A 2018 review pooled 133 double-blind randomized trials, with results taken closest to 12 weeks. They covered 14,346 children and adolescents and 10,296 adults with a primary ADHD diagnosis.
On clinicians' ratings, every medicine beat a placebo on core symptoms except modafinil in adults. They worked less well, and were less well tolerated, in adults. On teachers' ratings of children and adolescents, only methylphenidate and modafinil beat a placebo among available comparisons. Amphetamines worked best on clinicians' ratings in both age groups.
Amphetamines raised side-effect dropouts over a placebo in both age groups. Guanfacine did so in children and adolescents only. Atomoxetine, methylphenidate and modafinil did so in adults only. Methylphenidate in children and adolescents and amphetamines in adults were significantly more acceptable than a placebo.
Low risk of bias, meaning flaws were unlikely to skew results, was rated in only 23.5% of child and adolescent studies. For adult studies it was 27.5%. Most others were unclear (65.4% and 56.8%). The rest were high (11.1% and 15.7%). Head-to-head trials were few. Only one of 42 mixed comparisons earned high confidence. Of 59 indirect comparisons, 37 were rated very low. Data at 26 and 52 weeks were scarce.
Weighing efficacy, tolerability and acceptability together, the authors favor methylphenidate for children and adolescents and amphetamines for adults as the preferred first medication choice for short-term treatment, stress weight and blood pressure checks with atomoxetine as much as with stimulants, and call the choice shared among patients, caregivers and clinicians.
The numbers Stats and what the terms mean
The statistics behind the plain-language claims above.
- Cortese, 2018: clinician-rated core symptoms in children and adolescents versus placebo, closest to 12 weeks, SMD -1.02 (95% CI -1.19 to -0.85) for amphetamines, -0.78 (-0.93 to -0.62) for methylphenidate, -0.56 (-0.66 to -0.45) for atomoxetine.
- Cortese, 2018: teacher ratings in children and adolescents versus placebo, methylphenidate SMD -0.82 (95% CI -1.16 to -0.48), modafinil -0.76 (-1.15 to -0.37).
- Cortese, 2018: clinician-rated core symptoms in adults versus placebo, amphetamines SMD -0.79 (95% CI -0.99 to -0.58), methylphenidate -0.49 (-0.64 to -0.35), bupropion -0.46 (-0.85 to -0.07), atomoxetine -0.45 (-0.58 to -0.32); modafinil 0.16 (-0.28 to 0.59), not better than placebo.
- Cortese, 2018: dropout due to side effects versus placebo, amphetamines OR 2.30 (95% CI 1.36 to 3.89) in children and adolescents and 3.26 (1.54 to 6.92) in adults; guanfacine 2.64 (1.20 to 5.81) in children and adolescents only; atomoxetine 2.33 (1.28 to 4.25), methylphenidate 2.39 (1.40 to 4.08) and modafinil 4.01 (1.42 to 11.33) in adults only.
- Cortese, 2018: amphetamines favored head-to-head over modafinil, atomoxetine and methylphenidate on clinicians' ratings, SMDs -0.46 to -0.24 in children and adolescents; -0.94 to -0.29 in adults.
- Cortese, 2018: acceptability versus placebo, methylphenidate OR 0.69 (0.52 to 0.91) in children and adolescents and amphetamines 0.68 (0.49 to 0.95) in adults. What the terms mean:
- SMD (standardized mean difference) is how far apart two groups ended up, in a common unit that lets different rating scales be compared. Roughly, 0.2 is small, 0.5 is moderate and 0.8 is large. A minus sign shows the direction of the change, not its size.
- 95% CI (confidence interval) is the range the true value most likely falls in, and when it does not cross zero for an SMD or one for an OR, the result is unlikely to be down to chance.
- OR (odds ratio) compares the odds of an event between two groups, where above 1 means the event was more likely with the medicine than with placebo and below 1 means less likely.
Source: Samuele Cortese, Nicoletta Adamo, Cinzia Del Giovane, et al.. 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 (2018). doi:10.1016/s2215-0366(18)30269-4