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:
-
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.
Dasotraline has been tested for use in ADHD. RCTs showed an effect size of up to 0.48
Sunuvion is said to have discontinued the development of dasotraline in the meantime
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. 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. 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.
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.
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 improvement
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
There were no serious side effects or clinically relevant changes in blood pressure or heart rate.
