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22 Jun 2018

Moreira-Maia CR et al. Medicine (Baltimore) 2018; 97: e10923

Pharmacological therapy is part of the multimodal treatment strategy for patients with ADHD, with some ADHD guidelines recommending pharmacological therapy as the first-line treatment option. Debate is ongoing as to whether ADHD is under- or over-diagnosed worldwide, and, consequently, the question of whether ADHD is pharmacologically under- or over-treated remains controversial. Evidence from several countries suggests that there has been an increase in the rate of prescription of pharmacological treatments for ADHD in the past decade; however, the extent to which this may reflect ‘over-prescribing’ remains unclear. Prescription rates of pharmacological treatments that are higher than the estimated worldwide prevalence of ADHD would signify over-treatment, potentially giving rise to unnecessary side effects, whereas prescription rates lower than the estimated ADHD prevalence would suggest that some patients with ADHD are not benefiting from available medications.

This systematic review and meta-analysis aims to address this concern by providing an estimate of the worldwide prevalence of pharmacological treatment of ADHD in individuals with and without the disorder (primary outcome). ‘Treatment’ will be considered as either of two approaches: any reported dose of ADHD medication or only the use of ADHD medications for ≥3 weeks.* Secondary outcomes are the prevalence of individuals with ADHD receiving the recommended doses of medications according to International guidelines, and additionally, the prevalence of medication use for a period of ≥3 weeks. An overview of the study protocol is outlined here.

The eligibility criteria are as follows:

  • Study types: All published and unpublished population-based, cohort or follow-up studies, as well as data from insurance health system and third-party reimbursements will be included. For longitudinal studies, only data from the first wave or earliest time point will be eligible for inclusion. Randomised and non-randomised clinical trials reporting only the prevalence/prescription rate of ADHD medication without a diagnosis of ADHD will be excluded.
  • Population: Children (aged <12 years), adolescents (aged ≥12 to <18 years) and adults (aged ≥18 years) with a primary diagnosis of ADHD or hyperkinetic disorder as determined by any of the following: a categorical diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) Editions II to 5, the International Statistical Classification of Diseases and Related Health Problems (ICD)-9 or -10, or other diagnostic instruments; the presence of ADHD symptoms above a prespecified threshold on a validated ADHD questionnaire; a self- or carer-reported diagnosis of ADHD in response to a question such as “has any doctor diagnosed you [or your familiar] with ADHD?”; or a diagnosis recorded in medical files obtained from healthcare agencies.
    • Studies in which all participants have ADHD with psychiatric comorbidities will be excluded, since this may impact on the rate of pharmacological treatment prescription for ADHD; however, studies in which some patients have ADHD with psychiatric comorbidities can be included.
    • Studies that included some ADHD patients with an intelligence quotient (IQ) <70, or with neurological comorbidities, will be included.
    • A sensitivity analysis excluding studies in which some patients have psychiatric/neurological comorbidities or an IQ >70 will be conducted, if feasible.
    • Those individuals without any neuropsychiatric diagnoses will constitute the control group.
  • Interventions: All studies on first- or second-line pharmacological treatments for ADHD, according to the most commonly used international guidelines, will be eligible for inclusion. Pharmacological treatments can include psychostimulants (methylphenidate [immediate-, modified- or extended-release], dexmethylphenidate and amfetamines [including dexamfetamine, mixed amfetamine salts and lisdexamfetamine]) and non-psychostimulants (atomoxetine, guanfacine).
    • Studies in which a diagnosis of ADHD is assumed based on prescription of pharmacological treatment will be excluded (e.g. studies based on GPs’ prescribing habits or pharmacy dispensing rates).

Literature searches on the Medline, Embase, CINAHL, PsychINFO, Web of Science and Scopus databases will be performed by a health librarian at the University of Southampton, UK. Additional keyword searches, without language or date restrictions, will also be conducted on a number of databases and additional sources, including websites. Following the search process, the title and abstracts of all identified studies will be screened by two independent reviewers, and subsequently, the full text of all selected articles will be read by three independent reviewers to ensure that the studies entirely fulfil the eligibility criteria.

On selection, each study will be stored on a secure cloud storage system, and data pertaining to the following will be extracted for processing: study details/design; patient demographics and clinical characteristics; type, dose and duration of pharmacological treatment; the number of patients with and without an ADHD diagnosis receiving pharmacological treatment (primary outcome); and any other descriptive information, including type of diagnosis and presence of psychiatric comorbidities. The data extraction sheets will then be compared by independent reviewers working in pairs, with missing or ambiguous data obtained or clarified by contacting the authors via email. A modified version of the Newcastle-Ottawa scale will be used to rate the quality of the selected studies and the risk of bias, and heterogeneity between studies will be evaluated using the Cochran’s chi-squared text, followed by a jackknife sensitivity analysis to explore potential sources of heterogeneity.

The authors will present a qualitative systematic review of the data collected, including a PRISMA flowchart and data tables. Meta-analysis of odds ratios (ORs) will be conducted using R software, and results will be presented as adjusted and unadjusted ORs if feasible. Normality tests will be performed on the rates of pharmacological treatment for ADHD reported by each study, and, according to their distribution, the best estimation method will be chosen and the independent estimate for the pooled prevalence of pharmacological ADHD treatment computed, with 95% confidence intervals. The authors aim to estimate the global prevalence of pharmacological treatment of ADHD, and anticipate that this systematic review and meta-analysis will help to determine whether ADHD medications are under- or over-prescribed.

Read more about
the systematic review and meta-analysis protocol to estimate the worldwide prevalence of ADHD medication here

*Pharmacological treatment of ADHD over a period of ≥3 weeks was chosen based on the minimum time of response and efficacy to treatment in clinical trials
ADHD diagnoses could include ADHD, ADHD-NOS (not otherwise specified) or ADHD-U (unspecified)
The most commonly used international guidelines include those issued by the American Academy of Child and Adolescent Psychiatry, the American Academy of Pediatrics, the Canadian Attention Deficit Hyperactivity Disorder Resource Alliance, the European Network Adult ADHD, the European Network for Hyperkinetic Disorders and the National Institute for Health and Care Excellence

Moreira-Maia CR, Massuti R, Tessari L, et al. Are ADHD medications under or over prescribed worldwide? Protocol for a systematic review and meta-analysis. Medicine (Baltimore) 2018; 97: e10923.

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