Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force

Kamilla W Miskowiak; Zacharias K Obel; Riccardo Guglielmo; Caterina Del Mar Bonnin; Christopher R Bowie; Vicent Balanzá-Martínez; Katherine E Burdick; Andre F Carvalho; Annemieke Dols; Katie Douglas; Peter Gallagher; Lars V Kessing; Beny Lafer; Kathryn E Lewandowski; Carlos López-Jaramillo; Anabel Martinez-Aran; Roger S McIntyre; Richard J Porter; Scot E Purdon; Ayal Schaffer; Paul R A Stokes; Tomiki Sumiyoshi; Ivan J Torres; Tamsyn E Van Rheenen; Lakshmi N Yatham; Allan H Young; Eduard Vieta; Gregor Hasler

doi:10.1111/bdi.13414

Efficacy and safety of established and off-label ADHD drug therapies for cognitive impairment or attention-deficit hyperactivity disorder symptoms in bipolar disorder: A systematic review by the ISBD Targeting Cognition Task Force

Bipolar Disord. 2024 May;26(3):216-239. doi: 10.1111/bdi.13414. Epub 2024 Mar 3.

Authors

Kamilla W Miskowiak^{1

2}, Zacharias K Obel^{1

2}, Riccardo Guglielmo^{3

4}, Caterina Del Mar Bonnin⁵, Christopher R Bowie⁶, Vicent Balanzá-Martínez⁷, Katherine E Burdick^{8

9}, Andre F Carvalho¹⁰, Annemieke Dols¹¹, Katie Douglas¹², Peter Gallagher¹³, Lars V Kessing^{2

14}, Beny Lafer¹⁵, Kathryn E Lewandowski^{8

16}, Carlos López-Jaramillo¹⁷, Anabel Martinez-Aran⁵, Roger S McIntyre¹⁸, Richard J Porter¹², Scot E Purdon¹⁹, Ayal Schaffer²⁰, Paul R A Stokes²¹, Tomiki Sumiyoshi²², Ivan J Torres²³, Tamsyn E Van Rheenen^{24

25}, Lakshmi N Yatham²³, Allan H Young²¹, Eduard Vieta⁵, Gregor Hasler³

Affiliations

¹ Neurocognition and Emotion in Affective Disorders (NEAD) Centre, Department of Psychology, University of Copenhagen | Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.
² Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
³ Psychiatry Research Unit, University of Fribourg, Fribourg, Switzerland.
⁴ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, Genoa, Italy.
⁵ Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
⁶ Department of Psychology, Queen's University, Kingston, Canada.
⁷ Department of Medicine, University of Valencia, Valencia, Spain.
⁸ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Department of Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹⁰ IMPACT Strategic Research Centre (Innovation in Mental and Physical Health and Clinical Treatment), Deakin University, Geelong, Victoria, Australia.
¹¹ Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
¹² Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
¹³ Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.
¹⁴ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
¹⁵ Bipolar Disorder Research Program, Institute of Psychiatry, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
¹⁶ McLean Hospital, Schizophrenia and Bipolar Disorder Program, Belmont, Massachusetts, USA.
¹⁷ Research Group in Psychiatry, Department of Psychiatry, Universidad de Antioquia, Medellín, Colombia.
¹⁸ Mood Disorders Psychopharmacology Unit, Brain and Cognition Discovery Foundation, University of Toronto, Toronto, Canada.
¹⁹ Department of Psychiatry, University of Alberta, Edmonton, Canada.
²⁰ Department of Psychiatry, University of Toronto, Toronto, Canada.
²¹ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²² Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.
²³ Department of Psychiatry, University of British Columbia, Vancouver, Canada.
²⁴ Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Carlton, Australia.
²⁵ Centre for Mental Health, Faculty of Health, Arts and Design, Swinburne University, Melbourne, Australia.

PMID: 38433530
DOI: 10.1111/bdi.13414

Abstract

Background: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD.

Methods: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials.

Results: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias.

Conclusions: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.

Keywords: ISBD task force; attention‐deficit hyperactivity disorder, cognitive impairment; bipolar disorder; medication; recommendations; systematic review.

Publication types

Systematic Review
Review

MeSH terms

Attention Deficit Disorder with Hyperactivity* / drug therapy
Bipolar Disorder* / drug therapy
Central Nervous System Stimulants* / adverse effects
Central Nervous System Stimulants* / therapeutic use
Cognitive Dysfunction* / drug therapy
Cognitive Dysfunction* / etiology
Humans
Methylphenidate / adverse effects
Methylphenidate / therapeutic use
Off-Label Use

Substances

Central Nervous System Stimulants
Methylphenidate