Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by impairing and age-inappropriate levels of inattention, impulsivity or hyperactivity, or a combination of these (American Psychiatric Association, 2013). ADHD has a global prevalence of ~5% in children (Polanczyk et al., 2007) and these symptoms are believed to persist into adulthood in up to 65% of cases (Faraone et al., 2006). This persistence combined with de novo adult diagnoses contribute to an estimated prevalence of ~2.5% in adults (Cortese and Coghill, 2018; Simon et al., 2009).

ADHD remains a controversial disorder, particularly regarding its prevalence. Raman et al. (2018) report that the past few decades have witnessed an increase in diagnosis and pharmacological management of ADHD. Social constructionists have seen this as a reflection of the contextual nature of ADHD and question the validity of the disorder (Roy, 2008). Furthermore, when UK primary care witnessed a sharp increase in ADHD diagnoses and methylphenidate prescriptions, NICE (2013) issued a statement to avoid the use of stimulants in young people with mild-moderate ADHD because of concerns about the safety and effectiveness of these medications.

Three years ago there was considerable discussion and debate when a Cochrane review by Storebø et al (2015) questioned the efficacy and tolerability of methylphenidate in children and adolescents with ADHD.

In light of controversies such as these, the robust evidence provided by Cortese et al. (2018) ‘Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis’ is an important step forward in understanding ADHD pharmacotherapies.

Methods

The authors conducted a literature search across PubMed, BIOSIS Previews, CINAHL, the Cochrane Central Register of Controlled Trials, EMBASE, ERIC, MEDLINE, PsychINFO, OpenGrey, Web of Science Core Collection, ProQuest Dissertations and Theses (UK and Ireland), ProQuest Dissertations and Theses (abstracts and international) and the WHO International Trials Registry Platform, from the date of database inception until 7 April, 2017, with no language restriction.

The websites of the US Food and Drug Administration, European Medicines Agency and relevant drug manufacturers, as well references of previous systematic reviews and guidelines were searched for further information.

The investigators contacted drug manufacturers and study authors to gain access to additional unpublished information and data.

Studies were included if they were:

• Double-blind randomised controlled trials lasting at least one week
• Investigating children, adolescents or adults with a primary diagnosis of ADHD, assessed using DSM or ICD criteria
• Comparing amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate or modafinil against placebo or each other.

Data were extracted by at least two independent investigators. The primary outcomes were efficacy (measured as a change in clinicians’ ratings of ADHD symptom severity) and tolerability (the proportion of participants who left a study because of side-effects).

Results

• 133 studies were included in the network meta-analysis:
  • 81 studies of children and adolescents
  • 51 studies of adults
  • 1 study of children, adolescents and adults
• This gave a total of 14,346 children and adolescents and 10,296 adults in the review
• For 83% of studies, additional unpublished data were used

Efficacy

• In children and adolescents, all drugs were superior to placebo regarding improvement in ADHD core symptoms, as rated by clinicians
• In adults, amphetamines, methylphenidate, atomoxetine and bupropion were better than placebo at attenuating core ADHD symptoms. Modafinil was worse than placebo
• In all age groups, amphetamines had significantly greater efficacy to modafinil, atomoxetine and methylphenidate
• In children and adolescents, amphetamines and guanfacine were less well tolerated than placebo
• In adults, modafinil, amphetamines, methylphenidate and atomoxetine had inferior tolerability than placebo
• In children and adolescents, all medications, except clonidine were superior to placebo on the Clinical Global Impression-Improvement (CGI-I) scale
• In adults, methylphenidate, bupropion and amphetamines were superior to placebo on the CGI-I scale.

Tolerability

• Amphetamines, methylphenidate, atomoxetine and modafinil all caused significant weight reduction compared with placebo, in all age groups
• Systolic blood pressure was significantly increased with the use of amphetamines and atomoxetine in children and adolescents and with the use of methylphenidate in adults
• Diastolic blood pressure was significantly increased by amphetamines in children and adolescents only
• Only methylphenidate in children and adolescents and amphetamines in adults had better acceptability than placebo
• In children and adolescents, only amphetamines and guanfacine were less well tolerated than placebo
• Methylphenidate, amphetamines and atomoxetine had worse tolerability than placebo in adults.

