Re: “Dasotraline in Children with Attention-Deficit/Hyperactivity Disorder: A Six-Week,Placebo-Controlled,Fixed-Dose Trial” by Findling et al. (J Child Adolesc Psychopharmacol 2019;29:80–89)

To the Editor:

Findling et al. (2019) describe a 6-week trial of dasotraline in children 6 to 12 years old with attention-deficit/hyperactivity disorder (ADHD). In this trial, psychosis was reported in 6 of 115 (5.2%) subjects receiving 4 mg/day, 1 of 111 (0.9%) subjects receiving 2 mg/day, and 0 of 116 placebo-treated subjects. A subgroup analysis of dasotraline-treated subjects who weighed ≥30 kg found 1 psychotic event among 119 subjects (0.84%). The authors argue that the risk in the subgroup of children weighing ≥30 kg compares favorably with the risk reported in a pooled analysis of 49 placebo-controlled ADHD drug trials by Mosholder et al. (2009). In that analysis, psychotic or manic adverse events occurred in 0 of 3990 placebo-treated subjects and in 11 of 5717 (0.19%) drug-treated subjects.

Comparing the rates of events adjusted for duration of exposure, rather than simply the proportion of subjects affected, may provide further insight, although the statistical precision of the rate estimates is limited by the relatively short duration of exposure in the trial. In the pooled analysis of 49 trials, the 11 psychotic or manic adverse events occurred at a rate of 1.48 per 100 person-years of ADHD drug exposure (95% confidence interval: 0.74–2.65). Findling et al. did not report actual duration of use in their trial, but assuming 6 weeks of exposure per subject, 1 psychotic adverse event among 119 subjects weighing ≥30 kg represents 7.3 events per 100 person-years. Finally, if one ignores weight, the 6 psychotic events among 115 subjects receiving 4 mg/day (assuming 6 weeks of exposure per subject) correspond to 45.3 psychotic events per 100 person-years, roughly 30 times the rate in the prior analysis (Mosholder et al. 2009).

From these data, dasotraline appears to be associated with a much greater risk for psychosis than other ADHD treatments. The mechanism(s) for this increased risk is not known. One hypothesis is that dasotraline's long elimination half-life (reported by Findling et al. to be 56–84 hours) leads to night-time drug exposure that might interfere with normal sleep architecture. Sleep dysfunction has been linked to the occurrence of psychotic experiences in general as well as in clinical populations (Reeve et al. 2015). Consistent with this hypothesis is the finding that insomnia was the most frequent adverse event associated with dasotraline at a rate higher than placebo in the study described by Findling et al.