Dasotraline for ADHD

Dasotraline [(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetra-hydronaphthalene-1-amine] is a dopamine and noradrenaline reuptake inhibitor with weak serotonin reuptake inhibition:¹

• DAT: IC50 = 3 nM
• NET: IC50 = 4 nM
• SERT: IC50 = 15 nM

Tetrodotoxin blocks neuronal firing and abolished the ability of dasotraline to increase synaptic monoamine concentrations, demonstrating that dasotraline is a reuptake inhibitor and not a monoamine releaser.¹

Dasotraline has been tested for use in ADHD.²³ RCTs showed an effect size of up to 0.48⁴
Sunuvion is said to have discontinued the development of dasotraline in the meantime ⁵⁴

Oral dasotraline is slowly absorbed in humans, with a tmax of 10-12 hours and a very long terminal elimination half-life of 47-77 hours.¹ Dasotraline may have a sustained treatment benefit in ADHD due to its stable plasma concentration over 24 hours when administered once daily with a low potential for abuse.⁶ Dasotraline thus differs significantly from the rapid, large and short-lasting increase in dopamine efflux of d-amphetamine and MPH.

In a placebo-controlled double-blind study, a single daily dose of 8 mg dasotraline (but not 4 mg dasotraline) showed a significant improvement in ADHD-HI symptoms (ADHD-HI Rating Scale) and CGI-S scores after 4 weeks compared to placebo.⁷

At 4 mg, a good 10 % of the test subjects terminated the study prematurely, at 8 mg just under 28 %. This appears to be quite high.
The high insomnia could result from the long half-life of 47 hours, which on the other hand would allow a daily single dose that leads to a constant plasma level after 10 days of intake.⁸⁹
On the other hand, insomnia was not a predictor for dropping out of the study.

Another 6-week RCT with 342 children aged 6-12 years found a significantly better improvement in ADHD symptoms at 4 mg/day than placebo with an effect size of 0.48. 2 mg/day showed no improvement¹⁰
The discontinuation rates due to adverse events were 12.2 % (4 mg/day), 6.3 % (2 mg/day) and 1.7 % (placebo).

Side effects in the studies were predominant (compared to placebo):

• Sleep problems
  • These are likely to result from the long half-life
• Dry mouth
• Nausea
• Postural orthostatic tachycardia syndrome (5.4 % vs. 0 %)
• Perceptual disorders (5.4 % vs. 0 %)
• Reduced appetite (10.7 % vs. 3.6 %)
• Weight loss
• Irritability (5.4 % vs. 3.6 %)
• Headaches (10.7 % vs. 8.9 %)
• Affect lability (8.9 % vs. 7.1 %)

A study on adults with 6 mg/day found only partially significant improvements in ADHD symptoms compared to placebo, but a trend towards improvement. This was due to a surprisingly large improvement in the placebo group ¹¹¹²

There were no serious side effects or clinically relevant changes in blood pressure or heart rate.