Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis
Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the rela...
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| Published in | PloS one Vol. 15; no. 10; p. e0240584 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
21.10.2020
Public Library of Science (PLoS) |
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| Online Access | Get full text |
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| Abstract | Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.
We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.
Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.
Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.
PROSPERO no. CRD 42015026049. |
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| AbstractList | Background Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. Methods We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane’s Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. Results Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. Conclusions Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. Registration PROSPERO no. CRD 42015026049 Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. PROSPERO no. CRD 42015026049. BackgroundAttention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.MethodsWe searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.ResultsEighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.ConclusionsOverall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.RegistrationPROSPERO no. CRD 42015026049. Background Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD. Methods We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane’s Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework. Results Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration. Conclusions Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs. Registration PROSPERO no. CRD 42015026049 |
| Audience | Academic |
| Author | Bai, Zemin Chojecki, Dagmara Wells, George A Johnston, Amy Husereau, Don Tsakonas, Eva Kelly, Shannon E Eagles, Caroline Hsieh, Shu-Ching Skidmore, Becky Elliott, Jesse Charach, Alice Hossain, Alomgir Mamdani, Muhammad |
| AuthorAffiliation | 4 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada 6 Independent Information Specialist, Ottawa, Ontario, Canada Copenhagen University Hospital, DENMARK 1 Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada 7 Independent Research Consultant, Montreal, Quebec, Canada 8 Independent Information Specialist, Edmonton, Alberta, Canada 9 Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada 5 The Hospital for Sick Children, Toronto, Ontario, Canada 3 Brain and Heart Nexus Research Program, University of Ottawa Heart Institute, Ottawa, Ontario, Canada 2 School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada |
| AuthorAffiliation_xml | – name: 6 Independent Information Specialist, Ottawa, Ontario, Canada – name: 9 Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada – name: 7 Independent Research Consultant, Montreal, Quebec, Canada – name: 8 Independent Information Specialist, Edmonton, Alberta, Canada – name: 3 Brain and Heart Nexus Research Program, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – name: 2 School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada – name: 4 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada – name: Copenhagen University Hospital, DENMARK – name: 1 Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – name: 5 The Hospital for Sick Children, Toronto, Ontario, Canada |
| Author_xml | – sequence: 1 givenname: Jesse orcidid: 0000-0002-2501-1641 surname: Elliott fullname: Elliott, Jesse organization: School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada – sequence: 2 givenname: Amy orcidid: 0000-0003-1934-7867 surname: Johnston fullname: Johnston, Amy organization: Brain and Heart Nexus Research Program, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – sequence: 3 givenname: Don surname: Husereau fullname: Husereau, Don organization: School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada – sequence: 4 givenname: Shannon E surname: Kelly fullname: Kelly, Shannon E organization: School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada – sequence: 5 givenname: Caroline surname: Eagles fullname: Eagles, Caroline organization: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – sequence: 6 givenname: Alice surname: Charach fullname: Charach, Alice organization: The Hospital for Sick Children, Toronto, Ontario, Canada – sequence: 7 givenname: Shu-Ching surname: Hsieh fullname: Hsieh, Shu-Ching organization: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – sequence: 8 givenname: Zemin surname: Bai fullname: Bai, Zemin organization: Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada – sequence: 9 givenname: Alomgir surname: Hossain fullname: Hossain, Alomgir organization: School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada – sequence: 10 givenname: Becky orcidid: 0000-0001-8293-9238 surname: Skidmore fullname: Skidmore, Becky organization: Independent Information Specialist, Ottawa, Ontario, Canada – sequence: 11 givenname: Eva surname: Tsakonas fullname: Tsakonas, Eva organization: Independent Research Consultant, Montreal, Quebec, Canada – sequence: 12 givenname: Dagmara surname: Chojecki fullname: Chojecki, Dagmara organization: Independent Information Specialist, Edmonton, Alberta, Canada – sequence: 13 givenname: Muhammad surname: Mamdani fullname: Mamdani, Muhammad organization: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada – sequence: 14 givenname: George A surname: Wells fullname: Wells, George A organization: School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33085721$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | COPYRIGHT 2020 Public Library of Science 2020 Elliott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2020 Elliott et al 2020 Elliott et al |
| Copyright_xml | – notice: COPYRIGHT 2020 Public Library of Science – notice: 2020 Elliott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2020 Elliott et al 2020 Elliott et al |
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| DOI | 10.1371/journal.pone.0240584 |
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| Notes | Competing Interests: Don Husereau has provided advice and analysis for Eli Lilly Canada and Purdue Canada Inc. He is also an expert advisor for the Ontario Ministry of Health and Long Term Care. Alice Charach has received a limited one-time speaker honorarium from Janssen, Inc. She has no additional biomedical financial interests or potential conflicts of interest to declare. Ms. Skidmore is a paid information consultant/contractor to the Ottawa Hospital Heart Institute. Muhammad Mamdani has served as a member of an advisory board for Hoffman La Roche, Pfizer, Novartis, GlaxoSmithKline and Eli Lilly Canada. None declared for JE, AJ, SK, C.E., SH, ZB, ET, DC, or GW. This does not alter our adherence to PLOS ONE policies on sharing data and materials. |
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| Snippet | Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative... Background Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the... BackgroundAttention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the... Background Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the... |
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| SubjectTerms | Adult Adults Amphetamine - adverse effects Amphetamine - therapeutic use Amphetamines Atomoxetine Hydrochloride - adverse effects Atomoxetine Hydrochloride - therapeutic use Attention Deficit Disorder with Hyperactivity - drug therapy Attention Deficit Disorder with Hyperactivity - epidemiology Attention Deficit Disorder with Hyperactivity - pathology Attention deficit hyperactivity disorder Bayes Theorem Bayesian analysis Bias Biology and Life Sciences Bupropion Bupropion - adverse effects Bupropion - therapeutic use Central Nervous System Stimulants - adverse effects Clinical decision making Clinical trials Computer and Information Sciences Decision making Dextroamphetamine - adverse effects Dextroamphetamine - therapeutic use Drug therapy Drug-Related Side Effects and Adverse Reactions - classification Drug-Related Side Effects and Adverse Reactions - epidemiology Drug-Related Side Effects and Adverse Reactions - pathology Emergency medical care Emergency medical services Executive function Female Guanfacine - adverse effects Guanfacine - therapeutic use Health risks Humans Intervention Lisdexamfetamine Dimesylate - adverse effects Lisdexamfetamine Dimesylate - therapeutic use Long-term effects Male Medicine and Health Sciences Meta-analysis Methylphenidate Methylphenidate - adverse effects Methylphenidate - therapeutic use Modafinil Modafinil - adverse effects Modafinil - therapeutic use Network Meta-Analysis Patient outcomes Patients Pharmacology Physical Sciences Quality of Life Randomized Controlled Trials as Topic Research and Analysis Methods Risk analysis Risk assessment Salts |
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| Title | Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/33085721 https://www.proquest.com/docview/2452935631 https://pubmed.ncbi.nlm.nih.gov/PMC7577505 https://doaj.org/article/a7e4bade2cdd411ea9b226da59e7951d http://dx.doi.org/10.1371/journal.pone.0240584 |
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