Conclusions

The authors made the following conclusions:

All medications, except for modafinil in adults, were more efficacious than placebo for the short-term treatment of ADHD, and they were less efficacious and less well tolerated in adults than in children and adolescents.

Amphetamines were the most efficacious compounds in children, adolescents and adults.

Strengths and limitations

Strengths

• This study is incredibly comprehensive, including published and unpublished data for children, adolescents and adults.
• The use of a network meta-analysis allows for greater precision of estimates compared with standard pairwise meta-analyses.
• The study demonstrated high external validity by including participants with a range of comorbidities and previous exposure and response to ADHD medication. This heterogeneity was distributed across the studies and so is unlikely to cause bias. Instead, it reflects what is seen in ‘real-world’ clinical practice.
• The inclusion of multiple, complementary ratings (teachers and clinicians) of efficacy for children and adolescents increases the validity of the diagnosis.

Limitations

• Due to a paucity of data, the authors could not assess the effect of gender or further sub-divisions of age on efficacy and tolerability of ADHD medications.
• Most drug comparisons were indirect due to a lack of head-to-head trials. The authors found that the ‘confidence of estimate’ ratings were lower for indirect comparisons and suggest there is a need for additional, well-designed head-to-head trials.
• The authors aimed to analyse the outcomes at 12, 26 and 52 weeks. However, there was insufficient data for meaningful analysis beyond 12 weeks. As such, these findings can only inform the choice of short-term medication treatment.

Implications for practice

• The authors recommend that the first line pharmacological choice for ADHD should be methylphenidate in children and adolescents and amphetamines in adults.
• The findings indicate a need to monitor changes to blood pressure and weight in patients taking atomoxetine, similarly to those taking stimulants.
• The authors highlighted that they were unable to assess the long-term effects of these medications and called for urgent funding to investigate this.

Conflicts of interest

The blogger Dean Connolly has no conflict of interest to declare.

Links

Primary paper

Cortese, S., Adamo, N., Del Giovane, C., Mohr-Jensen, C., Hayes, A. J., Carucci, S., … Cipriani, A. (2018). Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. The Lancet Psychiatry, 5(9), 727–738. https://doi.org/10.1016/S2215-0366(18)30269-4

Other references

American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders DMS V. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. https://doi.org/10.1176/appi.books.9780890425596.744053

Polanczyk, G., De Lima, M. S., Horta, B. L., Biederman, J., & Rohde, L. A. (2007). The worldwide prevalence of ADHD: A systematic review and metaregression analysis. American Journal of Psychiatry. https://doi.org/10.1176/ajp.2007.164.6.942

Faraone, S. V., Biederman, J., & Mick, E. (2006). The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up studies. Psychological Medicine. https://doi.org/10.1017/S003329170500471X

Cortese, S., & Coghill, D. (2018). Twenty years of research on attention-deficit/hyperactivity disorder (ADHD): looking back, looking forward. Evidence Based Mental Health, 21(4), 173 LP-176. https://doi.org/10.1136/ebmental-2018-300050

Simon, V., Czobor, P., Bálint, S., Mészáros, Á., & Bitter, I. (2009). Prevalence and correlates of adult attention-deficit hyperactivity disorder: Meta-analysis. British Journal of Psychiatry. https://doi.org/10.1192/bjp.bp.107.048827

Raman, S. R., Man, K. K. C., Bahmanyar, S., Berard, A., Bilder, S., Boukhris, T., … Wong, I. C. K. (2018). Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. The Lancet Psychiatry. https://doi.org/10.1016/S2215-0366(18)30293-1

Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth C, Magnusson FL, Moreira-Maia CR, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, Kirubakaran R, Forsbøl B, Simonsen E, Gluud C. (2015a) Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD009885. DOI: 10.1002/14651858.CD009885.pub2.

Roy, A. (2008). The relationships between attention-deficit/hyperactive disorder (ADHD), conduct disorder (CD) and problematic drug use (PDU). Drugs: Education, Prevention and Policy, 15(1), 55–75. https://doi.org/10.1080/09687630701489481

https://www.nice.org.uk/news/article/avoid-drug-treatment-for-children-and-young-people-with-moderate-adhd

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