D4 receptor antagonists in ADHD

To date, there appears to be only one study of D4 antagonists in 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 subjects was thus small and the treatment duration relatively short.
In light of the fact that D4-KO mice show ADHD symptoms as well, we could imagine that the treatment dose, which should antagonize 90% of D4 receptors, may have been too high. It is conceivable that in D4.7R subjects, a lower dose that only reduces D4-7-R hyperfunctionality could be helpful.
However, even the subset of subjects who tested positive for at least one D4.7 allele showed no statistically significant treatment effect (neither worse nor better response) compared with subjects without a D4.7R allele.

The highly selective D4 antagonist L-745,870 affected working memory in rats depending on its baseline condition:¹

• good output of working memory:
  • low doses: no effect
  • high doses: working memory impaired
• poor output of working memory:
  • low doses: improved working memory, especially in high demand situations
  • high doses: working memory impaired

We also believe that this study may suggest that lower doses of D4 antagonists may be more helpful than complete D4R antagonization.

Another D4 antagonist prevented stress-induced cognitive impairment in monkeys.²