D4 receptor antagonists for ADHD

To date, there appears to be only one study on D4 antagonists for ADHD. This showed no significant effect compared to placebo.
This was a randomized, double-blind, cross-over study of the selective D4R antagonist L-745,870 (MK-0929) in 35 adults with ADHD in outpatient treatment for 4 weeks at 15 mg/day, designed to bind more than 90% of D4 receptors.
The number of test subjects was therefore small and the duration of treatment relatively short.
Considering that D4-KO mice also show ADHD symptoms, we could imagine that the treatment dose, which should antagonize 90% of the D4 receptors, may have been too high. It is conceivable that a lower dose, which only reduces the hyperfunctionality of D4-7-R, could be helpful in D4.7R carriers.
However, the subgroup of subjects who tested positive for at least one D4.7 allele also showed no statistically significant treatment effect (neither worse nor better response) compared to the subjects without a D4.7R allele.

The highly selective D4 antagonist L-745,870 influenced the working memory of rats depending on their initial state:¹

• good working memory output:
  • low doses: no effect
  • high doses: impaired working memory
• poor working memory output:
  • low doses: improved working memory, especially when the demand is high
  • high doses: impaired working memory

We believe that this study could also indicate that a lower dose of D4 antagonists could be more helpful than complete D4R antagonization.

Another D4 antagonist prevented cognitive impairment caused by stress in monkeys.²

The D4R-selective agonist ABT-724 improved the existing SHR in adolescents:³

• Hyperactivity
• Impairment of spatial learning
• but not the impairment of non-selective attention