration had shorter follow-up times (mean 3.2 years total study length) than those with longer treatment durations (mean 7.1 years total study length). Studies with follow-up times <3 years reported benefit with treatment for 93% of outcomes, whereas those with follow-up times ≥3 years reported treatment benefit for 57% of outcomes. Post-hoc analysis indicated that this result was related to the measurement of outcomes at longer periods (3.2 versus 0.4 years) after treatment cessation in studies with longer total study length.

Conclusions: While the majority of long-term outcomes of ADHD improve with all treatment modalities, the combination of pharmacological and non-pharmacological treatment was most consistently associated with improved long-term outcomes and large effect sizes. Older treatment initiation age or longer durations did not markedly affect proportion of improved outcomes reported, but measurement of outcomes long periods after treatment cessation may attenuate results.

Conflict of interest statement

Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Arnold has received research funding from Curemark, Lilly, Forest, and Shire; advisory board honoraria from Astra-Zeneca, Biomarin, Noven, Otsuka, Roche, Seaside Therapeutics, and Shire; consulting fees from Tris Pharma, Gowlings, and Pfizer; and travel support from Noven (nothing for contributing to this article). At the time this analysis was performed and the manuscript written, Dr. Hodgkins was an employee of Shire Development LLC, owned Shire stock, and had Shire stock options. Dr. Caci has received consulting fees from Shire (nothing for contributing to this article). Dr. Kahle is owner of BPS International, which received consultancy fees from Shire Development LLC for this and previous research. Dr. Young has received research funding or consulting fees from Janssen-Cilag, Eli-Lilly, Novartis, Flynn-Pharma, and Shire (nothing for contributing to this article). She was a member of the United Kingdom NICE Guideline Development Group for ADHD and is a consultant at the Cognitive Centre of Canada. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.


Fig 1
Fig 1. Flow diagram showing the selection process and results during the study screening process.
Fig 2
Fig 2. Effect Sizes.
Effect sizes for outcomes reported to have statistically significant improvement with treatment compared with pre-treatment baseline scores (A) or a group of individuals with untreated ADHD (B). Effect sizes were grouped according to treatment modality used in each study and graphed with Y-axis scales appropriate for each index (Cohen’s d, f, or w) that were then matched at conventional criteria [23] for small, medium, and large effect sizes (dashed lines) for comparison (values for each index shown on right Y-axis).
Fig 3
Fig 3. Treatment Modalities.
(A) Benefit with each treatment modality for each outcome domain. Each bar represents the percentage of outcomes reported to exhibit benefit (either significantly improved from untreated baseline or significantly improved compared with a group of untreated individuals with ADHD) with each treatment modality. (B) Benefit with each treatment modality for different age groups at follow-up. The colored sections within bars represent the percentage of outcomes reported to improve (benefit) or not (no benefit) for each treatment modality for children (mid-range age 6–12 years) and adolescents (mid-range age 13–17 years), and all ages. Adults (mid-range age 18–84 years) are not presented separately because there were only studies of pharmacological treatment in this age group at follow-up. The numbers on the bars indicate the number of outcomes represented in each bar. Some studies reported outcomes with more than one type of treatment.
Fig 4
Fig 4. Effect of age of treatment initiation, treatment duration, and follow-up time.
Bars represent the percentage of outcomes reported for each age-of-initiation group (A), treatment duration (B), or time to follow-up measures (C). The numbers on the bars are the number of outcomes represented by the section of the bar. The number of studies represented in each bar is presented below the bars.
Fig 5
Fig 5. Treatment benefit by follow-up age group for each outcome domain.
Colors and shades within bars represent the percentage of outcomes reported for each outcome domain. Blue = benefit; orange-yellow = no benefit. Darker shades indicate younger age groups. The numbers on the bars are the number of outcomes represented by the section of the bar.

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    1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. 4th ed Washington, DC: American Psychiatric Association.
    1. Brod M, Pohlman B, Lasser R, Hodgkins P (2012) Comparison of the burden of illness for adults with ADHD across seven countries: a qualitative study. Health Qual Life Outcomes 10: 47 10.1186/1477-7525-10-47 - DOI - PMC - PubMed
    1. Shaw M, Hodgkins P, Caci H, Young S, Kahle J, et al. (2012) A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med 10: 99 10.1186/1741-7015-10-99 - DOI - PMC - PubMed
    1. Mill J, Caspi A, Williams BS, Craig I, Taylor A, et al. (2006) Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts. Arch Gen Psychiatry 63: 462–469. - PubMed
    1. Rasmussen P, Gillberg C (2000) Natural outcome of ADHD with developmental coordination disorder at age 22 years: a controlled, longitudinal, community-based study. J Am Acad Child Adolesc Psychiatry 39: 1424–1431. - PubMed

Grant support

This work was sponsored by Shire Development LLC ( The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.