Cited by 197Attention Deficit Hyperactivity DisorderSchizophrenia research and treatmentSubstance Abuse Treatment and Outcomes

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Efficacy of Methylphenidate for Adults with Attention-Deficit Hyperactivity Disorder: A Meta-Regression Analysis

Castells, Xavier, Ramos-Quiroga, Josep Antoni, Rigau, David, Bosch, Rosa, Nogueira, Mariana, Vidal, Xavier, Casas, Miguel·2011·CNS Drugs

DOI 10.2165/11539440-000000000-00000

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Abstract

Background The efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder (ADHD) shows wide between-study variability, which yields heterogeneous results in meta-analysis. The reasons for this variability have not been comprehensively investigated.Objectives To determine the influence of treatment-related covariates of methylphenidate for adults with ADHD by means of meta-analysis. Clinical and methodological moderators and clinical trial reporting quality were also collected to control for their potential confounding effect.Methods We searched for randomized, placebo-controlled clinical trials investigating the efficacy of methylphenidate for adults with ADHD. The study outcome was the efficacy of methylphenidate for reducing ADHD symptom severity. Treatment-related covariates included dose, type of drug-release formulation (formulations with a continuous drug release vs those with a non-continuous drug release), dose regimen (fixed vs flexible) and treatment length. Clinical (presence of co-morbid substance use disorders [SUD]) and methodological (design and rater) covariates were also collected, in addition to clinical trial reporting quality. The standardized mean difference (SMD) was calculated for each study. The analysis of the influence of methylphenidate effect modifiers was performed by means of random-effects meta-regression.Results Eighteen studies were included. Dose, type of formulation and SUD appeared to modify the efficacy of methylphenidate in the bivariate analysis. These variables were included in a multivariate meta-regression, which showed that methylphenidate, at an average dose of 57.4 mg/day, delivered by means of non-continuous-release formulations, had a moderate effect on ADHD symptoms compared with placebo (SMD 0.57-0.58). A dose-response relationship was found, indicating that efficacy could be increased by SMD 0.11-0.12 for every 10 mg increment of methylphenidate. Continuous-release formulations and co-morbid SUD appeared to reduce the efficacy of methylphenidate. Nevertheless, the effect of treatment formulation may have been confounded by co-morbid SUD, since all studies using this continuous-release formulation were conducted in dual ADHD-SUD patients. No residual heterogeneity was found.Conclusions This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion. The efficacy of methylphenidate appears to be reduced in patients with co-morbid SUD. It is unclear whether methylphenidate efficacy is influenced by the type of formulation, because the effect of this covariate is confounded by that of co-morbid SUD.

