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Review
, 5 (5), CD012069

Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) in Children and Adolescents - Assessment of Adverse Events in Non-Randomised Studies

Affiliations
Review

Methylphenidate for Attention Deficit Hyperactivity Disorder (ADHD) in Children and Adolescents - Assessment of Adverse Events in Non-Randomised Studies

Ole Jakob Storebø et al. Cochrane Database Syst Rev.

Abstract

Background: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events.

Objectives: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies.

Search methods: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies.

Selection criteria: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention.

Data collection and analysis: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses.

Main results: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants).

Authors' conclusions: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Conflict of interest statement

Ole Jakob Storebø is an Associate Editor with Cochrane Developmental, Psychosocial and Learning Problems. Nadia Pedersen ‐ none known. Erica Ramstad ‐ none known. Maja Lærke Kielsholm ‐ none known. Signe Sofie Nielsen ‐ none known. Helle B Krogh ‐ none known. Carlos R Moreira‐Maia (CRMM) receives financial research support from the government agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). CRMM received fees in February 2016 for the development of educational materials on excessive daytime sleepiness for Libbs. Libbs also make products for the treatment of ADHD. CRMM received travel awards from the Health Technology Assessment Institute (IATS), Universidade Federal do Rio Grande do Sul (UFRGS); and travel, accommodation, and registration support to the fourth and fifth World Congresses on ADHD from the World Federation of ADHD. Carlos is an author on Maia 2008 and declares that he was not involved in assessing the eligibility of this study, extracting data, assessing risk of bias or grading the quality of the evidence. Frederik L Magnusson ‐ none known. Mathilde Holmskov ‐ none known. Trine Gerner ‐ none known. Maria Skoog ‐ none known. Susanne Rosendal ‐ none known. Camilla Groth's (CGr) institution received funds from the Lundbeck Foundation to finance part of her PhD in the paediatric field on Tourette syndrome. CGr confirms that none of these funds were used to work on this review. Donna Gillies is an Editor with Cochrane Developmental, Psychosocial, and Learning Problems. Kirsten Buch Rasmussen ‐ none known. Dorothy Gauci ‐ none known. Morris Zwi sits on the UK Paediatric Medicines Expert Advisory Group at the Medicines and Healthcare Regulatory Agency, which considers applications regarding the licensing of paediatric medicines. Payment for MZ's attendance at this meeting goes to his NHS organisation. As a clinician working with patients who have ADHD, he prescribes methylphenidate regularly. Richard Kirubakaran is currently employed by Cochrane South Asia, funded by the Indian Council for Medical Research, India, and Effective Healthcare Research Consortium for the Department for International Development, UK. Sasja J Håkonsen ‐ none known. Lise Aagaard (LA) received travelling grants from the pharmaceutical companies Pfizer, Swedish Orphan BioVitrum and Shire. None of the travelling grants are related to this review. LA confirms that she has nothing to declare in relation to ADHD research. The Pfizer travel grants were received in 2015 and 2016 for attending the European Association of Hospital Pharmacist Annual Conferences. No activities in relation to treatment of ADHD were observed. A travel grant was received in 2015 from Swedish Orphan Biovitrum for attending the C1 Inhibitor Conference in Budapest. C1 inhibitor drugs are involved in the treatment of the rare disease hereditary angioedema. Travel grants were received in 2015 and 2016 from Shire for attending the Bradykinin Scientific Meeting in Copenhagen and Stockholm. Bradykinin mediator drugs are involved in the treatment of the rare disease hereditary angioedema. Erik Simonsen ‐ none known. Christian Gluud is Co‐ordinating Editor of Cochrane Hepato‐Biliary.

Figures

Figure 1
Figure 1
Study flow diagram
Figure 2
Figure 2
Proportion of participants on methylphenidate with any serious adverse events
Figure 3
Figure 3
Proportion of participants withdrawn from methylphenidate due to serious adverse events
Figure 4
Figure 4
Proportion of participants withdrawn from methylphenidate due to adverse events of unknown severity
Figure 5
Figure 5
Proportion of participants on methylphenidate with any non‐serious adverse event
Figure 6
Figure 6
Proportion of participants withdrawn from methylphenidate due to non‐serious adverse events
Figure 7
Figure 7
Proportion of participants withdrawn from methylphenidate for unknown reasons
Analysis 1.1
Analysis 1.1
Comparison 1 Comparative studies: number of serious adverse events, Outcome 1 Any serious adverse events.
Analysis 1.2
Analysis 1.2
Comparison 1 Comparative studies: number of serious adverse events, Outcome 2 Central nervous system.
Analysis 2.1
Analysis 2.1
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 1 Central nervous system: sleep‐related adverse events.
Analysis 2.2
Analysis 2.2
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 2 Central nervous system: other specific sleep‐related adverse events.
Analysis 2.3
Analysis 2.3
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 3 Central nervous system: other specific adverse events.
Analysis 2.4
Analysis 2.4
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 4 Cardiovascular and respiratory system.
Analysis 2.5
Analysis 2.5
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 5 Gastrointestinal system.
Analysis 2.6
Analysis 2.6
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 6 Musculoskeletal system.
Analysis 2.7
Analysis 2.7
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 7 Musculoskeletal system: body mass index (BMI).
Analysis 2.8
Analysis 2.8
Comparison 2 Comparative studies: number of participants with non‐serious adverse events, Outcome 8 Musculoskeletal system: z scores.
Analysis 3.1
Analysis 3.1
Comparison 3 Comparative studies: number of participants withdrawn from methylphenidate treatment, Outcome 1 Proportion of participants withdrawn from methylphenidate for unknown reasons.

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  • Cochrane Database Syst Rev. doi: 10.1002/14651858.CD012069

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