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“These drugs have also shown efficacy in ADHD patients (Castells et al., 2010).”
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Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET: Serotonin Transporter in ADHD Revealed by PET
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“58 This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion [90]”
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“Recently, Castells et al. (2011) performed a multivariate meta-regression with 18 studies which showed that methylphenidate had a moderate effect on ADHD symptoms compared with placebo in a dose-dependent fashion with effect sizes between 0.57 and 0.58.”
MethodInfluential
Pharmacotherapeutic strategies for the treatment of attention-deficit hyperactivity (ADHD) disorder with comorbid substance-use disorder (SUD)
Perugi, G., Pallucchini, A., Rizzato, S., Rossi, P. D., Sani, G., Maremmani, A. G. I., Pinzone, V., & Maremmani, I. (2018) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2018.1551878 · Cited by 38
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“In this sense, the utility of the use of small effect genes might be questioned in terms of application to clinical practice, especially considering the large effect sizes attributed to ADHD stimulant treatment (Castells et al., 2011; Wigal, 2009).”
Background
Pharmacological and clinical dilemmas of prescribing in co‐morbid adult attention‐deficit/hyperactivity disorder and addiction
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Methylphenidate regulation of osteoclasts in a dose- and sex-dependent manner adversely affects skeletal mechanical integrity
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“As a result, in patientswith ADHDand comorbid SUD, pharmacological treatments have exerted a moderate or negligible effect on ADHD symptoms; however, the effect of these treatments on substance abuse is uncertain (Castells et al., 2011; Cunill, Castells, Tobias, & Capella, 2014;Wilens et al., 2005).”
BackgroundResultInfluential
New Formulations of Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder: Pharmacokinetics, Efficacy, and Tolerability
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“Numerous studies have shown that treatment with methylphenidate results in improved ADHD symptoms [9–11] and appears to be safe with, in general, mild and transient side effects [12–14].”
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“12 for every 10-mg increment of methylphenidate [19].”
Influential
The South African Society of Psychiatrists/Psychiatry Management Group management guidelines for adult attention-deficit/hyperactivity disorder
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“11,12 The novel psychostimulant, lisdexamfetamine (LDX), is also efficacious in the treatment of ADHD.”
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“Safety and efficacy have also been demonstrated in adults with ADHD (Castells et al., 2011; Cortese et al., 2018; Solmi et al., 2020), however, despite evidence based guidelines, only half of the European countries have approved the use of MPH for the management of adult ADHD (Chappuy et al.”
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Attention Deficit Hyperactivity Disorder Symptoms are Common in Patients in Opioid Maintenance Treatment
Abel, K. F., Ravndal, E., Clausen, T., & Bramness, J. (2018) · European Addiction Research · doi:10.1159/000484240 · Cited by 21
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A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients
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“For example, in a recent metaanalysis of methylphenidate studies, five of the 18 studies included had not used pure DSM-IV diagnostic criteria for entry (Castells et al., 2011).”
BackgroundResult
Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research
Higgins, G. A., Silenieks, L. B., MacMillan, C., Thevarkunnel, S., Parachikova, A. I., Mombereau, C., Lindgren, H. S., & Bastlund, J. F. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00427 · Cited by 26
Neural and Behavioral Endophenotypes in ADHD
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Relationship Between Treatment Duration and Efficacy of Pharmacological Treatment for ADHD: A Meta-Analysis and Meta-Regression of 87 Randomized Controlled Clinical Trials
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“As a dose–response relationship has been suggested for psychostimulants (Biederman et al., 2002; Castells et al., 2011), the dose of methylphenidate or amphetamine derivatives of the RCTs investigating these drugs was classified as “high” or “low,” using the midpoint between the lowest and highest…”
Background
ADHD and Substance Use Disorders in Young People
Taubin, D., Wilson, J. C., & Wilens, T. E. (2022) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2022.01.005 · Cited by 26
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Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence
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“However, in ADHD patients with comorbid cocaine dependence (ADHD+COC), controlled studies have shown little to no effect of MPH treatment in reducing symptoms of ADHD or cocaine use (Castells et al., 2011; Levin et al., 1998, 2007a, 2007b; Schubiner et al., 2002; Somoza et al., 2004; Szobot et al., 2008a).”
Background
Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults
Cândido, R. C. F., de Padua, C. A. M., Golder, S., & Junqueira, D. R. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013011.pub2 · Cited by 35
“The reasons for the variability in the available evidence are not clearly documented in the literature, but they appear to be related to factors such as dose, type of formulation and treatment regimen (Castells 2011), as well as the comparison methods used (Cortese 2018).”
BackgroundMethod
Often Overlooked and Ignored, but Do Not Underestimate Its Relevance: ADHD in Addiction – Addiction in ADHD
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Normal Neurochemistry in the Prefrontal and Cerebellar Brain of Adults with Attention-Deficit Hyperactivity Disorder
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“Treatment options for adult ADHD include pharmacological interventions (Castells et al., 2011) and psychotherapy (Philipsen, 2012).”
Background
Methylphenidate Use for Emotional Dysregulation in Children and Adolescents with ADHD and ADHD and ASD: A Naturalistic Study
Ventura, P., de Giambattista, C., Trerotoli, P., Cavone, M., Di Gioia, A., & Margari, L. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11102922 · Cited by 22
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“A meta-regression [25] and an RCT [40] reported that as a treatment for ADHD, methylphenidate was ineffective in the presence of SUD.”
Method
The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder
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Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD
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Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults
Cândido, R. C. F., Menezes de Padua, C. A., Golder, S., & Junqueira, D. R. (2021) · White Rose Research Online (University of Leeds, The University of Sheffield, University of York) · Cited by 20
Meta-analysis of the association of the SLC6A3 3′-UTR VNTR with cognition
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Skills training groups for men with ADHD in compulsory care due to substance use disorder: a feasibility study
Muld, B. B., Jokinen, J., Bölte, S., & Hirvikoski, T. (2016) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-016-0195-4 · Cited by 23
Microdosing with psychedelics to self-medicate for ADHD symptoms in adults: a prospective naturalistic study
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“Overall, 22 they have been proven to work effectively in adults with ADHD [14-16], inducing fast symptom 23 relief and thereby enhancing the person’s quality of life.”
Background
Increased rates of intermittent rhythmic delta and theta activity in the electroencephalographies of adult patients with attention-deficit hyperactivity disorder
Endres, D., Maier, S. J., Feige, B., Mokhtar, N. B., Nickel, K., Goll, P., Meyer, S. A., Matthies, S., Ebert, D., Philipsen, A., et al. (2017) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2017.06.039 · Cited by 21
Integrated cognitive behavioral therapy for patients with Substance Use Disorder and Comorbid ADHD: Two case presentations
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“…(Ercan, Coskunol, Varan, & Toksoz, 2003) and the pharmacological treatment of ADHD are less successful in comorbid patients: e.g. most doubleblind randomized controlled trials failed to show efficacy of methylphenidate for the treatment of ADHD symptoms in SUD patients (Castells et al., 2011).”
Background
Wandering minds in attention-deficit/hyperactivity disorder and borderline personality disorder
Moukhtarian, T. R., Reinhard, I., Morillas-Romero, A., Ryckaert, C., Mowlem, F. D., Bozhilova, N. S., Moran, P., Ebner‐Priemer, U., & Asherson, P. J. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.07.005 · Cited by 24
Long-Term (1 Year) Safety and Efficacy of Methylphenidate Modified-Release Long-Acting Formulation (MPH-LA) in Adults with Attention-Deficit Hyperactivity Disorder: A 26-Week, Flexible-Dose, Open-Label Extension to a 40-Week, Double-Blind, Randomised, Placebo-Controlled Core Study
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“Methylphenidate remains one of the most commonly prescribed medications for the treatment of ADHD in adults because of availability of efficacy and safety data [5–16].”
Background
Do effects of methylphenidate on cognitive performance last beyond treatment? A randomized placebo-controlled trial in boys and men with ADHD
Tamminga, H. G. H., Reneman, L., Schrantee, A., Bottelier, M. A., Bouziane, C., Geurts, H. M., & Groenman, A. P. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.02.002 · Cited by 19

Authors: Castells, X., Ramos-Quiroga, J. A., Rigau, D., Bosch, R., Nogueira, M., Vidal, X., & Casas, M.
Affiliations: Vall d'Hebron Hospital Universitari (ES)
Universitat Autònoma de Barcelona (ES)
ORCID: Bosch, Rosa
Vidal, Xavier
Casas, Miguel
Venue: CNS Drugs
Publisher: Springer Science and Business Media LLC
Published: 2011-02
Volume: 25
Issue: 2
Pages: 157-169
ISSN: 1172-7047 (ISSN-L)
DOI: 10.2165/11539440-000000000-00000
OpenAlex: W2330451900
Semantic Scholar: 10b8118ac40b4e13bd9ab65989f9149be93a6f39
Cited by: 197
References: 62
Citations by year: 2026: 2 · 2025: 1 · 2024: 5 · 2023: 10 · 2022: 14 · 2021: 14 · 2020: 16 · 2019: 11 · 2018: 15 · 2017: 21 · 2016: 15 · 2015: 15 · 2014: 20 · 2013: 17 · 2012: 14
FWCI: 12.54
Type: journal article
Language: en
Open access: closed
Locations: CNS Drugs (publishedVersion)
PubMed (publishedVersion)
Funders: Departament de Salut, Generalitat de Catalunya
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords: methylphenidate, adult ADHD, dose-response relationship, substance use disorders, ADHD symptom severity, effect modifiers, meta-regression, trial reporting quality, treatment duration, dosing regimen, confounding by comorbidity, standardized mean difference
MeSH terms: Adult, Attention Deficit Disorder with Hyperactivity, Delayed-Action Preparations, Dose-Response Relationship, Drug, Humans, Methylphenidate, Regression Analysis, Comorbidity, Randomized Controlled Trials as Topic, Treatment Outcome, Substance-Related Disorders, Diagnostic and Statistical Manual of Mental Disorders

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Efficacy of Methylphenidate for Adults with Attention-Deficit Hyperactivity Disorder: A Meta-Regression Analysis

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